Information about diseases

Metalosis Maligna reference

2008-07-14T19:58:00.000-07:00

Metalosis Maligna :is one of the most impressive and powerful diseases the human body has ever being capable of development, a virus called STREPTOCOCCCUS METALOMALIGNA is the responsible for this impressive disorder involving the human tissue and the metal implant.

Symtoms: you start feeling itchy and are forced to use a metal object to scratch your back.

Cure: Theres is no cure or treatment for this disease.

AIDS reference

2008-07-12T13:40:00.000-07:00

Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV).[1] This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.[2][3] This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.

AIDS is now a pandemic.[4] In 2007, an estimated 33.2 million people lived with the disease worldwide, and it killed an estimated 2.1 million people, including 330,000 children.[5] Over three-quarters of these deaths occurred in sub-Saharan Africa,[5] retarding economic growth and destroying human capital.[6] Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century.[7] The disease was first identified by the U.S. Centers for Disease Control and Prevention in 1981 and its cause identified by American and French scientists in the late 1980s.[8]

Although treatments for AIDS and HIV can slow the course of the disease, there is currently no vaccine or cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.[9] Due to the difficulty in treating HIV infection, preventing infection is a key aim in controlling the AIDS epidemic, with health organizations promoting safe sex and needle-exchange programmes in attempts to slow the spread of the virus.

The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages. Opportunistic infections are common in people with AIDS.[10] HIV affects nearly every organ system. People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas. Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.[11][12] The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.

Pulmonary infections
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia

Pneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. It is caused by Pneumocystis jirovecii. Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 cells per µL of blood.[13]

Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multidrug resistance is a potentially serious problem. Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system.[14]

Gastrointestinal infections

Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.

Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and viruses,[16] astrovirus, adenovirus, rotavirus and cytomegalovirus, (the latter as a course of colitis). In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.[17]

Neurological and psychiatric involvement

HIV infection may lead to a variety of neuropsychiatric sequelae, either by infection of the now susceptible nervous system by organisms, or as a direct consequence of the illness itself.

Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain causing toxoplasma encephalitis but it can infect and cause disease in the eyes and lungs.[18] Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.[19]

AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia which secrete neurotoxins of both host and viral origin.[20] Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is 10–20% in Western countries[21] but only 1–2% of HIV infections in India.[22][23] This difference is possibly due to the HIV subtype in India. AIDS related mania is sometimes seen in patients with advanced HIV illness; it presents with more irritability and cognitive impairment and less euphoria than a manic episode associated with true bipolar disorder. Unlike the latter condition, it may have a more chronic course. This syndrome is less often seen with the advent of multi-drug therapy.

Tumors and malignancies
Kaposi's sarcoma

Patients with HIV infection have substantially increased incidence of several malignant cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV).[24][25]

Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs.

High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. In some cases these lymphomas are AIDS-defining. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas.

Cervical cancer in HIV-infected women is considered AIDS-defining. It is caused by human papillomavirus (HPV).[26]

In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, such as Hodgkin's disease and anal and rectal carcinomas. However, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.[27]

Other opportunistic infections

AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness. Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.[28]

AIDS is the most severe acceleration of infection with HIV. HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells.[29] Once HIV has killed so many CD4+ T cells that there are fewer than 200 of these cells per microliter (µL) of blood, cellular immunity is lost. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified either on the basis of the amount of CD4+ T cells remaining in the blood, and/or the presence of certain infections, as noted above.[30]

In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months.[31] However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years. Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function.[32][33] Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people. Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression.[31][34][35] The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV. An example of this is people with the homozygous CCR5-Δ32 variation are resistant to infection with certain strains of HIV.[36] HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression.[37][38][39]

Sexual transmission

Sexual transmission occurs with the contact between sexual secretions of one person with the rectal, genital or oral mucous membranes of another. Unprotected receptive sexual acts are riskier than unprotected insertive sexual acts, and the risk for transmitting HIV through unprotected anal intercourse is greater than the risk from vaginal intercourse or oral sex. However, oral sex is not entirely safe, as HIV can be transmitted through both insertive and receptive oral sex.[40] The risk of HIV transmission from exposure to saliva is considerably smaller than the risk from exposure to semen, one would have to swallow liters of saliva from a carrier to run a significant risk of becoming infected.[41] Sexual assault greatly increases the risk of HIV transmission as protection is rarely employed and physical trauma to the vagina frequently occurs, facilitating the transmission of HIV.[42]

Other sexually transmitted infections (STI) increase the risk of HIV transmission and infection, because they cause the disruption of the normal epithelial barrier by genital ulceration and/or microulceration; and by accumulation of pools of HIV-susceptible or HIV-infected cells (lymphocytes and macrophages) in semen and vaginal secretions. Epidemiological studies from sub-Saharan Africa, Europe and North America suggest that genital ulcers, such as those caused by syphilis and/or chancroid, increase the risk of becoming infected with HIV by about four-fold. There is also a significant although lesser increase in risk from STIs such as gonorrhea, Chlamydial infection and trichomoniasis, which all cause local accumulations of lymphocytes and macrophages.[43]

Transmission of HIV depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. An undetectable plasma viral load does not necessarily indicate a low viral load in the seminal liquid or genital secretions. However, each 10-fold increase in the level of HIV in the blood is associated with an 81% increased rate of HIV transmission.[43][44] Women are more susceptible to HIV-1 infection due to hormonal changes, vaginal microbial ecology and physiology, and a higher prevalence of sexually transmitted diseases.[45][46] People who have been infected with one strain of HIV can still be infected later on in their lives by other, more virulent strains.

Infection is unlikely in a single encounter. High rates of infection have been linked to a pattern of overlapping long-term romantic relationships. This allows the virus to quickly spread to multiple partners who in turn infect their partners. A pattern of serial monogamy or occasional casual encounters is associated with lower rates of infection.[47]

Exposure to blood-borne pathogens
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
CDC poster from 1989 highlighting the threat of AIDS associated with drug use

This transmission route is particularly relevant to intravenous drug users, hemophiliacs and recipients of blood transfusions and blood products. Sharing and reusing syringes contaminated with HIV-infected blood represents a major risk for infection with HIV. Needle sharing is the cause of one third of all new HIV-infections in North America, China, and Eastern Europe. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV-infected person is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce this risk.[48] This route can also affect people who give and receive tattoos and piercings. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training. The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections.[49] Because of this, the United Nations General Assembly has urged the nations of the world to implement precautions to prevent HIV transmission by health workers.[50]

The risk of transmitting HIV to blood transfusion recipients is extremely low in developed countries where improved donor selection and HIV screening is performed. However, according to the WHO, the overwhelming majority of the world's population does not have access to safe blood and between 5% and 10% of the world's HIV infections come from transfusion of infected blood and blood products.[51]

Perinatal transmission

The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between a mother and her child during pregnancy, labor and delivery is 25%. However, when the mother takes antiretroviral therapy and gives birth by caesarean section, the rate of transmission is just 1%.[52] The risk of infection is influenced by the viral load of the mother at birth, with the higher the viral load, the higher the risk. Breastfeeding also increases the risk of transmission by about 4 %.[53]

Misconceptions

A number of misconceptions have arisen surrounding HIV/AIDS. Three of the most common are that AIDS can spread through casual contact, that sexual intercourse with a virgin will cure AIDS, and that HIV can infect only homosexual men and drug users. Other misconceptions are that any act of anal intercourse between gay men can lead to AIDS infection, and that open discussion of homosexuality and HIV in schools will lead to increased rates of homosexuality and AIDS.

Cells affected

The virus, entering through which ever route, acts primarily on the following cells:[61]

1. Lymphoreticular system:
1. CD4+ T-Helper cells
2. CD4+ Macrophages
3. CD4+ Monocytes
4. B-lymphocytes
2. Certain endothelial cells
3. Central nervous system:
1. Microglia of the nervous system
2. Astrocytes
3. Oligodendrocytes
4. Neurones - indirectly by the action of cytokines and the gp-120

The effect

The virus has cytopathic effects but how it does it is still not quite clear. It can remain inactive in these cells for long periods, though. This effect is hypothesized to be due to the CD4-gp120 interaction.

* The most prominent effect of the HIV virus is its T-helper cell suppression and lysis. The cell is simply killed off or deranged to the point of being function-less (they do not respond to foreign antigens). The infected B-cells can not produce enough antibodies either. Thus the immune system collapses leading to the familiar AIDS complications, like infections and neoplasms (vide supra).
* Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex.
* The CD4-gp120 interaction (vide supra) is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i.e. cytopathy.

Molecular basis

For details, see:

* Structure and genome of HIV,
* HIV replication cycle
* HIV tropism

Diagnosis

The diagnosis of AIDS in a person infected with HIV is based on the presence of certain signs or symptoms. Since June 5, 1981, many definitions have been developed for epidemiological surveillance such as the Bangui definition and the 1994 expanded World Health Organization AIDS case definition. However, clinical staging of patients was not an intended use for these systems as they are neither sensitive, nor specific. In developing countries, the World Health Organization staging system for HIV infection and disease, using clinical and laboratory data, is used and in developed countries, the Centers for Disease Control (CDC) Classification System is used.

In 1990, the World Health Organization (WHO) grouped these infections and conditions together by introducing a staging system for patients infected with HIV-1.[63] An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.

* Stage I: HIV infection is asymptomatic and not categorized as AIDS
* Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
* Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
* Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.

CDC classification system

There are two main definitions for AIDS, both produced by the Centers for Disease Control and Prevention (CDC). The older definition is to referring to AIDS using the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4+ T cell count below 200 per µL of blood or 14% of all lymphocytes.[66] The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

HIV test

Many people are unaware that they are infected with HIV.[67] Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities.[67] Therefore, donor blood and blood products used in medicine and medical research are screened for HIV.

HIV tests are usually performed on venous blood. Many laboratories use fourth generation screening tests which detect anti-HIV antibody (IgG and IgM) and the HIV p24 antigen. The detection of HIV antibody or antigen in a patient previously known to be negative is evidence of HIV infection. Individuals whose first specimen indicates evidence of HIV infection will have a repeat test on a second blood sample to confirm the results. The window period (the time between initial infection and the development of detectable antibodies against the infection) can vary since it can take 3–6 months to seroconvert and to test positive. Detection of the virus using polymerase chain reaction (PCR) during the window period is possible, and evidence suggests that an infection may often be detected earlier than when using a fourth generation EIA screening test. Positive results obtained by PCR are confirmed by antibody tests.[68] Routinely used HIV tests for infection in neonates, born to HIV-positive mothers, have no value because of the presence of maternal antibody to HIV in the child's blood. HIV infection can only be diagnosed by PCR, testing for HIV pro-viral DNA in the children's lymphocytes

Sexual contact

The majority of HIV infections are acquired through unprotected sexual relations between partners, one of whom has HIV. The primary mode of HIV infection worldwide is through sexual contact between members of the opposite sex.[78][79][80] During a sexual act, only male or female condoms can reduce the chances of infection with HIV and other STDs and the chances of becoming pregnant. The best evidence to date indicates that typical condom use reduces the risk of heterosexual HIV transmission by approximately 80% over the long-term, though the benefit is likely to be higher if condoms are used correctly on every occasion.[81] The male latex condom, if used correctly without oil-based lubricants, is the single most effective available technology to reduce the sexual transmission of HIV and other sexually transmitted infections. Manufacturers recommend that oil-based lubricants such as petroleum jelly, butter, and lard not be used with latex condoms, because they dissolve the latex, making the condoms porous. If necessary, manufacturers recommend using water-based lubricants. Oil-based lubricants can however be used with polyurethane condoms.[82]

The female condom is an alternative to the male condom and is made from polyurethane, which allows it to be used in the presence of oil-based lubricants. They are larger than male condoms and have a stiffened ring-shaped opening, and are designed to be inserted into the vagina. The female condom contains an inner ring, which keeps the condom in place inside the vagina – inserting the female condom requires squeezing this ring. However, at present availability of female condoms is very low and the price remains prohibitive for many women. Preliminary studies suggest that, where female condoms are available, overall protected sexual acts increase relative to unprotected sexual acts, making them an important HIV prevention strategy.[83]

Studies on couples where one partner is infected show that with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year.[84] Prevention strategies are well-known in developed countries, however, recent epidemiological and behavioral studies in Europe and North America have suggested that a substantial minority of young people continue to engage in high-risk practices and that despite HIV/AIDS knowledge, young people underestimate their own risk of becoming infected with HIV.[85]

Randomized controlled trials have shown that male circumcision lowers the risk of HIV infection among heterosexual men by up to 60%.[86] It is expected that this procedure will be actively promoted in many of the countries affected by HIV, although doing so will involve confronting a number of practical, cultural and attitudinal issues. Some experts fear that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior, thus negating its preventive effects.[87]

Exposure to infected body fluids

Health care workers can reduce exposure to HIV by employing precautions to reduce the risk of exposure to contaminated blood. These precautions include barriers such as gloves, masks, protective eyeware or shields, and gowns or aprons which prevent exposure of the skin or mucous membranes to blood borne pathogens. Frequent and thorough washing of the skin immediately after being contaminated with blood or other bodily fluids can reduce the chance of infection. Finally, sharp objects like needles, scalpels and glass, are carefully disposed of to prevent needlestick injuries with contaminated items.[88] Since intravenous drug use is an important factor in HIV transmission in developed countries, harm reduction strategies such as needle-exchange programmes are used in attempts to reduce the infections caused by drug abuse.

Mother-to-child transmission (MTCT)

Current recommendations state that when replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected mothers should avoid breast-feeding their infant. However, if this is not the case, exclusive breast-feeding is recommended during the first months of life and discontinued as soon as possible.[91]

Treatment

Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
The chemical structure of Abacavir
The chemical structure of Abacavir

There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus or, failing that, an antiretroviral treatment directly after a highly significant exposure, called post-exposure prophylaxis (PEP).[92] PEP has a very demanding four week schedule of dosage. It also has very unpleasant side effects including diarrhea, malaise, nausea and fatigue.[93]

Antiviral therapy

Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[94] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.[9] Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[95] In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.[96]

HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[97][98] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[99] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality. In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months. HAART is thought to increase survival time by between 4 and 12 years.

For some patients, which can be more than fifty percent of patients, HAART achieves far less than optimal results, due to medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. Non-adherence and non-persistence with therapy are the major reasons why some people do not benefit from HAART.[105] The reasons for non-adherence and non-persistence are varied. Major psychosocial issues include poor access to medical care, inadequate social supports, psychiatric disease and drug abuse. HAART regimens can also be complex and thus hard to follow, with large numbers of pills taken frequently.[106][107][108] Side effects can also deter people from persisting with HAART, these include lipodystrophy, dyslipidaemia, diarrhoea, insulin resistance, an increase in cardiovascular risks and birth defects.[109] Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.

Future research

It has been postulated that only a vaccine can halt the pandemic because a vaccine would possibly cost less, thus being affordable for developing countries, and would not require daily treatments. However, even after almost 30 years of research, HIV-1 remains a difficult target for a vaccine.

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. A number of studies have shown that measures to prevent opportunistic infections can be beneficial when treating patients with HIV infection or AIDS. Vaccination against hepatitis A and B is advised for patients who are not infected with these viruses and are at risk of becoming infected.[111] Patients with substantial immunosuppression are also advised to receive prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP), and many patients may benefit from prophylactic therapy for toxoplasmosis and Cryptococcus meningitis as well.[93]

Alternative medicine

Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease.[112] Acupuncture has been used to alleviate some symptoms, such peripheral neuropathy, but cannot cure the HIV infection.[113] Several randomized clinical trials testing the effect of herbal medicines have shown that there is no evidence that these herbs have any effect on the progression of the disease, but may instead produce serious side-effects.[114]

Some data suggest that multivitamin and mineral supplements might reduce HIV disease progression in adults, although there is no conclusive evidence on if they reduce mortality among people with good nutritional status.[115] Vitamin A supplementation in children probably has some benefit.[115] Daily doses of selenium can suppress HIV viral burden with an associated improvement of the CD4 count. Selenium can be used as an adjunct therapy to standard antiviral treatments, but cannot itself reduce mortality and morbidity.[116]

Current studies indicate that that alternative medicine therapies have little effect on the mortality or morbidity of the disease, but may improve the quality of life of individuals afflicted with AIDS. The psychological benefits of these therapies are the most important use.

Epidemiology

Estimated prevalence of HIV among young adults (15-49) per country at the end of 2005

The AIDS pandemic can also be seen as several epidemics of separate subtypes; the major factors in its spread are sexual transmission and vertical transmission from mother to child at birth and through breast milk.[4] Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.1 million (range 1.9–2.4 million) lives in 2007 of which an estimated 330,000 were children under 15 years.[5] Globally, an estimated 33.2 million people lived with HIV in 2007, including 2.5 million children. An estimated 2.5 million (range 1.8–4.1 million) people were newly infected in 2007, including 420,000 children.[5]

Sub-Saharan Africa remains by far the worst affected region. In 2007 it contained an estimated 68% of all people living with AIDS and 76% of all AIDS deaths, with 1.7 million new infections bringing the number of people living with HIV to 22.5 million, and with 11.4 million AIDS orphans living in the region. Unlike other regions, most people living with HIV in sub-Saharan Africa in 2007 (61%) were women. Adult prevalence in 2007 was an estimated 5.0%, and AIDS continued to be the single largest cause of mortality in this region.[5] South Africa has the largest population of HIV patients in the world, followed by Nigeria and India.[117] South & South East Asia are second worst affected; in 2007 this region contained an estimated 18% of all people living with AIDS, and an estimated 300,000 deaths from AIDS.[5] India has an estimated 2.5 million infections and an estimated adult prevalence of 0.36%.[5] Life expectancy has fallen dramatically in the worst-affected countries; for example, in 2006 it was estimated that it had dropped from 65 to 35 years in Botswana.[4]

Prognosis

Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[5] and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.[118] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to about 20 years.

As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year. Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[120] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function health care and co-infections,[ as well as which particular strain of the virus is involved.

History

AIDS was first reported June 5, 1981, when the U.S. Centers for Disease Control and Prevention recorded a cluster of Pneumocystis carinii pneumonia (now still classified as PCP but known to be caused by Pneumocystis jirovecii) in five homosexual men in Los Angeles.[123] In the beginning, the Centers for Disease Control and Prevention (CDC) did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] They also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.[124] In the general press, the term GRID, which stood for Gay-related immune deficiency, had been coined.[125] The CDC, in search of a name, and looking at the infected communities coined “the 4H disease,” as it seemed to single out Haitians, homosexuals, hemophiliacs, and heroin users.[126] However, after determining that AIDS was not isolated to the homosexual community,[124] the term GRID became misleading and AIDS was introduced at a meeting in July 1982.[127] By September 1982 the CDC started using the name AIDS, and properly defined the illness.[128]

A more controversial theory known as the OPV AIDS hypothesis suggests that the AIDS epidemic was inadvertently started in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a poliomyelitis vaccine.[129][130] According to scientific consensus, this scenario is not supported by the available evidence.[131][132][133]

A recent study states that HIV probably moved from Africa to Haiti and then entered the United States around 1969.

Society and culture

Stigma
Ryan White became a poster child for HIV after being expelled from school because of his infection.
Ryan White became a poster child for HIV after being expelled from school because of his infection.

AIDS stigma exists around the world in a variety of ways, including ostracism, rejection, discrimination and avoidance of HIV infected people; compulsory HIV testing without prior consent or protection of confidentiality; violence against HIV infected individuals or people who are perceived to be infected with HIV; and the quarantine of HIV infected individuals.[135] Stigma-related violence or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing treatment, possibly turning what could be a manageable chronic illness into a death sentence and perpetuating the spread of HIV.

AIDS stigma has been further divided into the following three categories:

* Instrumental AIDS stigma—a reflection of the fear and apprehension that are likely to be associated with any deadly and transmissible illness.[137]
* Symbolic AIDS stigma—the use of HIV/AIDS to express attitudes toward the social groups or lifestyles perceived to be associated with the disease.[137]
* Courtesy AIDS stigma—stigmatization of people connected to the issue of HIV/AIDS or HIV- positive people.[138]

Often, AIDS stigma is expressed in conjunction with one or more other stigmas, particularly those associated with homosexuality, bisexuality, promiscuity, and intravenous drug use.

In many developed countries, there is an association between AIDS and homosexuality or bisexuality, and this association is correlated with higher levels of sexual prejudice such as anti-homosexual attitudes.[139] There is also a perceived association between AIDS and all male-male sexual behavior, including sex between uninfected men.[137]

Economic impact

Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda
Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda

HIV and AIDS affects economic growth by reducing the availability of human capital.[6] Without proper nutrition, health care and medicine that is available in developed countries, large numbers of people are falling victim to AIDS. They will not only be unable to work, but will also require significant medical care. The forecast is that this will likely cause a collapse of economies and societies in countries with a significant AIDS populationi. In some heavily infected areas, the epidemic has left behind many orphans cared for by elderly grandparents.

The increased mortality in this region will result in a smaller skilled population and labor force. This smaller labor force will be predominantly young people, with reduced knowledge and work experience leading to reduced productivity. An increase in workers’ time off to look after sick family members or for sick leave will also lower productivity. Increased mortality will also weaken the mechanisms that generate human capital and investment in people, through loss of income and the death of parents. By killing off mainly young adults, AIDS seriously weakens the taxable population, reducing the resources available for public expenditures such as education and health services not related to AIDS resulting in increasing pressure for the state's finances and slower growth of the economy. This results in a slower growth of the tax base, an effect that will be reinforced if there are growing expenditures on treating the sick, training (to replace sick workers), sick pay and caring for AIDS orphans. This is especially true if the sharp increase in adult mortality shifts the responsibility and blame from the family to the government in caring for these orphans.[140]

On the level of the household, AIDS results in both the loss of income and increased spending on healthcare by the household. The income effects of this lead to spending reduction as well as a substitution effect away from education and towards healthcare and funeral spending. A study in Côte d'Ivoire showed that households with an HIV/AIDS patient spent twice as much on medical expenses as other households.[141]

AIDS denialism

A small group of activists, including several scientists who do not study HIV/AIDS, question the connection between HIV and AIDS,[142] the existence of HIV itself,[143] or the validity of current testing and treatment methods. Though these claims have been examined and thoroughly rejected by the scientific community,[144] they continue to be promulgated through the Internet[145] and have had a significant political impact, particularly in South Africa, where President Thabo Mbeki's embrace of AIDS denialism has been blamed for an ineffective response to that country's AIDS epidemic.

allergies reference

2008-07-12T13:38:00.000-07:00

Allergy is a disorder of the immune system often also referred to as atopy. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.[1]

Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions and potentially death.

A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.

Classification and history

The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.

A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.

Cause

Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. There have been recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[14]

Genetic basis

Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[15] Allergic parents are more likely to have allergic children,[16] and their allergies are likely to be more severe than those from non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[16]

The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[17] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16] although for some diseases, namely asthma in young adults, females are more likely to be affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration.[16] Interestingly, it has been suggested that different genetic loci are responsible for asthma, specifically, in people of Caucasian, Hispanic, Asian, and African origins.[20]

Environmental factors

International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[21]

Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy.[14] Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis".[21] Exposure to endotoxin and other components of bacteria may reduce atopic diseases.[22] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[23] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[24]

Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[25] Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[26] This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[27] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[28] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[21] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[29] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[29] For more information on this topic, see Helminthic therapy.

Pathophysiology

The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.

Acute response
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)

In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]

If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[14]

Late-phase response

After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction.[30] Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[31]

Diagnosis
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base

Before a diagnosis of allergic disease can be confirmed, the other possible causes of the presenting symptoms should be carefully considered.[32] Vasomotor rhinitis, for example, is one of many maladies that shares symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[33] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.

Skin testing
Skin Testing

For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is preferred over blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive.[34] Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[35] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[36]

If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines sometime the last several days.

Blood testing

Various blood allergy testing methods are also available for detecting allergy to specific substances. This kind of testing measures a "total IgE level" - an estimate of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Radiometric assays include the radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[34] Other newer methods use colorimetric or fluorometric technology in the place of radioactive isotopes. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study.[37]

A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.

Pharmacotherapy

Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics, decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in chronic treatment of allergic disorders.

Immunotherapy

Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production, to block excessive IgE production seen in atopys. In a sense, the person builds up immunity to increasing amounts of the allergen in question. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy.[40] Meta-analyses have also confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation needed] A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect based on numerous well-designed scientific studies.[41] Additionally, national and international guidelines confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed.[42]

A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as this would stimulate the allergic inflammatory response. The first agent of this class is Omalizumab. While this form of immunotherapy is very effective in treating several types of atopy, it should not be used in treating the majority of people with food allergies.[citation needed]

A third type, Sublingual immunotherapy, is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]

Unproven or ineffective treatments

An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[43] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[43]

In alternative medicine, a number of allergy treatments are described by its practitioners, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology. Systematic literature searches conducted by the Mayo Clinic through 2006, involving hundreds of articles studying multiple conditions, including asthma and upper respiratory tract infection showed no effectiveness of any alternative treatments, and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of alternative treatments.[44]

Epidemiology

Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and allergic diseases—hay fever and asthma—have increased in the Western world over the past 2-3 decades.[45] Rapid increases in allergic asthma and other atopic disorders in industrialized nations probably began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[46] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[47] The incidence of atopy in developing countries has generally remained much lower.

Alzheimer's disease reference

2008-07-12T13:35:00.000-07:00

Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's, is the most common cause of dementia. Alzheimer's is a degenerative and terminal disease for which there is no known cure. In its most common form, it afflicts individuals over 65 years old, although a less prevalent early-onset form also exists. It is estimated that 26.6 million people worldwide were afflicted by AD in 2006, which could quadruple by 2050,[1] although estimations vary greatly.[2]

Each individual experiences the symptoms of AD in unique ways.[3] The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if available.[4] A prognosis for Alzheimer's is hard to make, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent, sometimes escaping diagnosis for years. Generally, life with Alzheimer's disease lasts between 5 and 20 years.[5][6] In the early stages, the most commonly recognised symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of stress.[7] As the disease advances, progressive symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.[7][8] Gradually, minor and major bodily functions are lost, leading ultimately to death.[9]

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[10] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease

Characteristics

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment expressed during each stage.

Predementia

Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.[16] These early symptoms can have an effect on the most complex daily living activities.[17] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.[18][19] In addition, subtle executive function problems (attention, planning, flexibility, abstraction...) or impairments in semantic memory (memory of meanings and concept relationships) can also occur.[20][21] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.[22][23][24] This stage of the disease has also been termed mild cognitive impairment,[25] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[26]

Early dementia
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.

In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them difficulties with language, executive functions, recognition of perceptions (agnosia) or execution of movements (apraxia) will be more salient.[27] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.[28][29] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.[27]

Moderate dementia

In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.[27]

Speech difficulties become clearly noticeable: due to difficulties in finding words the person makes frequent incorrect substitutions (paraphasias) , and content is poor. Reading and writing are also progressively forgotten.[30][34] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.[35] Memory problems worsen, and the person may not recognize close relatives.[36] Long-term memory, which was previously left intact, is now also impaired.[37] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.[22][38] Often urinary incontinence develops.[39] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.[40] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.[27][41]

Advanced

In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.[30] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.[42] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[27] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,[43] and to lose the ability to feed oneself,[44] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.[45][46]

Causes

Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[47] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[48] leading to generalised neuroinflammation.[49]

In 1991 the amyloid hypothesis was proposed,[50] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[51]

The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.[52] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[53] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[54]

A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.[51] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. It should be noted further that APOE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[58] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[59]

Pathophysiology

Main article: Biochemistry of Alzheimer's disease

Neuropathology
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.

At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[49]

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[10] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[60]

Biochemical characteristics

Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[61] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[62][63] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.[64] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[65][10]

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A protein called tau makes the microtubules stable when phosphorylated, and is therefore called a microtubule-associated protein.[66] In AD, tau is changed chemically, becoming phosphate saturated (hyperphosphorylated).

Disease mechanism

If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.[67] The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid peptides as the central event triggering neurons degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces apoptosis (programmed cell death).[68] It is also known that Aβ selectively builds up in the cells mitochondria of brains with AD and inhibits certain enzyme functions and the utilization of glucose by neurons. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis.[69]

Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.

Genetic

While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.[71]

Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.[71][72] These mutations have been discovered in three different genes: amyloid precursor protein or APP,[73] and presenilins 1,[74] and 2[75]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.[76]

Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.[77] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.[71] Over 400 genes have been tested for association with late-onset sporadic AD.[78]

Diagnosis

Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[79][80] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[81] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[82] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.[83]

Diagnostic criteria

The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.[84] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[85] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.[86][87]

Diagnostic tools
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.

Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.[82] In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.[90] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[91] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[92] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[82] which rarely may even be reversible;[93] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.[94][95]

Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.[96] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[97] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[98][99][100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[84][82]

Prevention
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.

At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.[102] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.[103]

The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.[106] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[113][114] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[115]

Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.[116][117] Bilingualism is also related to a later onset of Alzheimer.[118]

Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as magnetic field exposure,[119][120], metals intake and specifically aluminium,[121][122] or solvents.[123] The quality of some of these studies has been criticized,[124] and other research does not confirm this link.[125][126] [127][128]

[edit] Management

There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

Pharmaceutical
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms

Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.

Because reduction in the activity of the cholinergic neurons in the disease is well known, acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.[130] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[131] galantamine (Razadyne),[132] and rivastigmine (branded as Exelon,[133] and Exelon Patch[134]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[135] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[136] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[137] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[138][139][140][141]

Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[142] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[143] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[142] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.[144] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[145] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[146]

Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[147][148][149]

Psychosocial intervention
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia

Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.[150]

Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[151] but can help to reduce some specific problem behaviors, such as incontinence.[152] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[153][154]

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.[150] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[155] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[156][157] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.[158][159]

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[160][161] although in some works these effects were transient and negative effects, such as frustration, have also been reported.[150]

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.[150]

Caregiving

Further information: Caregiving and dementia

Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[162] Many family members choose to look after their relatives,[12] but two-thirds of nursing home residents have dementias.[163]

Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[164][165] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[166]

Prognosis

As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.[27] Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.

History
Auguste D, first described patient with AD by Alöis Alzheimer in 1901

Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[179] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[179] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies.[182] This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[183] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[184]

Society and culture

Social costs

Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total disability adjusted life years (DALYs) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.[185] The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure.

The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations

anxiety disorders reference

2008-07-12T13:33:00.000-07:00

Anxiety disorder is a blanket term covering several different forms of abnormal, pathological anxiety, fears, and phobias.

Anxiety and fear are ubiquitous emotions. The terms anxiety and fear have specific scientific meanings, but common usage has made them interchangeable. For example, a phobia is a kind of anxiety that is also defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) as a "persistent or irrational fear." Fear is defined as an emotional and physiological response to a recognized external threat. Anxiety is an unpleasant emotional state, the sources of which are less readily identified. It is frequently accompanied by physiological symptoms that may lead to fatigue or even exhaustion. Because fear of recognized threats causes similar unpleasant mental and physical changes, patients sometimes use the terms fear and anxiety interchangeably. Distinguishing among different anxiety disorders is important, since accurate diagnosis is more likely to result in effective treatment and a better prognosis. Surveys have shown as many as 30% of Americans may be affected by anxiety disorders

Diagnosis

Anxiety disorders are often debilitating chronic conditions, which can be present from an early age or begin suddenly after a triggering event. They are prone to flare up at times of high stress.

A good assessment is essential for the initial diagnosis of an anxiety disorder, preferably using a standardized interview or questionnaire procedure alongside expert evaluation and the views of the affected person. There should be a medical examination in order to identify possible medical conditions that can cause the symptoms of anxiety. A family history of anxiety disorders is often suggestive of the possibility of an anxiety disorder.

Anxiety can be accompanied by headache, sweating, palpitations, and hypertension.

It is important to note that a patient with an anxiety disorder will often exhibit symptoms of Clinical Depression and vice-versa. Rarely does a patient exhibit symptoms of only one or the other.

Causes and contributing factors

Clinical and animal studies suggest a correlation between anxiety disorders and difficulty in maintaining balance.

A possible mechanism is malfunction in the parabrachial nucleus, a structure in the brain, that among other functions, coordinates signals from the amygdala with input concerning balance. The amygdala is involved in the emotion of fear. [6]

Biochemical factors come into play. Low levels of GABA, a neurotransmitter that reduces overactivity in the central nervous system, contributes to anxiety. A number of anxiolytics achieve their effect by modulating the GABA receptors.[7] [8] [9]

Types

Generalized anxiety disorder

Generalized anxiety disorder is a common chronic disorder that affects twice as many women as men and can lead to considerable impairment (Brawman-Mintzer & Lydiard, 1996, 1997). As the name implies, generalized anxiety disorder is characterized by long-lasting anxiety that is not focused on any particular object or situation. In other words it is unspecific or free-floating. People with this disorder feel afraid of something but are unable to articulate the specific fear. They fret constantly and have a hard time controlling their worries. Because of persistent muscle tension and autonomic fear reactions, they may develop headaches, heart palpitations, dizziness, insomnia and chest pain. These physical symptoms, combined with the intense, long-term anxiety, make it difficult to cope with normal daily activities.

Panic disorder

In panic disorder, a person suffers from brief attacks of intense terror and apprehension that cause trembling and shaking, confusion, dizziness, nausea, difficulty breathing, and feelings of impending doom or a situation that would be embarrassing. One who is often plagued by sudden bouts of intense anxiety might be said to be afflicted by this disorder. The American Psychiatric Association (2000) defines a panic attack as fear or discomfort that arises abruptly and peaks in 10 minutes or less, and can occasionally last hours.

Although panic attacks sometimes seem to occur out of nowhere, they generally happen after frightening experiences, prolonged stress, or even exercise. Many people who have panic attacks (especially their first one) think they are having a heart attack and often end up at the doctor or emergency room. Even if the tests all come back normal the person will still worry, with the physical manifestations of anxiety only reinforcing their fear that something is wrong with their body. Heightened awareness (hypervigilance) of any change in the normal function of the human body will be noticed and interpreted as a possible life threatening illness by an individual suffering from panic attacks.

Normal changes in heartbeat, such as when climbing a flight of stairs will be noticed by a panic sufferer and lead them to think something is wrong with their heart or they are about to have another panic attack. Some begin to worry excessively and even quit jobs or refuse to leave home to avoid future attacks. Panic disorder can be diagnosed when several apparently spontaneous attacks lead to a persistent concern about future attacks.

Agoraphobia

A common complication of panic disorder is agoraphobia, anxiety about being in a place or situation where escape is difficult or embarrassing (Craske, 2000; Gorman, 2000). It seems that the definition of the word has expanded to refer to avoidance behaviors that sufferers often develop. If a sufferer of panic attacks seems to have them while driving, for example, then he or she may avoid driving, which relieves the anxiety, and subsequently makes future driving more difficult, as a result of behavioral reinforcement.

Phobias

This category involves a strong, irrational fear and avoidance of an object or situation. The person knows the fear is irrational, yet the anxiety remains. Phobic disorders differ from generalized anxiety disorders and panic disorders because there is a specific stimulus or situation that elicits a strong fear response. A person suffering from a phobia of spiders might feel so frightened by a spider that he or she would try to jump out of a speeding car to get away from one.

People with phobias have especially powerful imaginations, so they vividly anticipate terrifying consequences from encountering such feared objects as knives, bridges, blood, enclosed places, certain animals or situations. These individuals generally recognize that their fears are excessive and unreasonable but are generally unable to control their anxiety.

Social anxiety disorder

Social anxiety disorder is also known as social phobia. Individuals with this disorder experience intense fear of being negatively evaluated by others or of being publicly embarrassed because of impulsive acts. Almost everyone experiences "stage fright" when speaking or performing in front of a group. Since occasionally there are artists or performers with social anxiety disorder who are able to perform publicly without significant anxiety, their love of performing and practicing their art may be diminishing their anxiety. Although some high-functioning phobics such as Glenn Gould are able to perform despite anxiety, most people with social phobias become so anxious that performance is out of the question. In fact, their fear of public scrutiny and potential humiliation becomes so pervasive that normal life can become impossible (den Boer 2000; Margolis & Swartz, 2001). Another social phobia is fear of intimacy, or "love-shyness", which most adversely affects certain men. Those afflicted find themselves unable to initiate intimate adult relationships (Gilmartin 1987).

Obsessive-compulsive disorder

Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by obsessions and/or compulsions. Obsessions are distressing, repetitive, intrusive thoughts or images that the individual often realizes are senseless. Compulsions are repetitive behaviors that the person feels forced or compelled into doing, sometimes, in order to relieve anxiety. The OCD thought pattern may be likened to superstitions: if X is done, Y won't happen—in spite of how unlikely it may be that doing X will actually prevent Y, if Y is even a real threat to begin with. A common example of this behavior would be obsessing that one's door is unlocked, which may lead to compulsive constant checking and rechecking of doors. Another example is obsession with the state of one's personal items, such as eyeglasses, leading to their excessive cleaning or adjustment. Often the process seems much less logical. For example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession that something bad is about to happen. More often, though, the compulsion is inexplicable, simply an urge to complete a ritual triggered by nervousness. Light switches and other household items are also common objects of obsession.

Post-traumatic stress disorder

Post-traumatic stress disorder is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as being involved in warfare, rape, hostage situations, or involvement in a serious accident. It can also result from long term (chronic) exposure to a severe stressor,[10] for example soldiers who endure individual battles but cannot cope with an unceasing sequence of battles. The sufferer may experience flashbacks, avoidant behavior, and other symptoms.

Separation anxiety

Separation anxiety disorder is the feeling of excessive and inappropriate levels of anxiety over being separated from an attachment figure or from a person or place that gives a feeling of safety. While it is seen mostly in children (for example on being left at school) it is also seen in adolescents and adults.

Separation anxiety itself is a normal part of development in babies or children.[11] It is only when this feeling is excessive or inappropriate that it can be considered a disorder.

Treatment

The choices of treatment include cognitive behavioral therapy, lifestyle changes, and/or pharmaceutical therapy (medications). Mainstream treatment for anxiety consists of the prescription of anxiolytic agents and/or antidepressants and/or referral to a Psychologist/cognitive-behavioral therapist. Treatment controversy arises because some studies indicate that a combination of the medications and behavioral therapy can be more effective than either one alone; however, others studies suggest pharmacological interventions are largely just pallative, and can actually interfere with the mechanisms of successful therapy

arthritis reference

2008-07-12T13:31:00.000-07:00

Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) is a group of conditions involving damage to the joints of the body. Arthritis is the leading cause of disability in people older than fifty-five years.

There are different forms of arthritis; each has a different cause. The most common form of arthritis, osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age. Emerging evidence suggests that abnormal anatomy might contribute to the early development of osteoarthritis. Other arthritis forms are rheumatoid arthritis and psoriatic arthritis, autoimmune diseases in which the body attacks itself. Septic arthritis is caused by joint infection. Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation. There is also an uncommon form of gout caused by the formation of rhomboid crystals of calcium pyrophosphate. This gout is known as pseudogout

History and physical examination

All arthritides feature pain. Pain patterns may differ depending on the arthritides and the location. Rheumatoid arthritis is generally worse in the morning and associated with stiffness; in the early stages, patients often have no symptoms after a morning shower. In the aged and children, pain might not be the main feature; the aged patient simply moves less, the infantile patient refuses to use the affected limb.

Elements of the history of the disorder guide diagnosis. Important features are speed and time of onset, pattern of joint involvement, symmetry of symptoms, early morning stiffness, tenderness, gelling or locking with inactivity, aggravating and relieving factors, and other systemic symptoms. Physical examination may confirm the diagnosis, or may indicate systemic disease. Radiographs are often used to follow progression or assess severity in a more quantitative manner.

Types of arthritis

Primary forms of arthritis:

* Osteoarthritis
* Rheumatoid arthritis
* Septic arthritis
* Gout and pseudogout
* Juvenile idiopathic arthritis
* Still's disease
* Ankylosing spondylitis

Secondary to other diseases:

* Lupus erythematosus
* Henoch-Schönlein purpura
* Psoriatic arthritis
* Reactive arthritis
* Haemochromatosis
* Hepatitis
* Wegener's granulomatosis (and many other vasculitis syndromes)
* Lyme disease
* Familial Mediterranean fever
* Hyperimmunoglobulinemia D with recurrent fever
* TNF receptor associated periodic syndrome
* Inflammatory bowel disease (Including Crohn's Disease and Ulcerative Colitis)

Diseases that can mimic arthritis include:

* Hypertrophic osteoarthropathy
* Multiple myeloma
* Osteoporosis
* Fifth disease

Treatment

Treatment options vary depending on the type of arthritis and include physical and occupational therapy, lifestyle changes (including exercise and weight control), medications and dietary supplements (symptomatic or targeted at the disease process causing the arthritis). Arthroplasty (joint replacement surgery) may be required in eroding forms of arthritis.

In general, studies have shown that physical exercising of the affected joint can have noticeable improvement in terms of long-term pain relief. Furthermore, exercising of the arthritic joint is encouraged to maintain the health of the particular joint and the overall body of the person.

Another form of non-drug treatment that does have a body of proper research to support its efficacy is marine oil, from both fish and the New Zealand green-lipped mussel (Perna canaliculus). Diets high in marine oils from cold-water fish such as salmon, mackerel, and tuna have been shown to reduce the inflammation of joint conditions such as arthritis[citation needed]. Massage on joints with neem oil has reported improvement in chronic and acute cases[citation needed].

History

While evidence of primary ankle (kaki) osteoarthritis has been discovered in dinosaurs, the first known traces of human arthritis date back as far as 4500 BC. It was noted in skeletal remains of Native Americans found in Tennessee and parts of what is now Olathe, Kansas. Evidence of arthritis has been found throughout history, from Ötzi, a mummy (circa 3000 BC) found along the border of modern Italy and Austria, to the Egyptian mummies circa 2590 BC

asthma reference

2008-07-12T13:27:00.001-07:00

Asthma is a chronic condition involving the respiratory system in which the airways occasionally constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more triggers.[1] These episodes may be triggered by such things as exposure to an environmental stimulant such as an allergen, environmental tobacco smoke, cold or warm air, perfume, pet dander, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.[2] This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children

Signs and symptoms

In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.[4] Although the former is "often regarded as the sine qua non of asthma",[4] some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.[5]

Cause

Asthma is caused by a complex interaction of genetic and environmental factors that researchers do not fully understand yet.[6] These factors can also influence how severe a person’s asthma is and how well they respond to medication.[7] As with other complex diseases, many genetic and environmental factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.

The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.[8][9][10] All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

Environmental

Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association:

* Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.[11][12]
* Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.[11]
* Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.[11][13][14]
* Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).[8]
* Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).[9]
* Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.[11]

Genetic

Over 100 genes have been associated with asthma in at least one genetic association study.[15] However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma

Bronchoconstriction

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.[17]

The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

The normal calibre of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal centre, then down the vagal afferent pathway to again reach the bronchus. Acetylcholine is released from the afferent nerve endings. This acetylcholine results in the excessive formation of cyclic Guanine Mono phosphate (GMP). This initiates bronchoconstriction.

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack.

Stimuli

* Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;[citation needed]
* Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.[citation needed]
* Medications, including aspirin,[18] β-adrenergic antagonists (beta blockers), and penicillin.[citation needed]
* Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.[citation needed]
* Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.[citation needed]
* Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH2Cl), dichloramine (NHCl2) and trichloramine (NCl3)—in the air around them, which are known to induce asthma.[19]
* Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.[citation needed]
* Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. It is known that exercising regularly actually helps to cure asthma.[citation needed]
* Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.[citation needed]
* Emotional stress which is poorly understood as a trigger.[citation needed] Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
* Cold weather can make it harder for asthmatics to breathe.[20] Whether high altitude helps or worsens asthma is debatable and may vary from person to person.[21]

Pathogenesis

The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.[22] Szentivanyi's Beta Adrenergic Theory is a citation classic[23] and has been cited more times than any other article in the history of the Journal of Allergy.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[24] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[25]

The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),[26] Charles Reed (Chief of Allergy at Mayo Medical School),[27] and Craig Venter (Human Genome Project).[28]

John P. McGovern, President of the American Association of Allergy nominated Szentivanyi for The 1968 Nobel Prize in Medicine in recognition of The Beta Adrenergic Theory.

In 2006, Researchers at Harvard Medical School found evidence that asthma is caused by over-proliferation of a special type of natural "killer" cell.[29]

Asthma and sleep apnea

It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.[30] CPAP is not effective in patients with nocturnal asthma only.[31]

Asthma and gastro-esophageal reflux disease

Main article: gastro-esophageal reflux disease

If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.[citation needed] GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma.[32]

Diagnosis

Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:[33]

* ≥20% difference on at least three days in a week for at least two weeks;
* ≥20% improvement of peak flow following treatment, for example:
o 10 minutes of inhaled β-agonist (e.g., salbutamol);
o six week of inhaled corticosteroid (e.g., beclometasone);
o 14 days of 30mg prednisolone.
* ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).

In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.

Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software.[34] This allows patients to track their peak flow readings and pass information back to their doctor or nurse.[35]

In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,[36] along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.

Pulmonary aspiration, whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.

A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.[37]

The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Allergy tests can help identify avoidable symptom triggers.

After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine — or, even less commonly, histamine — may be performed.

Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories: intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.

Prevention

Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.

Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.

Preventive agents include the following.

* Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gain. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.
* Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
* Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
* Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)
* Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.
* Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation.
* Hyposensitization, (also known as immunodesensitisation therapy) may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Depending on the allergen, it can be given orally or by injection.
* Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.
* Methotrexate is occasionally used in some difficult-to-treat patients.
* If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.

Trigger avoidance

As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications.[38] Automobile emissions are considered an even more significant cause and aggravating factor. [1] Asthmatics who smoke or who live near traffic [2] typically require additional medications to help control their disease. Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.[39] Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.[40]

For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.[4]

Air Filters

If an asthmatic lives with a smoker, use of air filter or room air cleaner is likely to be helpful. Secondhand smoke can worsen the symptoms. The same is true for those with hay fever (allergic rhino sinusitis) or COPD (emphysema or chronic bronchitis). Room air cleaners remove small particles that are in the air near the air cleaner. However, room air cleaners do not remove small allergen particles that are caused by local disturbances, such as the microscopic house dust mite feces that surround a pillow when your head hits it or you turn over in bed. There are several types of air filters available.[41]

* Mechanical air filters use a fan to force air through a special screen that traps particles such as smoke, pollens, and other airborne allergens. The high-efficiency particulate air (HEPA) filter is the best-known air filter. HEPA (which is a type of filter, not a brand name) was developed during World War II to prevent radioactive particles from escaping from laboratories.
* Electronic air filters use electrical charges to attract and deposit allergens and irritants. If the device contains collecting plates, the particles are captured within the system; otherwise, they stick to room surfaces and have to be cleared away.
* Hybrid air filters contain elements of both mechanical and electrostatic filters.
* Gas phase air filters use activated carbon granules to remove odors (volatile organic compounds or VOCs) and non-particulate pollution such as cooking gas, gases emitted from paint or building materials (such as formaldehyde), and perfume.
* Germicidal air cleaners use ultraviolet (UV) lights to kill bacteria, viruses, and molds that pass through the area with the UV light. Such UV lights can be included with other air cleaner devices, which use a fan.
* Ozone generators are devices that intentionally produce high concentrations of ozone to clean the air in a room. They are often used to decontaminate rooms after smoke exposure following a fire.

Treatment

The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. If trigger avoidance is insufficient, medical treatment is available. Desensitization is currently the only known "cure" to the disease.[42] Other forms of treatment include relief medication, prevention medication, long-acting β2-agonists, and emergency treatment.

Medical

The specific medical treatment recommended to patients with asthma depends on the severity of their illness and the frequency of their symptoms. Specific treatments for asthma are broadly classified as relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)[40] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[43] are broadly used and supported by many doctors. On August 29, 2007 the final Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma was officially released. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks.

The discovery in 2006 by researchers at Harvard Medical School that asthma may be caused by over-proliferation of a special type of natural "killer" cell may ultimately lead to the development of better and more targeted drugs. Natural killer T cells seem to be resistant to the corticosteroids, one of the mainstays of current treatment.[29] Other promising avenues of current research include using cholesterol-lowering drugs (statins) and fish oil supplementation to reduce airway inflammation [44].

Pharmaceutical

Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. These are typically provided in pocket-sized, metered-dose inhalers (MDIs). In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer (see top image) is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.

A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapour, which the patient inhales continuously until the full dosage is administered. There is no clear evidence, however, that they are more effective than inhalers used with a spacer. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.

Relievers include:

* Short-acting, selective beta2-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol.
Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
* Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[45] [46] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[45] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
* Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β2-adrenoreceptor agonists.
* Inhaled glucocorticoids are usually considered preventive medications; however, a randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.[47]

Long-acting β2-agonists
A typical inhaler, of Serevent (salmeterol), a long-acting bronchodilator.

Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required. In November 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β2-agonists could lead to a worsening of symptoms, and in some cases death.[48]

Currently available long-acting beta2-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, and Seretide in the United Kingdom). Another combination is budesonide/formoterol which is commercially known as Symbicort.

A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. The study, published in the Annals of Internal Medicine in 2006, found that long-acting beta-agonists increased the risk for asthma hospitalizations and asthma deaths 2- to 4-fold, compared with placebo.[49] "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a press release after the publication of the study. The release goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".[50] This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine, "Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts."

Dr. Shelley Salpeter, in a letter to the Annals of Internal Medicine, responds to the comments of Dr. Nelson, "It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonists. This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids... In the recent past, inhaled corticosteroid use has increased steadily while long-acting beta-agonist use has begun to stabilize and short-acting beta-agonist use has declined... Using this estimate, we can imagine that if long-acting beta-agonists were withdrawn from the market while maintaining high inhaled corticosteroid use, the death rate in the United States could be reduced significantly..."

Emergency

When an asthma attack is unresponsive to a patient's usual medication, other treatments are available to the physician or hospital:[51]

* Oxygen to alleviate the hypoxia (but not the asthma itself) that results from extreme asthma attacks.
* Nebulized salbutamol or terbutaline (short-acting beta-2-agonists), often combined with ipratropium (an anticholinergic).
* Systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone). Some research has looked into an alternative inhaled route.[52]
* Other bronchodilators that are occasionally effective when the usual drugs fail:
o Intravenous salbutamol
o Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
o Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
o Methylxanthines (theophylline, aminophylline)
o Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
o The dissociative anaesthetic ketamine, often used in endotracheal tube induction
o Magnesium sulfate, intravenous
* Intubation and mechanical ventilation, for patients in or approaching respiratory arrest.
* Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a more laminar flow than ambient air and moves more easily through constricted airways.

Non-medical treatments

Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.[53][54] There is little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.[55] A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[56] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvres, found there is insufficient evidence to support or refute their use in treating asthma;[57] these manoeuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." One meta-analysis finds that homeopathy may have a potentially mild benefit in reducing the intensity of symptoms.[58] However, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.[59] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs,[60] yogasanas, Pranayama, meditation, and kriyas, to sahaja yoga,[61] a form of 'new religious' meditation.

Treatment controversies

In November 2007 The New York Times reported a review of more than 500 studies finding that independently backed studies on inhaled corticosteroids are up to four times more likely to find adverse effects than studies paid for by drug companies.[62][63]

Prognosis

The prognosis for asthmatics is good; especially for children with mild disease. For asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes.[17] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters.[64] For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities. The mortality rate for asthma is low, with around 6000 deaths per year in a population of some 10 million patients in the United States.[4] Better control of the condition may help prevent some of these deaths.
The prevalence of childhood asthma has increased since 1980, especially in younger children.
The prevalence of childhood asthma has increased since 1980, especially in younger children.

Epidemiology

More than 6% of children in the United States have been diagnosed with asthma, a 75% increase in recent decades. The rate soars to 40% among some populations of urban children.[citation needed]

Asthma is usually diagnosed in childhood. The risk factors for asthma include:[citations needed]

* A personal or family history of asthma or atopy
* Triggers (see Pathophysiology above)
* Premature birth or low birth weight
* Viral respiratory infection in early childhood
* Maternal smoking
* Being male, for asthma in prepubertal children
* Being female, for persistence of asthma into adulthood

Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980 (see figure). The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago.[65] Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.

Population disparities

Asthma prevalence, morbidity, mortality, and drug response vary greatly across populations. There is an almost 30-fold difference in asthma prevalence between some of the countries included in the International Study of Asthma and Allergy in Childhood[3], with a trend toward more developed and westernized countries having higher asthma prevalence. Westernization can’t explain the entire difference in asthma prevalence between countries, however, and the disparities may also be affected by differences in genetic, social and environmental risk factors.[11] There are also worldwide disparities in asthma mortality, which is most common in low to middle income countries.[66]

Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.[11] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos and Native Hawaiians, and lowest in Mexicans and Koreans. Mortality rates follow similar trends, and response to albuterol is lower in Puerto Ricans than in African Americans or Mexicans.[70][71] As with worldwide asthma disparities, differences in asthma prevalence, mortality, and drug response in the US may be explained by differences in genetic, social and environmental risk factors.

Asthma prevalence also differs between populations of the same ethnicity who are born and live in different places.[72] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US.[73] This probably reflects differences in social and environmental risk factors associated with acculturation to the US.

Asthma prevalence and asthma deaths also differ by gender. Males are more likely to be diagnosed with asthma as children, but asthma is more likely to persist into adulthood in females. Sixty five percent more adult women than men will die from asthma. This difference may be attributable to hormonal differences, among other things. In support of this, girls who reach puberty before age 12 were found to have a later diagnosis of asthma more than twice as much as girls who reach puberty after age 12. Asthma is also the number one cause of children missing school.

Socioeconomic factors

The incidence of asthma is highest among low-income populations (asthma deaths are most common in low to middle income countries [4]), which in the western world are disproportionately ethnic minorities[74] and are more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighborhoods.

Asthma incidence and quality of treatment varies among different racial groups, though this may be due to correlations with income (and thus affordability of health care) and geography. For example, Black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.[75][76]

Asthma and athletics

Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games, in Atlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication.[77] These statistics have been questioned on at least two bases. Athletes with mild asthma may be more likely to be diagnosed with the condition than non-athletes, because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.[citation needed]

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.

In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.

History

Asthma was long considered a psychosomatic disease, and

... during the 1930s–50s, was even known as one of the 'holy seven' psychosomatic illnesses. At that time, psychoanalytic theories described the aetiology of asthma as psychological, with treatment often primarily involving psychoanalysis and other 'talking cures'. As the asthmatic wheeze was interpreted as the child's suppressed cry for his or her mother, psychoanalysts viewed the treatment of depression as especially important for individuals with asthma

asthma reference

2008-07-12T13:27:00.000-07:00

Astigmatism reference

2008-07-12T13:24:00.000-07:00

In optics, astigmatism is when an optical system has different foci for rays that propagate in two perpendicular planes. If an optical system with astigmatism is used to form an image of a cross, the vertical and horizontal lines will be in sharp focus at two different distances. The term comes from the Greek α- (a-) meaning "without" and στίγμα (stigma), "a mark, spot, puncture"

There are two distinct forms of astigmatism. The first is a third-order aberration, which occurs for objects (or parts of objects) away from the optical axis. This form of aberration occurs even when the optical system is perfectly symmetrical. This is often referred to as a "monochromatic aberration", because it occurs even for light of a single wavelength. This terminology may be misleading, however, as the amount of aberration can vary strongly with wavelength in an optical system.

The second form of astigmatism occurs when the optical system is not symmetric about the optical axis. This may be by design (as in the case of a cylindrical lens), or due to manufacturing error in the surfaces of the components or misalignment of the components. In this case, astigmatism is observed even for rays from on-axis object points. This form of astigmatism is extremely important in ophthalmology, since the human eye often exhibits this aberration due to imperfections in the shape of the cornea or the lens.

Third-order astigmatism
Page explaining and illustrating astigmatism

In the analysis of this form of astigmatism, it is most common to consider rays from a given point on the object, which propagate in two special planes. The first plane is the tangential plane. This is the plane which includes both the object point being considered and the axis of symmetry. Rays that propagate in this plane are called tangential rays. Planes that include the optical axis are meridional planes. It is common to simplify problems in radially-symmetric optical systems by choosing object points in the vertical ("y") plane only. This plane is then sometimes referred to as the meridional plane.

The second special plane is the sagittal plane. This is defined as the plane, orthogonal to the tangential plane, which contains the object point being considered and intersects the optical axis at the entrance pupil of the optical system. This plane contains the chief ray, but does not contain the optic axis. It is therefore a skew plane, in other words not a meridional plane. Rays propagating in this plane are called sagittal rays.

In third-order astigmatism, the sagittal and transverse rays form foci at different distances along the optic axis. These foci are called the sagittal focus and the transverse focus, respectively. In the presence of astigmatism, an off-axis point on the object is not sharply imaged by the optical system. Instead, sharp lines are formed at the sagittal and transverse foci. The image at the transverse focus is a short line, oriented in the direction of the sagittal plane; images of circles centered on the optic axis, or lines tangential to such circles, will be sharp in this plane. The image at the sagittal focus is a short line, oriented in the tangential direction; images of spokes radiating from the center are sharp at this focus. In between these two foci, a round but "blurry" image is formed. This is called the medial focus or circle of least confusion. This plane often represents the best compromise image location in a system with astigmatism.

The amount of aberration due to astigmatism is proportional to the square of the angle between the rays from the object and the optical axis of the system. With care, an optical system can be designed to reduce or eliminate astigmatism. Such systems are called anastigmats.

Astigmatism in systems that are not rotationally symmetric
Blur from astigmatic lens at different distances.

If an optical system is not axisymmetric, either due to an error in the shape of the optical surfaces or due to misalignment of the components, astigmatism can occur even for on-axis object points. This effect is often used deliberately in complex optical systems, especially certain types of telescope.

In the analysis of these systems, it is common to consider tangential rays (as defined above), and rays in a meridional plane (a plane containing the optic axis) perpendicular to the tangential plane. This plane is called either the sagittal meridional plane or, confusingly, just the sagittal plane.

Ophthalmic astigmatism

In ophthalmology, the vertical and horizontal planes are identified as tangential and sagittal meridians, respectively. Ophthalmic astigmatism is a refraction error of the eye in which there is a difference in degree of refraction in different meridians. It is typically characterized by an aspherical, non-figure of revolution cornea in which the corneal profile slope and refractive power in one meridian is greater than that of the perpendicular axis.

Astigmatism causes difficulties in seeing fine detail. In some cases vertical lines and objects such as walls may appear to the patient to be leaning over like the Tower of Pisa. Astigmatism can be often corrected by glasses with a lens that has different radii of curvature in different planes (a cylindrical lens), contact lenses, or refractive surgery.

Astigmatism is quite common. Studies have shown that about one in three people suffers from it.] The prevalence of astigmatism increases with age. Although a person may not notice mild astigmatism, higher amounts of astigmatism may cause blurry vision, squinting, asthenopia, fatigue, or headaches.

There are a number of tests used by ophthalmologists and optometrists during eye examinations to determine the presence of astigmatism and to quantify the amount and axis of the astigmatism.[8] A Snellen chart or other eye chart may initially reveal reduced visual acuity. A keratometer may be used to measure the curvature of the steepest and flattest meridians in the cornea's front surface.[9] A corneal topographer may also be used to obtain a more accurate representation of the cornea's shape.[10] An autorefractor or retinoscopy may provide an objective estimate of the eye's refractive error and the use of Jackson cross cylinders in a phoropter may be used to subjectively refine those measurements.[11][12][13] An alternative technique with the phoropter requires the use of a "clock dial" or "sunburst" chart to determine the astigmatic axis and power.[14][15]

Astigmatism due to misaligned or malformed lenses and mirrors

Grinding and polishing of precision optical parts, either by hand or machine, typically employs significant downward pressure, which in turn creates significant frictional side pressures during polishing strokes that can combine to locally flex and distort the parts. These distortions generally do not possess figure-of-revolution symmetry and are thus astigmatic, and slowly become permanently polished into the surface if the problems causing the distortion are not corrected. Astigmatic, distorted surfaces potentially introduce serious degradations in optical system performance.

Surface distortion due to grinding or polishing increases with the aspect ratio of the part (diameter to thickness ratio). To a first order, glass strength increases as the cube of the thickness. Thick lenses at 4:1 to 6:1 aspect ratios will flex much less than high aspect ratio parts, such as optical windows, which can have aspect ratios of 15:1 or higher. The combination of surface or wavefront error precision requirements and part aspect ratio drives the degree of back support uniformity required, especially during the higher down pressures and side forces during polishing. Optical working typically involves a degree of randomness that helps greatly in preserving figure-of-revolution surfaces, provided the part is not flexing during the grind/polish process.

Deliberate astigmatism in optical systems

Compact disc players use an astigmatic lens for focusing. When one axis is more in focus than the other, dot-like features on the disc project to oval shapes. The orientation of the oval indicates which axis is more in focus, and thus which direction the lens needs to move. A square arrangement of only four sensors can observe this bias and use it to bring the read lens to best focus, without being fooled by oblong pits or other features on the disc surface.

Bipolar disorder reference

2008-07-12T13:21:00.000-07:00

Bipolar disorder is not a single disorder, but a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood, clinically referred to as mania. Individuals who experience manic episodes also commonly experience depressive episodes or symptoms, or mixed episodes in which features of both mania and depression are present at the same time. These episodes are normally separated by periods of normal mood, but in some patients, depression and mania may rapidly alternate, known as rapid cycling. Extreme manic episodes can sometimes lead to psychotic symptoms such as delusions and hallucinations. The disorder has been subdivided into bipolar I, bipolar II, Bipolar NOS, and cyclothymia based on the type and severity of mood episodes experienced.

Also called bipolar affective mood disorder until recently, the current name is of fairly recent origin and refers to the cycling between high and low episodes; it has replaced the older term manic-depressive illness coined by Emil Kraepelin (1856–1926) in the late nineteenth century.[1] The new term is designed to be neutral, to avoid the stigma in the non-mental health community that comes from conflating "manic" and "depression."

Onset of symptoms generally occurs in young adulthood. Diagnosis is based on the person's self-reported experiences, as well as observed behavior. Episodes of illness are associated with distress and disruption, and a high risk of suicide, especially during depressive episodes.[2] Studies suggest that genetics, early environment, neurobiology, and psychological and social processes are important contributory factors. Psychiatric research is focused on the role of neurobiology, but a clear organic cause has not been found. Bipolar disorder is usually treated with medications and/or counseling. The mainstay of medication are a number of drugs termed 'mood stabilizers', in particular lithium and sodium valproate; these are a group of unrelated medications used to prevent relapses of further episodes. Antipsychotic medications, sometimes called neuroleptics, in particular olanzapine, are used in the treatment of manic episodes and in maintenance. The benefits of using antidepressants in depressive episodes is unclear. Depending on the jurisdiction, in serious cases where there is risk to self or others involuntary commitment may be used; these cases generally involve severe manic episodes with dangerous behaviour or depressive episodes with suicidal ideation. Hospital stays are less frequent and for shorter periods than they were in previous years.[citation needed]

Some studies have suggested a significant correlation between creativity and bipolar disorder. Though studies consistently show a positive correlation between the two, the exact nature of the relationship between the disorder and creativity is still relatively unclear.[3][4][5] One study indicated increased striving for and attainment of goals and achievements was correlated with onset of manic symptoms.[6] While the disorder affects people differently, individuals with bipolar disorder tend to be much more outgoing and daring than individuals without bipolar disorder. The disorder is also found in a large number of people involved in the arts. It is an ongoing study as to why many creative geniuses had bipolar disorder.

Course

Bipolar disorder is often a cyclic illness where people periodically exhibit elevated (manic) and depressive episodes. Most people will experience a number of episodes, averaging 0.4 to 0.7 a year with each lasting three to six months, although some will experience only a single mood episode.[7][8] Late adolescence and early adulthood are peak years for the onset of the illness.[9][10] These are critical periods in a young adult's social and vocational development, and they can be severely disrupted by disease onset.

Rapid cycling, defined as having four or more episodes per year, is found in a significant fraction of patients with bipolar disorder. It has been associated with greater disability or a worse prognosis, due to the confusing changeability and difficulty in establishing a stable state. Rapid cycling can be induced or made worse by antidepressants, unless there is adjunctive treatment with a mood stabilizer.[11][12]

The definition of rapid cycling most frequently cited in the literature is that of Dunner and Fieve: at least four major depressive, manic, hypomanic or mixed episodes are required to have occurred during a 12-month period.[13] There are references that describe very rapid (ultra-rapid) or extremely rapid[14] (ultra-ultra or ultradian) cycling. One definition of ultra-ultra rapid cycling is defining distinct shifts in mood within a 24–48-hour period.

Major depressive episode

Signs and symptoms of the depressive phase of bipolar disorder include: persistent feelings of sadness, anxiety, guilt, anger, isolation and/or hopelessness, disturbances in sleep and appetite, fatigue and loss of interest in usually enjoyed activities, problems concentrating, loneliness, self-loathing, apathy or indifference, depersonalization, loss of interest in sexual activity, shyness or social anxiety, irritability, chronic pain (with or without a known cause), lack of motivation, and morbid/suicidal ideation.[15] In severe cases, the individual may become psychotic, a condition also known as severe bipolar depression with psychotic features.

Manic episode

Mania is generally characterized by a distinct period of an elevated, expansive, or irritable mood state. People commonly experience an increase in energy and a decreased need for sleep. A person's speech may be pressured, with thoughts experienced as racing. Attention span is low and a person in a manic state may be easily distracted. Judgment may become impaired; sufferers may go on spending sprees or engage in behavior that is quite abnormal for them. They may indulge in substance abuse, particularly alcohol or other depressants, cocaine or other stimulants, or sleeping pills. Their behavior may become aggressive or intrusive. People may feel they have been "chosen", are "on a special mission", or other grandiose or delusional ideas. Sexual drive may increase. At more extreme phases, a person in a manic state can begin to experience psychosis, or a break with reality, where thinking is affected along with mood.[16] Many people in a manic state experience severe anxiety and are very irritable (to the point of rage), while others are euphoric and grandiose.

In order to be diagnosed with mania according to DSM-IV a person must experience this state of elevated or irritable mood, as well as other symptoms, for at least one week, less if hospitalisation is required. According to the National Institute of Mental Health, "A manic episode is diagnosed if elevated mood occurs with three or more of the other symptoms most of the day, nearly every day, for 1 week or longer. If the mood is irritable, four additional symptoms must be present."[17]

Hypomanic episode

Hypomania is generally a less extreme state than mania, and people in the hypomanic phase generally experience fewer symptoms of mania than those in a full-blown manic episode. During an episode, one might feel an uncontrollable impulse to laugh at things he or she does not normally find funny. The duration is usually also shorter than in mania. This is often a very "artistic" state of the disorder, where there is a flight of ideas, extremely clever thinking, and an increase in energy. Although hypomania does not last as long as a manic episode, and most cases do not involve all manic symptoms, this doesn't mean such episodes are completely less severe.

Mixed affective episode

Main article: Mixed state (psychiatry)

In the context of bipolar disorder, a mixed state is a condition during which symptoms of mania and clinical depression occur simultaneously (for example, agitation, anxiety, aggressiveness or belligerence, confusion, fatigue, impulsiveness, insomnia, irritability, morbid and/or suicidal ideation, panic, paranoia, persecutory delusions, pressured speech, racing thoughts, restlessness, and rage).[18]

Diagnosis

Diagnosis is based on the self-reported experiences of the patient as well as abnormalities in behavior reported by family members, friends or co-workers, followed by secondary signs observed by a psychiatrist, nurse, social worker, clinical psychologist or other clinician in a clinical assessment. There is a list of criteria that must be met for someone to be so diagnosed. These depend on both the presence and duration of certain signs and symptoms.

An initial assessment includes a comprehensive history and physical examination by a physician. Although there are no biological tests which confirm bipolar disorder, tests are carried out to exclude medical illnesses which may rarely present with psychiatric symptoms. These include blood tests measuring TSH to exclude hypo- or hyperthyroidism, basic electrolytes and serum calcium to rule out a metabolic disturbance, full blood count including ESR to rule out a systemic infection or chronic disease, and serology to exclude syphilis or HIV infection; two commonly ordered investigations are EEG to exclude epilepsy, and a CT scan of the head to exclude brain lesions.[citation needed]

There are several psychiatric illnesses which may present with similar symptoms; these include schizophrenia,[19], schizoaffective disorder, drug intoxication, brief drug-induced psychosis, schizophreniform disorder and borderline personality disorder. Alternately, patients currently in a hypomanic or mixed affective episode may display symptoms resembling borderline personality disorder.[citation needed]

The last is important as both diagnoses involve symptoms commonly known as "mood swings". In bipolar disorder, the term refers to the cyclic episodes of elevated and depressed mood which generally last weeks or months (notwithstanding Rapid Cycling variant of greater than four episodes a year). The term in borderline personality refers to the marked lability and reactivity of mood, known as emotional dysregulation, due to response to external psychosocial and intrapsychic stressors; these may arise or subside suddenly and dramatically and last for seconds, minutes, hours or days. A bipolar depression is generally more pervasive with sleep, appetite disturbance and nonreactive mood, whereas the mood in dysthymia of borderline personality remains markedly reactive and sleep disturbance not acute.[20]

The relationship between bipolar disorder and borderline personality disorder has been debated; some hold that the latter represents a subthreshold form of affective disorder, while others maintain the distinctness, though noting they often coexist.[23][24]

Investigations are not generally repeated for relapse unless there is a specific medical indication. These may include serum BSL if olanzapine has previously been prescribed, lithium or valproate level to check compliance or toxicity with those medications, renal or thyroid function if lithium has been previously prescribed and taken regularly. Assessment and treatment are usually done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to self or others.[citation needed]

The most widely used criteria for diagnosing bipolar disorder are from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the current version being DSM-IV-TR, and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, currently the ICD-10. The latter criteria are typically used in European countries while the DSM criteria are used in the USA or the rest of the world, as well as prevailing in research studies.

Recent studies by Dr. John Kelsoe have linked bipolar disorder to genetic defects. “…[M]utations in the G protein receptorhinase (GRK3) gene—which regulates sensitivity to brain neurotransmitters such as dopamine…”[25] Dr. John Kelsoe is currently with the University of California in San Diego in the Department of Psychiatry[26] Kelsoe’s genetic discovery seeks to provide alternative treatments for those with bipolar disease. In 1997 a genome survey was completed and Dr. Kelsoe, along with his colleges reported that, “results support the presence of a susceptibility locus for bipolar disorder on chromosome 22…These molecular data raise the possibility that common susceptibility genes may be involved.”[27]

Diagnostic criteria and classification

There is no clear consensus as to how many types of bipolar disorder exist.[28] In DSM-IV-TR and ICD-10, bipolar disorder is conceptualized as a spectrum of disorders occurring on a continuum. The DSM-IV-TR lists four types of mood disorders which fit into the bipolar categories: Bipolar I, Bipolar II, Cyclothymia, and Bipolar Disorder NOS (Not Otherwise Specified).

Bipolar I

In Bipolar I disorder, an individual has experienced one or more manic episodes with or without major depressive episodes. For a diagnosis of Bipolar I disorder according to the DSM-IV-TR, there requires one or more manic or mixed episodes. A depressive episode is not required for the diagnosis of Bipolar I disorder but it frequently occurs.

Bipolar II

Bipolar II disorder is characterized by more hypomanic episodes rather than actual manic episodes, as well as at least one major depressive episode. Hypomanic episodes usually do not go to the full extremes of mania (i.e. do not usually cause severe social or occupational impairment, and without psychosis), and this can make Bipolar II more difficult to diagnose, since the hypomanic episodes may simply appear as a period of successful high productivity and is reported less frequently than a distressing depression. For both disorders, there are a number of specifiers that indicate the presentation and course of the disorder, including "chronic", "rapid cycling", "catatonic" and "melancholic".

Cyclothymia

Cyclothymia involves a presence or history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes. A diagnosis of Cyclothymic Disorder requires the presence of numerous hypomanic episodes, intermingled with depressive episodes that do not meet full criteria for major depressive episodes. The main idea here is that there is a low-grade cycling of mood which appears to the observer as a personality trait, but interferes with functioning.

Bipolar-NOS

Bipolar Disorder Not Otherwise Specified is a catch-all diagnosis that is used to indicate bipolar illness that does not fit into the other diagnostic categories. If an individual clearly seems to be suffering from some type of bipolar disorder but does not meet the criteria for one of the subtypes above, he or she receives a diagnosis of Bipolar Disorder NOS (Not Otherwise Specified).

Although a patient will most likely be depressed when they first seek help,[citation needed] it is important to find out from the patient or the patient's family or friends if a manic or hypomanic episode has ever occurred. This will prevent misdiagnosis of Depressive Disorder and avoids the use of an antidepressant which may trigger a "switch" to hypomania or mania or induce rapid cycling. Recent screening tools such as the Hypomanic Check List Questionnaire (HCL-32) have been developed to assist the quite often difficult detection of Bipolar II disorders.

Delay in diagnosis

The behavioral manifestations of bipolar disorder are often not understood by patients nor recognized by mental health professionals, so diagnosis may sometimes be delayed for 10 years or more.[29] That treatment lag is apparently not decreasing, even though there is now increased public awareness of this mental health condition in popular magazines and health websites. Recent TV specials, for example the BBC's The Secret Life of the Manic Depressive,[30] MTV's True Life: I'm Bipolar, talk shows, and public radio shows, and the greater willingness of public figures to discuss their own bipolar disorder, have focused on psychiatric conditions thereby further raising public awareness. Despite this increased focus, individuals are still commonly misdiagnosed.[31]

Children

Children with bipolar disorder do not often meet the strict DSM-IV definition, tending to have rapid-cycling or mixed-cycling pattern.[32] The incidence in this age group has been traditionally held to be very rare.[citation needed] In September 2007, experts (from New York, Maryland and Madrid) found that the number of American children and adolescents treated for bipolar disorder increased 40-fold from 1994 to 2003, and it was increasing ever since. They concluded that doctors had been more aggressively applying the diagnosis to children, and not that the incidence of the disorder had increased. The study calculated the number of visits which increased, from 20,000 in 1994 to 800,000 in 2003, or 1% of the population under age 20.

Often other psychiatric conditions are diagnosed in bipolar children. These other diagnoses may be concurrent problems, or they may be misdiagnosed as bipolar disorder. Depression, ADHD, ODD, schizophrenia, and Tourette syndrome are common comorbid conditions. Furthermore some children with histories of abuse or neglect may have Bipolar I Disorder.

Other theoretical models

Flux is the fundamental nature of bipolar disorder.] Individuals with the illness have continual changes in energy, mood, thought, sleep, and activity. The diagnostic subtypes of bipolar disorder are thus static descriptions — snapshots, perhaps — of an illness in continual flux, with a great diversity of symptoms and varying degrees of severity. Individuals may stay in one subtype, or change into another, over the course of their illness (Goodwin & Jamison, 1990). The DSM V, to be published in 2012, will likely include further and more accurate sub-typing (Akiskal and Ghaemi, 2006).

Associated features

Associated features are clinical phenomenon that often accompany the disorder, but are not part of the diagnostic criteria for the disorder.

Cognitive impairment

Recent studies have found that bipolar disorder involves certain cognitive deficits or impairments, even in states of remission.

It is not known whether specific cognitive deficits are mood state dependent or disorder-specific features of bipolar disorder. Few studies have examined impairments throughout all the different mood states, and many studies show conflicting data compared to other studies on account of methodological differences. Furthermore, the presence of mixed mood states complicates the identification of accurate cognitive models for this condition. Some use theories that conform to the cognitive models for unipolar depression and others on theories that focus solely on physiological or biological aspects of mania. However, Deborah Yurgelun-Todd of McLean Hospital in Belmont, Massachusetts has argued that some deficits should be included as a core feature of bipolar disorder. According to McIntyre et al. (2006),

Study results now press the point that neurocognitive deficits are a primary feature of BD; they are highly prevalent and persist in the absence of overt symptomatology. Although disparate neurocognitive abnormalities have been reported, disturbances in attention, visual memory, and executive function are most consistently reported.[41]

However, in the April–June 2007 issue of the Journal of Psychiatric Research (41, 3–4, 265–272) Spanish researchers (Selva et al.) reported that people with bipolar I who have a history of psychotic symptoms do not necessarily experience an increase in cognitive impairment. Some individuals diagnosed with bipolar I may experience only mood-congruent psychotic symptoms which may suggest a less severe prognosis, but this is by no means conclusive.

Creativity

A number of recent studies have observed a correlation between creativity and bipolar disorder,[3][4][5] although it is unclear in which direction the cause lies, or whether both conditions are caused by a third unknown factor. Temperament has been hypothesized to be one such factor.

Epidemiology

Clinical depression and bipolar disorder are classified as separate illnesses. Some researchers increasingly view them as part of an overlapping spectrum that also includes anxiety and psychosis.

According to Hagop Akiskal, M.D., at the one end of the spectrum is bipolar type schizoaffective disorder, and at the other end is unipolar depression (recurrent or not recurrent), with the anxiety disorders present across the spectrum. Also included in this view is premenstrual dysphoric disorder, postpartum depression, and postpartum psychosis. This view helps to explain why many people who have the illness do not have first-degree relatives with clear-cut "bipolar disorder", but who have family members with a history of these other disorders.

In a 2003 study, Hagop Akiskal M.D. and Lew Judd M.D. re-examined data from the landmark Epidemiologic Catchment Area study from two decades before.[42] The original study found that 0.8 percent of the population surveyed had experienced a manic episode at least once (the diagnostic threshold for bipolar I) and 0.5 a hypomanic episode (the diagnostic threshold for bipolar II).

By tabulating survey responses to include sub-threshold diagnostic criteria, such as one or two symptoms over a short time-period, the authors arrived at an additional 5.1 percent of the population, adding up to a total of 6.4 percent of the entire population who can be thought of as having a bipolar spectrum disorder. This and similar recent studies have been interpreted by some prominent bipolar disorders researchers as evidence for a much higher prevalence of bipolar conditions in the general population than previously thought.

However these re-analyses should be interpreted cautiously because of substantive as well as methodological study limitations. Indeed, prevalence studies of bipolar disorder are carried out by lay interviewers (that is, not by expert clinicians/psychiatrists who are more costly to employ) who follow fully structured/fixed interview schemes; responses to single items from such interviews may suffer limited validity.

Furthermore, a well-known statistical problem arises when ascertaining disorders and conditions with a relatively low population prevalence or base-rate, such as bipolar disorder: even assuming that lay interviews diagnoses are highly accurate in terms of sensitivity and specificity and their corresponding area under the ROC curve (that is, AUC, or area under the receiver operating characteristic curve), a condition with a relatively low prevalence or base-rate is bound to yield high false positive rates, which exceed false negative rates; in such a circumstance a limited positive predictive value, PPV, yields high false positive rates even in presence of a specificity which is very close to 100%.[43] To simplify, it can be said that a very small error applied over a very large number of individuals (that is, those who are *not affected* by the condition in the general population during their lifetime; for example, over 95%) produces a relevant, non-negligible number of subjects who are incorrectly classified as having the condition or any other condition which is the object of a survey study: these subjects are the so-called false positives; such reasoning applies to the 'false positive' but not the 'false negative' problem where we have an error applied over a relatively very small number of individuals to begin with (that is, those who are *affected* by the condition in the general population; for example, less than 5%). Hence, a very high percentage of subjects who seem to have a history of bipolar disorder at the interview are false positives for such a medical condition and apparently never suffered a fully clinical syndrome (that is, bipolar disorder type I): the population prevalence of bipolar disorder type I, which includes at least a lifetime manic episode, continues to be estimated at 1%.[44] "Mild-to-severe versions of bipolar disorder afflict nearly 4 percent of adults at some time in their lives."[45]

A different but related problem in evaluating the public health significance of psychiatric conditions has been highlighted by Robert Spitzer of Columbia University: fulfillment of diagnostic criteria and the resulting diagnosis do not necessarily imply need for treatment.[46] As a consequence, subjects who experience bipolar symptoms but not a full-blown, impairing bipolar syndrome should not be automatically considered as patients in need of treatment.

Recent studies have indicated that at least 50% of adult sufferers report manifestation of symptoms before the age of 17. Moreover, there is a growing consensus that bipolar disorder originates in childhood. In young children the illness is now referred to as pediatric bipolar disorder. Today about 0.5% of children under 18 are believed to have the condition. For children, the main concern is that bipolar disorder needs to be diagnosed correctly and treated properly because it can look like unipolar depression, ADHD, or conduct disorder. Young children, adolescents and adults each express the condition differently according to child and adolescent bipolar disorders expert Demitri Papolos M.D. and the Child and Adolescent Bipolar Foundation. There is, however, controversy about this last point.[47]

Bipolar disorder manifests in late life as well. Some individuals with "hyperthymic" temperament (or "hypomanic" personality style) who experience depression in later life appear to have a form of bipolar disorder. Much more needs to be elucidated about late-life bipolar disorder.

Controversy

A debate rages in the medical community on the prevalence of bipolar disorders.[48] Concerns have arisen about the potential for overdiagnosis of BD.[49] One controversy has been the validity of the construct of a mental disorder across different cultural perspectives (Lopez & Guarnaccia 2000, Sher & Trull 1996).[50] Culture-bound syndromes represent recurrent patterns of maladaptive behaviors and/or troubling experiences specifically associated with different cultures or localities (APA, 1994b).[51] It can be difficult to distinguish between age-appropriate restlessness, the fidgeting of children with ADHD, and the purposeful busy activity of mania (Harrington & Myatt, 2003).[52] Further complicating the diagnosis: Abused or traumatized children can seem to have bipolar disorder when they are actually reacting to horrors in their lives.[53] Assumptions regarding behavior, particularly in regard to diagnosing bipolar disorder, ADHD, and mania in children and adolescents, have raised considerable questions regarding unnecessary treatment. Antipsychotic drugs prescribed for the treatment of BD may increase risk to health including heart problems, diabetes, liver failure, and death.[54] "Consequences of overdiagnosis … include exposure to a greater medication burden (in some cases requiring additional monitoring) as well as lesser likelihood of clinical improvement."[55] When checking for a misdiagnosis of Bipolar disorder or confirming a diagnosis of Bipolar disorder, it is useful to consider what other medical conditions might be possible misdiagnoses or other alternative conditions relevant to diagnosis.[56]

Causes

According to the U.S. government's National Institute of Mental Health (NIMH), "There is no single cause for bipolar disorder — rather, many factors act together to produce the illness." "Because bipolar disorder tends to run in families, researchers have been searching for specific genes passed down through generations that may increase a person's chance of developing the illness." "In addition, findings from gene research suggest that bipolar disorder, like other mental illnesses, does not occur because of a single gene.".[57]

It is well established that bipolar disorder is a genetically influenced condition which can respond very well to medication (Johnson & Leahy, 2004; Miklowitz & Goldstein, 1997; Frank, 2005). (See treatment of bipolar disorder for a more detailed discussion of treatment.)

Psychological factors also play a strong role in both the psychopathology of the disorder and the psychotherapeutic factors aimed at alleviating core symptoms, recognizing episode triggers, reducing negative expressed emotion in relationships, recognizing prodromal symptoms before full-blown recurrence, and, practising the factors that lead to maintenance of remission (Lam et al, 1999; Johnson & Leahy, 2004; Basco & Rush, 2005; Miklowitz & Goldstein, 1997; Frank, 2005). Modern evidence based psychotherapies designed specifically for bipolar disorder when used in combination with standard medication treatment increase the time the individual stays well significantly longer than medications alone (Frank, 2005). These psychotherapies are interpersonal and social rhythm therapy for bipolar disorder, family focused therapy for bipolar disorder, psychoeducation, cognitive therapy for bipolar disorder, and prodrome detection. All except psychoeducation and prodrome detection are available as books.

Abnormalities in brain function have been related to feelings of anxiety and lower stress resilience. When faced with a very stressful, negative major life event, such as a failure in an important area, an individual may have his first major depression. Conversely, when an individual accomplishes a major achievement he may experience his first hypomanic or manic episode. Individuals with bipolar disorder tend to experience episode triggers involving either interpersonal or achievement-related life events. An example of interpersonal-life events include falling in love or, conversely, the death of a close friend. Achievement-related life events include acceptance into an elite graduate school or by contrast, being fired from work (Miklowitz & Goldstein, 1997). Childbirth can also trigger a postpartum psychosis for bipolar women, which can lead in the worst cases to infanticide.

The "kindling" theory asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events,[58] each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and become recurrent) by itself. There is evidence of hypothalamic-pituitary-adrenal axis (HPA axis) abnormalities in bipolar disorder due to stress.[59] Some individuals experience subsequent mood episodes in the absence of positive or negative life events, however, which can be especially debilitating.

Individuals with late-adolescent/early adult onset of the disorder will very likely have experienced childhood anxiety and depression. Some argue that childhood-onset bipolar disorder should be treated when it occurs to prevent the full development of the disorder.

A family history of bipolar spectrum disorders can impart a genetic predisposition towards developing a bipolar spectrum disorder.[60] Since bipolar disorders are polygenic (involving many genes), there are apt to be many unipolar and bipolar disordered individuals in the same family pedigree. This is very often the case (Barondes, 1998). Anxiety disorders, clinical depression, eating disorders, premenstrual dysphoric disorder, postpartum depression, postpartum psychosis schizoaffective disorder and/or schizophrenia may be part of the patient's family history and reflects a term called "genetic loading".

Bipolar disorder is not either environmental or physiological, it is multifactorial; that is, many genes and environmental factors conspire to create the disorder (Johnson & Leahy, 2004).

Since bipolar disorder is so heterogeneous, it is likely that people experience different pathways towards the illness (Miklowitz & Goldstein, 1997).

For example, recent research done in Japan hypothesizes that dysfunctional mitochondria in the brain may play a role (Stork & Renshaw, 2005).

Heritability or inheritance

The disorder runs in families.[61] More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.

Studies seeking to identify the genetic basis of bipolar disorder indicate that susceptibility stems from multiple genes. Scientists are continuing their search for these genes, using advanced genetic analytic methods and large samples of families affected by the illness. The researchers are hopeful that identification of susceptibility genes for bipolar disorder, and the brain proteins they code for, will make it possible to develop better treatments and preventive interventions targeted at the underlying illness process.

Genetic research

There is increasing evidence for a genetic component in the causation of bipolar disorder, provided by a number of twin studies and gene linkage studies.

The monozygotic concordance rate for the disorder is 70%. This means that if a person has the disorder, an identical twin has a 70% likelihood of having the disorder as well. Dizygotic twins have a 23% concordance rate. These concordance rates are not universally replicated in the literature; recent studies have shown rates of around 40% for monozygotic and less than 10% for dizygotic twins (see Kieseppa, 2004 and Cardno, 1999).[62][63]

In 2003, a group of American and Canadian researchers published a paper that used gene linkage techniques to identify a mutation in the GRK3 gene as a possible cause of up to 10% of cases of bipolar disorder. This gene is associated with a kinase enzyme called G protein receptor kinase 3, which appears to be involved in dopamine metabolism, and may provide a possible target for new drugs for bipolar disorder.[64]

A 2007 gene-linkage study by an international team coordinated by the NIMH has identified a number of genes as likely to be involved in the etiology of bipolar disorder, suggesting that bipolar disorder may be a polygenic disease. The researchers at NIMH have found a correlation between DGKH (diacylglycerol kinase eta) and bipolar disorder. The portion of the genome that encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway.[65]

In 2008, one study detected association of PPARD gene polymorphisms with bipolar disorder.[66]

Treatment

Bipolar disorder cannot be cured; instead, the emphasis of treatment is on effective management of acute episodes and prevention of further episodes by use of pharmacological and psychotherapeutic techniques.

Hospitalization may occur, especially with manic episodes. This can be voluntary or (if mental health legislation allows it) involuntary (called civil or involuntary commitment). Long-term inpatient stays are now less common due to deinstitutionalization, although can still occur.[67] Following (or in lieu of) a hospital admission, support services available can include drop-in centers, visits from members of a community mental health team or Assertive Community Treatment team, supported employment and patient-led support groups.[68]

Medication

The mainstay of treatment is a mood stabilizer medication; these comprise several unrelated compounds which have been shown to be effective in preventing relapses of manic, or in the one case, depressive episodes. The first known and "gold standard" mood stabilizer is lithium,[69] while almost as widely used is sodium valproate,[70] originally used as an anticonvulsant. Other anticonvulsants used in bipolar disorder include carbamazepine, reportedly more effective in rapid cycling bipolar disorder, and lamotrigine, which is the first anticonvulsant shown to be of benefit in bipolar depression.[71]

Treatment of the agitation in acute manic episodes has often required the use of antipsychotic medications, such as Quetiapine, Olanzapine and Chlorpromazine. More recently, Olanzapine and Quetiapine have been approved as effective monotherapy for the maintenance of bipolar disorder.[72] A head-to-head randomized control trial in 2005 has also shown olanzapine monotherapy to be as effective and safe as lithium in prophylaxis.[73]

The use of antidepressants in bipolar disorder has been debated, with some studies reporting a worse outcome with their use triggering manic, hypomanic or mixed episodes, especially if no mood stabiliser is used. However, most mood stabilizers are of limited effectiveness in depressive episodes.

Research

The following studies are ongoing, and are recruiting volunteers:

The Maudsley Bipolar Twin Study, based at the Institute of Psychiatry in London is conducting research about the genetic basis of bipolar disorder using twin methodology. Currently recruiting volunteers: identical and non-identical twins pairs, where either one or both twins has a diagnosis of bipolar I or II.

The Maudsley Bipolar eMonitoring Project, another research study based at the Institute of Psychiatry in London, is conducting novel research on electronic monitoring methodologies (electronic mood diaries and actigraphy) for tracking bipolar symptom fluctuations in Bipolar individuals who are interested in self-managing their condition. The study is currently recruiting volunteers from all over the world (see Remote eMonitoring)

Medical imaging

Researchers are using advanced brain imaging techniques to examine brain function and structure in people with bipolar disorder, particularly using the functional MRI and positron emission tomography. An important area of neuroimaging research focuses on identifying and characterizing networks of interconnected nerve cells in the brain, interactions among which form the basis for normal and abnormal behaviors. Researchers hypothesize that abnormalities in the structure and/or function of certain brain circuits could underlie bipolar and other mood disorders, and studies have found anatomical differences in areas such as the amygdala,[74] prefrontal cortex[75] and hippocampus.

Better understanding of the neural circuits involved in regulating mood states, and genetic factors such as the cadherin gene FAT linked to bipolar disorder,[76] may influence the development of new and better treatments, and may ultimately aid in early diagnosis and even a cure.

New treatments

In late 2003, researchers at McLean Hospital found tentative evidence of improvements in mood during echo-planar magnetic resonance spectroscopic imaging (EP-MRSI), and attempts are being made to develop this into a form which can be evaluated as a possible treatment.[77][78]

NIMH has initiated a large-scale study at 20 sites across the United States to determine the most effective treatment strategies for people with bipolar disorder. This study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), will follow patients and document their treatment outcome for 5–8 years. For more information, visit the Clinical Trials page of the NIMH Web site.[79]

Transcranial magnetic stimulation is another fairly new technique being studied.

Pharmaceutical research in the United States is extensive and ongoing, as seen at clinicaltrials.gov.

Prognosis

A good prognosis results from good treatment, which, in turn, results from an accurate diagnosis. Because bipolar disorder continues to have a high rate of both under-diagnosis and misdiagnosis, it is often difficult for individuals with the condition to receive timely and competent treatment.

Bipolar disorder can be a severely disabling medical condition. However, with appropriate treatment, many individuals with bipolar disorder can live full and satisfying lives. Persons with bipolar disorder are likely to have periods of normal or near normal functioning between episodes.

Ultimately one's prognosis depends on many factors, which are, in fact, under the individual's control: the right medicines; the right dose of each; a very informed patient; a good working relationship with a competent medical doctor; a competent, supportive and warm therapist; a supportive family or significant other; and a balanced lifestyle including a regulated stress level, regular exercise and regular sleep and wake times.

There are obviously other factors that lead to a good prognosis as well, such as being very aware of small changes in one's energy, mood, sleep and eating behaviors, as well as having a plan in conjunction with one's doctor for how to manage subtle changes that might indicate the beginning of a mood swing. Some people find that keeping a log of their moods can assist them in predicting changes.[80]

Recurrence

Even when on medication, some people may still experience weaker episodes, or have a complete manic or depressive episode. In fact, a recent study found bipolar disorder to be "characterized by a low rate of recovery, a high rate of recurrence, and poor interepisodic functioning." Worse, the study confirmed the seriousness of the disorder as "the standardized all-cause mortality ratio among patients with BD is increased approximately 2-fold." Bipolar disorder is currently regarded "as possibly the most costly category of mental disorders in the United States."[81]

The following behaviors can lead to depressive or manic recurrence:

* Discontinuing or lowering one's dose of medication, without consulting one's physician.
* Being under- or over-medicated. Generally, taking a lower dosage of a mood stabilizer can lead to relapse into mania. Taking a lower dosage of an antidepressant, may cause the patient to relapse into depression, while higher doses can cause destabilization into mixed-states or mania.
* An inconsistent sleep schedule can destabilize the illness. Too much sleep (possibly caused by medication) can lead to depression, while too little sleep can lead to mixed states or mania.
* Caffeine can cause destabilization of mood toward irritability, dysphoria, and mania. Anecdotal evidence seems to suggest that lower dosages of caffeine can have effects ranging from anti-depressant to mania-inducing.
* Inadequate stress management and poor lifestyle choices. If unmedicated, excessive stress can cause the individual to relapse. Medication raises the stress threshold somewhat, but too much stress still causes relapse.
* Often bipolar individuals are subject to self-medication, the most common drugs being alcohol, and marijuana. Sometimes they may also turn to hard drugs, which can cause the condition to worsen. Studies show that tobacco smoking induces a calming effect on most bipolar people, and a very high percentage suffering from the disorder smoke.[82]

Recurrence can be managed by the sufferer with the help of a close friend, based on the occurrence of idiosyncratic prodromal events.[83] This theorizes that a close friend could notice which moods, activities, behaviours, thinking processes, or thoughts typically occur at the outset of bipolar episodes. They can then take planned steps to slow or reverse the onset of illness, or take action to prevent the episode from being damaging.[84] These sensitivity triggers show some similarity to traits of a highly sensitive person.

Mortality

"Mortality studies have documented an increase in all-cause mortality in patients with BD. A newly established and rapidly growing database indicates that mortality due to chronic medical disorders (eg, cardiovascular disease) is the single largest cause of premature and excess deaths in BD. The standardized mortality ratio from suicide in BD is estimated to be approximately 18 to 25, further emphasizing the lethality of the disorder."[85]

Although many people with bipolar disorder who attempt suicide never actually complete it, the annual average suicide rate in males and females with diagnosed bipolar disorder (0.4%) is 10 to more than 20 times that in the general population.[86]

Individuals with bipolar disorder may become suicidal, especially during mixed states such as dysphoric mania and agitated depression.[87] Persons suffering from Bipolar II have high rates of suicide compared to persons suffering from other mental health conditions, including Major Depression. Major Depressive episodes are part of the Bipolar II experience, and there is evidence that sufferers of this disorder spend proportionally much more of their life in the depressive phase of the illness than their counterparts with Bipolar I Disorder (Akiskal & Kessler, 2007).

History

Varying moods and energy levels have been a part of the human experience since time immemorial. The words "melancholia" (an old word for depression) and "mania" have their etymologies in Ancient Greek. The word melancholia is derived from melas/μελας, meaning "black", and chole/χολη, meaning "bile" or "gall",[88] indicative of the term’s origins in pre-Hippocratic humoral theories. Within the humoral theories, mania was viewed as arising from an excess of yellow bile, or a mixture of black and yellow bile. The linguistic origins of mania, however, are not so clear-cut. Several etymologies are proposed by the Roman physician Caelius Aurelianus, including the Greek word ‘ania’, meaning to produce great mental anguish, and ‘manos’, meaning relaxed or loose, which would contextually approximate to an excessive relaxing of the mind or soul (Angst and Marneros 2001). There are at least five other candidates, and part of the confusion surrounding the exact etymology of the word mania is its varied usage in the pre-Hippocratic poetry and mythologies (Angst and Marneros 2001).

The idea of a relationship between mania and melancholia can be traced back to at least the 2nd century AD.[citation needed] Soranus of Ephesus (98–177 AD) described mania and melancholia as distinct diseases with separate etiologies;[89] however, he acknowledged that “many others consider melancholia a form of the disease of mania” (Cited in Mondimore 2005 p.49).

A clear understanding of bipolar disorder as a mental illness was recognized by early Chinese authors. The encyclopedist Gao Lian (c. 1583) describes the malady in his Eight Treatises on the Nurturing of Life (Ts'un-sheng pa-chien).[90]

The earliest written descriptions of a relationship between mania and melancholia are attributed to Aretaeus of Cappadocia. Aretaeus was an eclectic medical philosopher who lived in Alexandria somewhere between 30 and 150 AD (Roccatagliata 1986; Akiskal 1996). Aretaeus is recognized as having authored most of the surviving texts referring to a unified concept of manic-depressive illness, viewing both melancholia and mania as having a common origin in ‘black bile’ (Akiskal 1996; Marneros 2001).

Avicenna, a Persian physician and psychological thinker who wrote The Canon of Medicine in 1025, identified bipolar disorder as a manic depressive psychosis, which he clearly distinguished from other forms of madness (Junun) such as as mania, rabies, and schizophrenia (Junun Mufrit or severe madness).[91]
Emil Kraepelin (1856–1926) refined the concept of psychosis.
Emil Kraepelin (1856–1926) refined the concept of psychosis.

The basis of the current conceptualisation of manic-depressive illness can be traced back to the 1850s; on January 31, 1854, Jules Baillarger described to the French Imperial Academy of Medicine a biphasic mental illness causing recurrent oscillations between mania and depression, which he termed folie à double forme (‘dual-form insanity’). Two weeks later, on February 14, 1854, Jean-Pierre Falret presented a description to the Academy on what was essentially the same disorder, and designated folie circulaire (‘circular insanity’) by him.(Sedler 1983) The two bitterly disputed as to who had been the first to conceptualise the condition.

These concepts were developed by the German psychiatrist Emil Kraepelin (1856–1926), who, using Kahbaum concept of cyclothymia,[92] categorized and studied the natural course of untreated bipolar patients. He coined the term manic depressive psychosis, after noting that periods of acute illness, manic or depressive, were generally punctuated by relatively symptom-free intervals where the patient was able to function normally.[93]

After World War II, Dr. John Cade, an Australian psychiatrist, was investigating the effects of various compounds on veteran patients with manic depressive psychosis. In 1949, Cade discovered that lithium carbonate could be used as a successful treatment of manic depressive psychosis.[94] Because there was a fear that table salt substitutes could lead to toxicity or death, Cade's findings did not immediately lead to treatments. In the 1950s, U.S. hospitals began experimenting with lithium on their patients. By the mid-'60s, reports started appearing in the medical literature regarding lithium's effectiveness. The U.S. Food and Drug Administration did not approve of lithium's use until 1970.[95]

The term "manic-depressive reaction" appeared in the first American Psychiatric Association Diagnostic Manual in 1952, influenced by the legacy of Adolf Meyer who had introduced the paradigm illness as a reaction of biogenetic factors to psychological and social influences.[96] Subclassification of bipolar disorder was first proposed by German psychiatrist Karl Leonhard in 1957; he was also the first to introduce the terms bipolar (for those with mania) and unipolar (for those with depressive episodes only).[97]

In 1968, both the newly revised classification systems ICD-8 and DSM-II termed the condition "manic-depressive illness" as biological thinking came to the fore.[98]

The current nosology, bipolar disorder, became popular only recently, and some individuals prefer the older term because it provides a better description of a continually changing multi-dimensional illness.[citation needed]

Sociological and cultural aspects

Cultural references

Kay Redfield Jamison is a clinical psychologist and Professor of Psychiatry at the Johns Hopkins University School of Medicine, who profiled her own bipolar disorder in her 1995 memoir An Unquiet Mind and argued for a connection between bipolar disorder and artistic creativity in her 1993 book, Touched with Fire.

Several films have portrayed characters with traits strongly suggestive of the diagnosis which have been the subject of discussion by psychiatrists and film experts alike. The 1993 film Mr. Jones is a notable example, with Richard Gere playing a person who swings from a manic episode into a depressive phase and back again, spending time in a psychiatric hospital and displaying many of the features of the syndrome.[99] Allie Fox, the character played by Harrison Ford in the 1992 movie The Mosquito Coast, displays some features including recklessness, grandiosity, increased goal-directed activity and mood lability, as well as some paranoia.

In the NBC drama ER, series of episodes follow Maura Tierney's Abby Lockhart character's relation with her bipolar mother Maggie[101], and later her brother, who had been misdiagnosed with depression, but who in fact had inherrited BD from Maggie

brain cancer reference

2008-07-12T13:20:00.000-07:00

A brain tumour is any intracranial tumor created by abnormal and uncontrolled cell division, normally either in the brain itself (neurons, glial cells (astrocytes, oligodendrocytes, ependymal cells), lymphatic tissue, blood vessels), in the cranial nerves (myelin-producing Schwann cells), in the brain envelopes (meninges), skull, pituitary and pineal gland, or spread from cancers primarily located in other organs (metastatic tumors). Primary (true) brain tumors are commonly located in the posterior cranial fossa in children and in the anterior two-thirds of the cerebral hemispheres in adults, although they can affect any part of the brain. In the United States in the year 2005, it was estimated that there were 43,800 new cases of brain tumors (Central Brain Tumor Registry of the United States, Primary Brain Tumors in the United States, Statistical Report, 2005 - 2006),[1] which accounted for 1.4 percent of all cancers, 2.4 percent of all cancer deaths,[2] and 20–25 percent of pediatric cancers. Ultimately, it is estimated that there are 13,000 deaths/year as a result of brain tumors.

Classification

Primary tumors

Tumors occurring in the brain include: astrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma.
MRI image showing a low-grade brain glioma in a 28 year-old male. Image created on 2007-07-10.
MRI image showing a low-grade brain glioma in a 28 year-old male. Image created on 2007-07-10.

Most primary brain tumors originate from glia (gliomas) such as astrocytes (astrocytomas), oligodendrocytes (oligodendrogliomas), or ependymal cells (ependymoma). There are also mixed forms, with both an astrocytic and an oligodendroglial cell component. These are called mixed gliomas or oligoastrocytomas. Plus, mixed glio-neuronal tumors (tumors displaying a neuronal, as well as a glial component, e.g. gangliogliomas, disembryoplastic neuroepithelial tumors) and tumors originating from neuronal cells (e.g. gangliocytoma, central gangliocytoma) can also be encountered.

Other varieties of primary brain tumors include: primitive neuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosis cerebri, astroblastoma), etc.

From a histological perspective, astrocytomas, oligondedrogliomas, oligoastrocytomas, and teratomas may be benign or malignant. Glioblastoma multiforme represents the most aggressive variety of malignant glioma. At the opposite end of the spectrum, there are so-called pilocytic astrocytomas, a distinct variety of astrocytic tumors. The majority of them are located in the posterior cranial fossa, affect mainly children and young adults, and have a clinically favorable course and prognosis. Teratomas and other germ cell tumors also may have a favorable prognosis, although they have the capacity to grow very large.

Another type of primary intracranial tumor is primary cerebral lymphoma, also known as primary CNS lymphoma, which is a type of non-Hodgkin's lymphoma that is much more prevalent in those with severe immunosuppression, e.g. AIDS.

In contrast to other types of cancer, primary brain tumors rarely metastasize, and in this rare event, the tumor cells spread within the skull and spinal canal through the cerebrospinal fluid, rather than via bloodstream to other organs.

There are various classification systems currently in use for primary brain tumors, the most common being the World Health Organization (WHO) brain tumor classification, introduced in 1993.

Secondary tumors and non-tumor lesions

Secondary or metastatic brain tumors originate from malignant tumors (cancers) located primarily in other organs. Their incidence is higher than that of primary brain tumors. The most frequent types of metastatic brain tumors originate in the lung, skin (malignant melanoma), kidney (hypernephroma), breast (breast carcinoma), and colon (colon carcinoma). These tumor cells reach the brain via the blood-stream.

Some non-tumoral masses and lesions can mimic tumors of the central nervous system. These include tuberculosis of the brain, cerebral abscess (commonly in toxoplasmosis), and hamartomas (for example, in tuberous sclerosis and von Recklinghausen neurofibromatosis).

WHO Classification of Tumors of the Central Nervous System

The website http://www.brainlife.org describes the various WHO (World Health Organization) classifications of brain tumors, from 1979 to 2007. The most recent WHO classification of brain tumors is on page http://www.brainlife.org/who/2007_classification.htm.

Brain tumors in infants and children

In 2000 approximately 2.76 children per 100,000 were affected by a CNS tumor in the United States. This rate has been increasing and by 2005 was 3.0 children per 100,000. This is approximately 2,500-3,000 pediatric brain tumors occurring each year in the US. The tumor incidence is increasing by about 2.7% per year. The CNS Cancer survival rate in children is approximately 60%.[4] However, this rate varies with the age of onset (younger has higher mortality) and cancer type.

In children under 2, about 70% of brain tumors are medulloblastoma, ependymoma, and low-grade glioma. Less commonly, and seen usually in infants, are teratoma and atypical teratoid rhabdoid tumor.[5]

Signs and symptoms

Symptoms of brain tumors may depend on two factors: tumor size (volume) and tumor location. The time point of symptom onset in the course of disease correlates in many cases with the nature of the tumor ("benign", i.e. slow-growing/late symptom onset, or malignant, fast growing/early symptom onset).

Many low-grade (benign) tumors can remain asymptomatic (symptom-free) for years and they may accidentally be discovered by imaging exams for unrelated reasons (such as a minor trauma).

New onset of epilepsy[6] is a frequent reason for seeking medical attention in brain tumor cases.

Large tumors or tumors with extensive perifocal swelling edema inevitably lead to elevated intracranial pressure (intracranial hypertension), which translates clinically into headaches, vomiting (sometimes without nausea), altered state of consciousness (somnolence, coma), dilatation of the pupil on the side of the lesion (anisocoria), papilledema (prominent optic disc at the funduscopic examination). However, even small tumors obstructing the passage of cerebrospinal fluid (CSF) may cause early signs of increased intracranial pressure. Increased intracranial pressure may result in herniation (i.e. displacement) of certain parts of the brain, such as the cerebellar tonsils or the temporal uncus, resulting in lethal brainstem compression. In young children, elevated intracranial pressure may cause an increase in the diameter of the skull and bulging of the fontanelles.

Depending on the tumor location and the damage it may have caused to surrounding brain structures, either through compression or infiltration, any type of focal neurologic symptoms may occur, such as cognitive and behavioral impairment, personality changes, hemiparesis, (hemi) hypesthesia, aphasia, ataxia, visual field impairment, facial paralysis, double vision, tremor etc. These symptoms are not specific for brain tumors - they may be caused by a large variety of neurologic conditions (e.g. stroke, traumatic brain injury). What counts, however, is the location of the lesion and the functional systems (e.g. motor, sensory, visual, etc.) it affects.

A bilateral temporal visual field defect (bitemporal hemianopia—due to compression of the optic chiasm), often associated with endocrine disfunction—either hypopituitarism or hyperproduction of pituitary hormones and hyperprolactinemia is suggestive of a pituitary tumor.

Diagnosis

Although there is no specific clinical symptom or sign for brain tumors, slowly progressive focal neurologic signs and signs of elevated intracranial pressure, as well as epilepsy in a patient with a negative history for epilepsy should raise red flags. However, a sudden onset of symptoms, such as an epileptic seizure in a patient with no prior history of epilepsy, sudden intracranial hypertension (this may be due to bleeding within the tumour, brain swelling or obstruction of cerebrospinal fluid's passage) is also possible.

Glioblastoma multiforme and anaplastic astrocytoma have been associated in case reports on Pubmed with the genetic acute hepatic porphyrias, including positive testing associated with drug refractory seizures. Unexplained complications associated with drug treatments with these tumors should alert physicians to an undiagnosed neurological porphyria.

Symptoms include phantom odors and tastes. Often, in the case of metastatic tumors, the smell of vulcanized rubber is prevalent.[citation needed]

Imaging plays a central role in the diagnosis of brain tumors. Early imaging methods—invasive and sometimes dangerous—such as pneumoencephalography and cerebral angiography, have been abandoned in recent times in favor of non-invasive, high-resolution modalities, such as computed tomography (CT) and especially magnetic resonance imaging (MRI). Benign brain tumors often show up as hypodense (darker than brain tissue) mass lesions on cranial CT-scans. On MRI, they appear either hypo- (darker than brain tissue) or isointense (same intensity as brain tissue) on T1-weighted scans, or hyperintense (brighter than brain tissue) on T2-weighted MRI. Perifocal edema also appears hyperintense on T2-weighted MRI. Contrast agent uptake, sometimes in characteristic patterns, can be demonstrated on either CT or MRI-scans in most malignant primary and metastatic brain tumors. This is due to the fact that these tumors disrupt the normal functioning of the blood-brain barrier and lead to an increase in its permeability.

Electrophysiological exams, such as electroencephalography (EEG) play a marginal role in the diagnosis of brain tumors.

The definitive diagnosis of brain tumor can only be confirmed by histological examination of tumor tissue samples obtained either by means of brain biopsy or open surgery. The histologic examination is essential for determining the appropriate treatment and the correct prognosis. This examination, performed by a pathologist, typically has three stages: interoperative examination of fresh tissue, preliminary microscopic examination of prepared tissues, and followup examination of prepared tissues after immunohistochemical staining or genetic analysis.

Treatment and prognosis

Many meningiomas, with the exception of some tumors located at the skull base, can be successfully removed surgically. In more difficult cases, stereotactic radiosurgery, such as Gamma Knife radiosurgery, remains a viable option.

Most pituitary adenomas can be removed surgically, often using a minimally invasive approach through the nasal cavity and skull base (trans-nasal, trans-sphenoidal approach). Large pituitary adenomas require a craniotomy (opening of the skull) for their removal. Radiotherapy, including stereotactic approaches, is reserved for the inoperable cases.

Although there is no generally accepted therapeutic management for primary brain tumors, a surgical attempt at tumor removal or at least cytoreduction (that is, removal of as much tumor as possible, in order to reduce the number of tumor cells available for proliferation) is considered in most cases.[7] However, due to the infiltrative nature of these lesions, tumor recurrence, even following an apparently complete surgical removal, is not uncommon. Postoperative radiotherapy and chemotherapy are integral parts of the therapeutic standard for malignant tumors. Radiotherapy may also be administered in cases of "low-grade" gliomas, when a significant tumor burden reduction could not be achieved surgically.

Survival rates in primary brain tumors depend on the type of tumor, age, functional status of the patient, the extent of surgical tumor removal, to mention just a few factors.[8]

UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis. They are the only institution in the United States that shows how brain tumor patients are performing on current therapies. They also show a listing of chemotherapy agents used to treat High Grade Giloma tumors.

Patients with benign gliomas may survive for many years,[9][10] while survival in most cases of glioblastoma multiforme is limited to a few months after diagnosis if treatment is ignored.

The main treatment option for single metastatic tumors is surgical removal, followed by radiotherapy and/or chemotherapy. Multiple metastatic tumors are generally treated with radiotherapy and chemotherapy. Stereotactic radiosurgery, such as Gamma Knife radiosurgery, remains a viable option. However, the prognosis in such cases is determined by the primary tumor, and it is generally poor.

A shunt operation is used not as a cure but to relieve the symptoms.[1] The hydrocephalus caused by the blocking drainage of the cerebrospinal fluid can be removed with this operation.

Research to treatment with the Vesicular stomatitis virus

In 2000, researchers at the University of Ottawa, led by John Bell M.D., have discovered that the Vesicular stomatitis virus, or VSV, can infect and kill cancer cells, without affecting healthy cells if coadministered with interferon. [11]

The initial discovery of the virus' oncolytic properties were limited to only a few types of cancer. Several independent studies have indentified many more types susceptible to the virus, including glioblastoma multiforme cancer cells, which account for the majority of brain tumors.

In 2008, researchers at Yale University, led by Dr. Anthony van den Pol, artificially engineered strains of VSV that were less cytotoxic to normal cells. This advance allows administration of the virus without coadministration with interferon. Consequently administration of the virus can be given intravenously or through the olfactory nerve. In the research, a human brain tumor was implanted into mice brains. The VSV was injected via their tails and within 3 days all tumor cells were either dead or dying.

Research on virus treatment like this has been conducted for some years, but no other viruses have been shown to be as efficient or specific as the VSV mutant strains. Future research will focus on the risks of this treatment, before it can be applied to humans.

breast cancer

2008-07-12T13:15:00.000-07:00

Breast cancer is a cancer that starts in the cells of the breast in men and women.[1] Worldwide, breast cancer is the second most common type of cancer after lung cancer (10.4% of all cancer incidence, both sexes counted)[2] and the fifth most common cause of cancer death.[3] Worldwide, breast cancer is by far the most common cancer amongst women, with an incidence rate more than twice that of colorectal cancer and cervical cancer and about three times that of lung cancer. However breast cancer mortality worldwide is just 25% greater than that of lung cancer in women.[2] In 2005, breast cancer caused 502,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).[3] The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world.

The incidence of breast cancer varies greatly around the world, being lower in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized incidence rates per 100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-Eastern Asia, 26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49; Southern Europe, 56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90.[6]

Women in the United States have the highest incidence rates of breast cancer in the world; 141 among white women and 122 among African American women.[7][8] Among women in the US, breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer). Women in the US have a 1 in 8 (12.5%) lifetime chance of developing invasive breast cancer and a 1 in 35 (3%) chance of breast cancer causing their death.[8] In 2007, breast cancer was expected to cause 40,910 deaths in the US (7% of cancer deaths; almost 2% of all deaths).

In the US, both incidence and death rates for breast cancer have been declining in the last few years. Nevertheless, a US study conducted in 2005 by the Society for Women's Health Research indicated that breast cancer remains the most feared disease,[11] even though heart disease is a much more common cause of death among women.

Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males.Incidences of breast cancer in men are approximately 100 times less common than in women, but men with breast cancer are considered to have the same statistical survival rates as women.

Breast cancers are described along four different classification schemes, or groups, each based on different criteria and serving a different purpose:

* Pathology - A pathologist will categorize each tumor based on its histological (microscopic anatomy) appearance and other criteria. The most common pathologic types of breast cancer are invasive ductal carcinoma, malignant cancer in the breast's ducts, and invasive lobular carcinoma, malignant cancer in the breast's lobules.
* Grade of tumor - The histological grade of a tumor is determined by a pathologist under a microscope. A well-differentiated (low grade) tumor resembles normal tissue. A poorly differentiated (high grade) tumor is composed of disorganized cells and, therefore, does not look like normal tissue. Moderately differentiated (intermediate grade) tumors are somewhere in between.
* Protein & gene expression status - Currently, all breast cancers should be tested for expression, or detectable effect, of the estrogen receptor (ER), progesterone receptor (PR) and HER2/neu proteins. These tests are usually done by immunohistochemistry and are presented in a pathologist's report. The profile of expression of a given tumor helps predict its prognosis, or outlook, and helps an oncologist choose the most appropriate treatment. More genes and/or proteins may be tested in the future.
* Stage of a tumor - The currently accepted staging scheme for breast cancer is the TNM classification.

There are five tumor classification values (Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast (e.g. to the skin of the breast, to the muscle or to the rib cage underneath):

* Tx - Primary tumor cannot be assessed.
* T0 - No evidence of primary tumor.
* Tis - Carcinoma in situ.
o Tis(DCIS) - Intraductal Carcinoma in situ.
o Tis(LCIS) - Lobular Carcinoma in situ.
o Tis(Paget's) - Paget's disease of the nipple with no tumor.
* T1 - Tumor 2cm or less in its greatest dimension.
o T1mic - Microinvasion 0.1cm or less in greatest dimension.
o T1a - Tumor more then 0.1cm but not more than 0.5cm in its greatest dimension.
o T1b - Tumor more than 0.5cm but not more than 1.0cm in its greatest dimension.
o T1c - Tumor more than 1.0cm but not more than 2.0cm in its greatest dimension.
* T2 - Tumor more than 2.0cm but not more than 5.0cm in its greatest dimension.
* T3 - Tumor more than 5cm in its greatest dimension.
* T4 - Tumor of any size with direct extension to (a) chest wall or (b) skin as described below:
o T4a - Extension to chest wall.
o T4b - Edema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules confined to the same breast.
o T4c - Both T4a and T4b.
o T4d - Inflammatory breast cancer.

Lymph Node - There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size and location of breast cancer cell deposits in lymph nodes.

* Nx - regional lymph nodes cannot be assessed. Perhaps due to previous removal.
* N0 - no regional lymph node metastasis.
* N1 - metastasis to movable regional axillary lymph nodes on the same side as the affected breast.
* N2 - metastasis to fixed regional axillary lymph nodes, or metastasis to the internal mammary lymph nodes, on the same side as the affected breast.
* N3 - metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes.

Metastases - There are two metastatic classification values (M0 or M1) which depend on the presence or absence of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung).

Pathologic types

Note: The following table includes benign tumours (non cancers) as well as malignant tumours (cancers)

The latest (2003) World Health Organization (WHO) classification of tumors of the breast[16] recommends the following pathological types:

Invasive breast carcinomas

* Invasive ductal carcinoma
o Most are "not otherwise specified"
o The remainder are given subtypes:
+ Mixed type carcinoma
+ Pleomorphic carcinoma
+ Carcinoma with osteoclastic giant cells
+ Carcinoma with choriocarcinomatous features
+ Carcinoma with melanotic features
* Invasive lobular carcinoma
* Tubular carcinoma
* Invasive cribriform carcinoma
* Medullary carcinoma
* Mucinous carcinoma and other tumours with abundant mucin
o Mucinous carcinoma
o Cystadenocarcinoma and columnar cell mucinous carcinoma
o Signet ring cell carcinoma
* Neuroendocrine tumours
o Solid neuroendocrine carcinoma (carcinoid of the breast)
o Atypical carcinoid tumour
o Small cell / oat cell carcinoma
o Large cell neuroendocrine carcioma
* Invasive papillary carcinoma
* Invasive micropapillary carcinoma
* Apocrine carcinoma
* Metaplastic carcinomas
o Pure epithelial metaplastic carciomas
+ Squamous cell carcinoma
+ Adenocarcinoma with spindle cell metaplasia
+ Adenosquamous carcinoma
+ Mucoepidermoid carcinoma
o Mixed epithelial/mesenchymal metaplastic carcinomas
* Lipid-rich carcinoma
* Secretory carcinoma
* Oncocytic carcinoma
* Adenoid cystic carcinoma
* Acinic cell carcinoma
* Glycogen-rich clear cell carcinoma
* Sebaceous carcinoma
* Inflammatory carcinoma
* Bilateral breast carcinoma

Mesenchymal tumors (including sarcoma)

* Haemangioma
* Angiomatosis
* Haemangiopericytoma
* Pseudoangiomatous stromal hyperplasia
* Myofibroblastoma
* Fibromatosis (aggressive)
* Inflammatory myofibroblastic tumour
* Lipoma
o Angiolipoma
* Granular cell tumour
* Neurofibroma
* Schwannoma
* Angiosarcoma
* Liposarcoma
* Rhabdomyosarcoma
* Osteosarcoma
* Leiomyoma
* Leiomysarcoma

Precursor lesions

* Lobular neoplasia
o lobular carcinoma in situ
* Intraductal proliferative lesions
o Usual ductal hyperplasia
o Flat epithelial hyperplasia
o Atypical ductal hyperplasia
o Ductal carcinoma in situ
* Microinvasive carcinoma
* Intraductal papillary neoplasms
o Central papilloma
o Peripheral papilloma
o Atypical papilloma
o Intraductal papillary carcinoma
o Intracystic papillary carcinoma

Benign epithelial lesions

* Adenosis, includin variants
o Sclerosing adenosis
o Apocrine adenosis
o Blunt duct adenosis
o Microglandular adenosis
o Adenomyoepithelial adenosis
* Radial scar / complex sclerosing lesion
* Adenomas
o Tubular adenoma
o Lactating adenoma
o Apocrine adenoma
o Pleomorphic adenoma
o Ductal adenoma

Myoepithelial lesions

* Myoepitheliosis
* Adenomyoepithelial adenosis
* Adenomyoepithelioma
* Malignant myoepithelioma

Fibroepithelial tumours

* Fibroadenoma
* Phyllodes tumour
o Benign
o Borderline
o Malignant
* Periductal stromal sarcoma, low grade
* Mammary hamartoma

Tumours of the nipple

* Nipple adenoma
* Syringomatous adenoma
* Paget's disease of the nipple

Malignant lymphoma

Metastatic tumours

Tumours of the male breast

* Gynecomastia
* Carcinoma
o In situ
o Invasive

The classifications above show that breast cancer is usually, but not always, classified by its histological appearance. Rare variants are defined on the basis of physical exam findings. For example, Inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinomas by the inflamed appearance of the affected breast.[17] In the future, some pathologic classifications may be changed. For example, a subset of ductal carcinomas may be re-named basal-like carcinoma (part of the "triple-negative" tumors).[citation needed]

Signs and symptoms

The first symptom, or subjective sign, of breast cancer is typically a lump that feels different than the surrounding breast tissue. According to the Merck Manual, greater than 80% of breast cancer cases are discovered as a lump by the woman herself.[18] According to the American Cancer Society (ACS), the first medical sign, or objective indication of breast cancer as detected by a physician, is discovered by mammogram.[9] Lumps found in lymph nodes located in the armpits[18] and/or collarbone[citation needed] can also indicate breast cancer.

Indications of breast cancer other than a lump may include changes in breast size or shape, skin dimpling, nipple inversion, or spontaneous single-nipple discharge. Pain is an unreliable tool in determining the presence of breast cancer, but may be indicative of other breast-related health issues such as mastodynia.[9][18][19]

When breast cancer cells invade the dermal lymphatics, small lymph vessels in the skin of the breast, its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer (IBC). Symptoms of inflammatory breast cancer include pain, swelling, warmth and redness throughout the breast, as well as an orange peel texture to the skin referred to as peau d'orange.[18]

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes such as redness and mild flaking of the nipple skin. As Paget's advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget's also have a lump in the breast.[20]

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. More common sites of metastasis include bone, liver, lung and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.[21]

Most symptoms of breast disorder do not turn out to represent underlying breast cancer. Benign breast diseases such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms. The appearance of a new symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.[22]

Epidemiology and etiology

Epidemiological risk factors for a disease can provide important clues as to the etiology, or cause, of a disease. The first case-controlled study on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.

Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. Some of these factors include:

1. Lesions to DNA such as genetic mutations. Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.[25] Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation in causing genetic mutations.[citation needed]
2. Failure of immune surveillance, a theory in which the immune system removes malignant cells throughout one's life.[26]
3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. For example, tumors can induce blood vessel growth (angiogenesis) by secreting various growth factors further facilitating cancer growth.
4. Inherited defects in DNA repair genes, such as BRCA1, BRCA2[27] and p53.[citation needed]

Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is often unknowable. In other words, epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. The primary risk factors that have been identified are sex,[28] age,[29] childbearing, hormones,[30] a high-fat diet,[31] alcohol intake,[32][33] obesity,[34] and environmental factors such as tobacco use, radiation[27] and shiftwork.[35]

No etiology is known for 95% of breast cancer cases, while approximately 5% of new breast cancers are attributable to hereditary syndromes.[36] In particular, carriers of the breast cancer susceptibility genes, BRCA1 and BRCA2, are at a 30-40% increased risk for breast and ovarian cancer, depending on in which portion of the protein the mutation occurs.[37]

Prevention

Lower age of first childbirth (less than 24 years maternal age), having more children (about 7% lowered risk per child), and breastfeeding (4% per breastfeeding year, with an average relative risk around 0.7[38][39]) have all been correlated to lowered breast cancer risk in large studies.[40] In addition, exercising three times a week for one hour each has been found to lower breast cancer by up to 40%.[citation needed]

Phytoestrogens and soy

Phytoestrogens such as found in soybeans have been extensively studied in animal and human in-vitro and epidemiological studies. The literature support the following conclusions:

1. Plant estrogen intake, such as from soy products, in early adolescence may protect against breast cancer later in life.[41]
2. Plant estrogen intake later in life is not likely to influence breast cancer incidence either positively or negatively.[42]
Avoiding exposure to secondhand tobacco smoke

Breathing secondhand smoke increases breast cancer risk by 70% in younger, primarily pre-menopausal women. The California Environmental Protection Agency has concluded that passive smoking causes breast cancer[51] and the US Surgeon General[52] has concluded that the evidence is "suggestive," one step below causal. There is some evidence that exposure to tobacco smoke is most problematic between puberty and first childbirth. The reason that breast tissue appears most sensitive to chemical carcinogens in this phase is that breast cells are not fully differentiated until lactation.[53]

Oophorectomy and mastectomy

Prophylactic oophorectomy (removal of ovaries), in high-risk individuals, when child-bearing is complete, reduces the risk of developing breast cancer by 60%, as well as reducing the risk of developing ovarian cancer by 96%.[54]

Medications

Hormonal therapy has been used for chemoprevention in individuals at high risk for breast cancer. In 2002, a clinical practice guideline by the US Preventive Services Task Force (USPSTF) recommended that "clinicians discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention" with a grade B recommendation.[55][verification needed][56][57]

Selective estrogen receptor modulators (SERMs)

The guidelines[clarify] were based on studies of SERMs from the MORE, BCPT P-1, and Italian trials. In the MORE trial, the relative risk reduction for raloxifene was 76%.[58] The P-1 preventative study demonstrated that tamoxifen can prevent breast cancer in high-risk individuals. The relative risk reduction was up to 50% of new breast cancers, though the cancers prevented were more likely estrogen-receptor positive (this is analogous to the effect of finasteride on the prevention of prostate cancer, in which only low-grade prostate cancers were prevented).[59][60] The Italian trial showed benefit from tamoxifen.[61]

Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen.[62] In 2006, the NSABP STAR trial demonstrated that raloxifene had equal efficacy in preventing breast cancer compared with tamoxifen, but that there were fewer side effects with raloxifene.[63] The RUTH Trial concluded that "benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke".[64] On September 14, 2007, the US Food and Drug Administration approved raloxifene (Evista) to prevent invasive breast cancer in postmenopausal women.[65]

Screening

Breast cancer screening is an attempt to find unsuspected cancers. The most common screening methods are self and clinical breast exams, x-ray mammography, and breast Magnetic resonance imaging (MRI)

X-ray mammography

Mammography is still the modality of choice for screening of early breast cancer, since it is relatively fast, reasonably accurate, and widely available in developed countries.

Due to the high incidence of breast cancer among older women, screening is now recommended in many countries. Recommended screening methods include breast self-examination and mammography. Mammography has been estimated to reduce breast cancer-related mortality by 20-30%.[66] Routine (annual) mammography of women older than age 40 or 50 is recommended by numerous organizations as a screening method to diagnose early breast cancer and has demonstrated a protective effect in multiple clinical trials.[67] The evidence in favor of mammographic screening comes from eight randomized clinical trials from the 1960s through 1980s. Many of these trials have been criticised for methodological errors, and the results were summarized in a review article published in 1993.[68]

Improvements in mortality due to screening are hard to measure; similar difficulty exists in measuring the impact of Pap smear testing on cervical cancer, though worldwide, the impact of that test is likely enormous. Nationwide mortality due to cancer before and after the institution of a screening test is a surrogate indicator about the effectiveness of screening, and results of mammography are favorable.
Normal (left) versus cancerous (right) mammography image.
Normal (left) versus cancerous (right) mammography image.

The U.S. National Cancer Institute recommends screening mammography every one to two years beginning at age 40.[69] In the UK, women are invited for screening once every three years beginning at age 50. Women with one or more first-degree relatives (mother, sister, daughter) with premenopausal breast cancer should begin screening at an earlier age. It is usually suggested to start screening at an age that is 10 years less than the age at which the relative was diagnosed with breast cancer.

A clinical practice guideline by the US Preventive Services Task Force recommended "screening mammography, with or without clinical breast examination (CBE), every 1 to 2 years for women aged 40 and older."[70] The Task Force gave a grade B recommendation.[55][verification needed]

In 2005, 67.9% of all U.S. women age 40–64 had a mammogram in the past two years (74.5% of women with private health insurance, 56.1% of women with Medicaid insurance, 38.1% of currently uninsured women, and 32.9% of women uninsured for > 12 months).[71]

Criticisms of screening mammography

Several scientific groups however have expressed concern about the public's perceptions of the benefits of breast screening.[72] In 2001, a controversial review published in The Lancet claimed that "there is no reliable evidence that screening for breast cancer reduces mortality".[73][74]The Cochrane Collaboration concluded, "for every 2000 women invited for screening throughout 10 years, one will have her life prolonged. In addition, 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. It is thus not clear whether screening does more good than harm."[75]

False positives are a major problem of mammographic breast cancer screening. Data reported in the UK Million Woman Study indicates that if 134 mammograms are performed, 20 women will be called back for suspicious findings, and four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the U.S. than in the UK.[76] The contribution of mammography to the early diagnosis of cancer is controversial, and for those found with benign lesions, mammography can create a high psychological and financial cost.

Mammography in women less than 50 years old

Part of the difficulty in interpreting mammograms in younger women stems from the problem of breast density. Radiographically, a dense breast has a preponderance of glandular tissue, and younger age or estrogen hormone replacement therapy contribute to mammographic breast density. After menopause, the breast glandular tissue gradually is replaced by fatty tissue, making mammographic interpretation much more accurate. Some authors speculate that part of the contribution of estrogen hormone replacement therapy to breast cancer mortality arises from the issue of increased mammographic breast density. Breast density is an independent adverse prognostic factor on breast cancer prognosis.

A systematic review by the American College of Physicians concluded "Although few women 50 years of age or older have risks from mammography that outweigh the benefits, the evidence suggests that more women 40 to 49 years of age have such risks".[77].

A report released November 27, 2007 by the Journal of the National Cancer Institute showed that the formula doctors use to calculate a woman's risk of breast cancer underestimates the danger for black women most of the time and especially for those age 50 and older — the age when they are most likely to benefit from screening tests and protective drugs, according to the first major reassessment of the widely used tool.[78]

Enhancements to mammography

CAD is especially established in US and the Netherlands. It is used in addition to the human evaluation of the diagnostician.

Breast MRI

Magnetic resonance imaging (MRI) has been shown to detect cancers not visible on mammograms, but has long been regarded to have disadvantages. For example, although it is 27-36% more sensitive, it is less specific than mammography.[79] As a result, MRI studies will have more false positives (up to 5%), which may have undesirable financial and psychological costs. It is also a relatively expensive procedure, and one which requires the intravenous injection of a chemical agent (from which there are side effects, potentially serious in a small number of people) to be effective. Proposed indications for using MRI for screening include:[80]

* Strong family history of breast cancer
* Patients with BRCA-1 or BRCA-2 tumour suppressor gene mutations
* Evaluation of women with breast implants
* History of previous lumpectomy or breast biopsy surgeries
* Axillary metastasis with an unknown primary tumor
* Very dense or scarred breast tissue

However, two studies published in 2007 demonstrated the strengths of MRI-based screening:

* In March 2007, an article published in the New England Journal of Medicine demonstrated that in 3.1% of patients with breast cancer, whose contralateral breast was clinically and mammographically tumor-free, MRI could detect breast cancer. Sensitivity for detection of breast cancer in this study was 91%, specificity 88%.[81]

* In August 2007, an article published in The Lancet compared MRI breast cancer screening to conventional mammographic screening in 7,319 women. MRI screening was highly more sensitive (97% in the MRI group vs. 56% in the mammography group) in recognizing early high-grade Ductal Carcinoma in situ (DCIS), the most important precursor of invasive carcinoma. Despite the high sensitivity, MRI screening had a positive predictive value of 52%, which is totally accepted for cancer screening tests.[82] The author of a comment published in the same issue of The Lancet concludes that "MRI outperforms mammography in tumour detection and diagnosis."[83]

Breast self-exam

Breast self-examination (BSE) was widely discussed in the 1990s as a useful modality for detecting breast cancer at an earlier stage of presentation. A large clinical trial in China reduced enthusiasm for breast self-exam. In the trial, reported in the Journal of the National Cancer Institute first in 1997 and updated in 2002, 132,979 female Chinese factory workers were taught by nurses at their factories to perform monthly breast self-exam, while 133,085 other workers were not taught self-exam. The women taught self-exam tended to detect more breast nodules, but their breast cancer mortality rate was no different from that of women in the control group. In other words, women taught breast self-exam were mostly likely to detect benign breast disease, but were just as likely to die of breast cancer.[84] In 2003, the American Cancer Society relegated structured BSE to an 'optional' method of detecting breast cancer, citing self awareness as more important than structured self exams based on recent research.[27]

Genetic testing

A clinical practice guideline by the US Preventive Services Task Force :[70]

* "recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2)" The Task Force gave a grade D recommendation.[verification needed]
* "recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing." The Task Force gave a grade B recommendation.[55][verification needed]

The Task Force noted that about 2% of women have family histories that indicate increased risk as defined by:

* For non–Ashkenazi Jewish women, any of the following:
o "2 first-degree relatives with breast cancer, 1 of whom received the diagnosis at age 50 years or younger"
o "3 or more first- or second-degree relatives with breast cancer regardless of age at diagnosis"
o "both breast and ovarian cancer among first- and second- degree relatives"
o "a first-degree relative with bilateral breast cancer"
o "a combination of 2 or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis"
o "a first- or second-degree relative with both breast and ovarian cancer at any age"
o "a history of breast cancer in a male relative."
* "For women of Ashkenazi Jewish heritage, an increased-risk family history includes any first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer

Breast cancer is staged according to the TNM system, updated in the AJCC Staging Manual, now on its sixth edition. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice. The information for staging is as follows:

TX: Primary tumor cannot be assessed. T0: No evidence of tumor. Tis: Carcinoma in situ, no invasion T1: Tumor is 2 cm or less T2: Tumor is more than 2 cm but not more than 5 cm T3: Tumor is more than 5 cm T4: Tumor of any size growing into the chest wall or skin, or inflammatory breast cancer

NX: Nearby lymph nodes cannot be assessed N0: Cancer has not spread to regional lymph nodes. N1: Cancer has spread to 1 to 3 axillary or one internal mammary lymph node N2: Cancer has spread to 4 to 9 axillary lymph nodes or multiple internal mammary lymph nodes N3: One of the following applies:

Cancer has spread to 10 or more axillary lymph nodes, or Cancer has spread to the lymph nodes under the clavicle (collar bone), or Cancer has spread to the lymph nodes above the clavicle, or Cancer involves axillary lymph nodes and has enlarged the internal mammary lymph nodes, or Cancer involves 4 or more axillary lymph nodes, and tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node biopsy.

MX: Presence of distant spread (metastasis) cannot be assessed. M0: No distant spread. M1: Spread to distant organs, not including the supraclavicular lymph node, has occurred

Summary of stages:

* Stage 0 - Carcinoma in situ
* Stage I - Tumor (T) does not involve axillary lymph nodes (N).
* Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive.
* Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary nodes).
* Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes
* Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10 axillary N
* Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular N, or internal mammary N.
* Stage IV – Distant metastasis (M)

Approximately 90% of new breast cancer cases in the US will be classified as a "Stage I" cases, due to early detection and prevention techniques. Early-stage treatment options are different from late-stage options.[85] Breast lesions are examined for certain markers, notably sex steroid hormone receptors. About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+).[86] Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.

Human epidermal growth factor two (HER2)

The breast cancer is also usually tested for the presence of human epidermal growth factor receptor 2, a protein also known as HER2, neu or erbB2. HER2 is a cell-surface protein involved in cell development. In normal cells, HER2 controls aspects of cell growth and division. When activated in cancer cells, HER2 accelerates tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients may be candidates for the drug trastuzumab, both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.[87]

Treatment

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.[88]

Interstitial laser thermotherapy (ILT) is an innovative method of treating breast cancer in a minimally invasive manner and without the need for surgical removal, and with the absence of any adverse effect on the health and survival of the patient during intermediate followup [89].

Radiation treatment is also used to help destroy cancer cells that may linger after surgery. Radiation can reduce the risk of recurrence by 50-66% (1/2 - 2/3rds reduction of risk) when delivered in the correct dose. [90]

Early-stage research

In mice, flaxseed oil reduced the growth and metastasis of breast cancer tumors that were cultured in the laboratory and implanted in mice. In humans, flaxseed oil reduced markers that are associated with cancer growth.

Psychological aspects of diagnosis and treatment

The emotional impact of cancer diagnosis, symptoms, treatment, and related issues can be severe. Most larger hospitals are associated with cancer support groups which can help patients cope with the many issues that come up in a supportive environment with other people with experience with similar issues. Online cancer support groups are also very beneficial to cancer patients, especially in dealing with uncertainty and body-image problems inherent in cancer treatment.

Not all breast cancer patients experience their illness in the same manner. Factors such as age can have a significant impact on the way a patient copes with a breast cancer diagnosis. For example, a recent study conducted by researchers at the College of Public Health of the University of Georgia showed that older women may face a more difficult recovery from breast cancer than their younger counterparts.[95] As the incidence of breast cancer in women over 50 rises and survival rates increase, breast cancer is increasingly becoming a geriatric issue that warrants both further research and the expansion of specialized cancer support services tailored for specific age groups.

Metastasis

Most people understand breast cancer as something that happens in the breast. However it can metastasize (spread) via lymphatics to nearby lymph nodes, usually those under the arm. That is why surgery for breast cancer always involves some type of surgery for the glands under the arm — either axillary clearance, sampling, or sentinel node biopsy.

Breast cancer can also spread to other parts of the body via blood vessels or the lymphatic system. So it can spread to the lungs, pleura (the lining of the lungs), liver, brain, and most commonly to the bones.[102] Seventy percent of the time that breast cancer spreads to other locations, it spreads to bone, especially the vertebrae and the long bones of the arms, legs, and ribs. Breast cancer cells "set up house" in the bones and form tumors. Usually when breast cancer spreads to bone, it eats away healthy bone, causing weak spots, where the bones can break easily. That is why breast cancer patients are often seen wearing braces or using a wheelchair, and have aching bones.

When breast cancer is found in bones, it has usually spread to more than one site. At this stage, it is treatable, often for many years, but it is not curable. Like normal breast cells, these tumors in the bone often thrive on female hormones, especially estrogen. Therefore treatment with medicines that lower estrogen levels may be prescribed.

Cultural references

In the month of October, breast cancer is recognized by survivors, family and friends of survivors and/or victims of the disease. A pink ribbon is worn to recognize the struggle that sufferers face when battling the cancer.

Pink for October is an initiative started by Matthew Oliphant, which asks that any sites willing to help make people aware of breast cancer, change their template or layout to include the color pink, so that when visitors view the site, they see that the majority of the site is pink. Then after reading a short amount of information about breast cancer, or being redirected to another site, they are aware of the disease itself.[106]

The patron saint of breast cancer is Saint Agatha of Sicily.

Cancer reference

2008-07-12T13:10:00.000-07:00

Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display the traits of uncontrolled growth (growth and division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not.

Cancer may affect people at all ages, even fetuses, but risk for the more common varieties tends to increase with age.[1] Cancer causes about 13% of all deaths.[2] According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007.[3] Cancers can affect other animals besides humans, and plants, too.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. Complex interactions between carcinogens and the host genome may explain why only some develop cancer after exposure to a known carcinogen. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly being recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are often inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Cancer is usually classified according to the tissue from which the cancerous cells originate, the primary tumor, as well as the normal cell type they most resemble. These are location and histology, respectively. A definitive diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Classification

Nomenclature

The following closely related terms may be used to designate abnormal growths:

* Tumor: originally, it meant any abnormal swelling, lump or mass. In current English, however, the word tumor has become synonymous with neoplasm, specifically solid neoplasm. Note that some neoplasms, such as leukemia, do not form tumors.
* Neoplasm: the scientific term to describe an abnormal proliferation of genetically altered cells. Neoplasms can be benign or malignant:
o Malignant neoplasm or malignant tumor: synonymous with cancer.
o Benign neoplasm or benign tumor: a tumor (solid neoplasm) that stops growing by itself, does not invade other tissues and does not form metastases.
* Invasive tumor is another synonym of cancer. The name refers to invasion of surrounding tissues.
* Pre-malignancy, pre-cancer or non-invasive tumor: A neoplasm that is not invasive but has the potential to progress to cancer (become invasive) if left untreated. These lesions are, in order of increasing potential for cancer, atypia, dysplasia and carcinoma in situ.

The following terms can be used to describe a cancer:

* Screening: a test done on healthy people to detect tumors before they become apparent. A mammogram is a screening test.
* Diagnosis: the confirmation of the cancerous nature of a lump. This usually requires a biopsy or removal of the tumor by surgery, followed by examination by a pathologist.
* Surgical excision: the removal of a tumor by a surgeon.
o Surgical margins: the evaluation by a pathologist of the edges of the tissue removed by the surgeon to determine if the tumor was removed completely ("negative margins") or if tumor was left behind ("positive margins").
* Grade: a number (usually on a scale of 3) established by a pathologist to describe the degree of resemblance of the tumor to the surrounding benign tissue.
* Stage: a number (usually on a scale of 4) established by the oncologist to describe the degree of invasion of the body by the tumor.
* Recurrence: new tumors that appear a the site of the original tumor after surgery.
* Metastasis: new tumors that appear far from the original tumor.
* Transformation: the concept that a low-grade tumor transforms to a high-grade tumor over time. Example: Richter's transformation.
* Chemotherapy: treatment with drugs.
* Radiation therapy: treatment with radiations.
* Adjuvant therapy: treatment, either chemotherapy or radiation therapy, given after surgery to kill the remaining cancer cells.
* Prognosis: the probability of cure after the therapy. It is usually expressed as a probability of survival five years after diagnosis. Alternatively, it can be expressed as the number of years when 50% of the patients are still alive. Both numbers are derived from statistics accumulated with hundreds of similar patients to give a Kaplan-Meier curve.

Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:

* Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
* Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
* Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
* Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
* Blastic tumor: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.

Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.

Child cancers

Cancer can also occur in young children and adolescents, but it is rare (about 150 cases per million yearly in the US). Statistics from the SEER program of the US NCI demonstrate that childhood cancers increased 19% between 1975 and 1990, mainly due to an increased incidence in acute leukemia. Since 1990, incidence rates have decreased.[5]

There is a reasonable doubt that children living near nuclear facilities face an increased risk of cancer.

Infant cancers

The age of peak incidence of cancer in children occurs during the first year of life, in infants. The average annual incidence in the United States, 1975-1995, was 233 per million infants.[5] Several estimates of incidence exist. According to SEER,[5] in the United States:

* Neuroblastoma comprised 28% of infant cancer cases and was the most common malignancy among these young children (65 per million infants).
* The leukemias as a group (41 per million infants) represented the next most common type of cancer, comprising 17% of all cases.
* Central nervous system malignancies comprised 13% of infant cancer, with an average annual incidence rate of nearly 30 per million infants.
* The average annual incidence rates for malignant germ cell and malignant soft tissue tumors were essentially the same at 15 per million infants. Each comprised about 6% of infant cancer.

According to another study:[4]

* Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing's sarcoma.

Teratoma (a germ cell tumor) often is cited as the most common tumor in this age group, but most teratomas are surgically removed while still benign, hence not necessarily cancer. Benign teratomas are not reportable to SEER.[citation needed] Prior to the widespread routine use of prenatal ultrasound examinations, the incidence of sacrococcygeal teratomas diagnosed at birth was 25 to 29 per million births.

Female and male infants have essentially the same overall cancer incidence rates, a notable difference compared to older children.

White infants have higher cancer rates than black infants. Leukemias accounted for a substantial proportion of this difference: the average annual rate for white infants (48.7 per million) was 66% higher than for black infants (29.4 per million).[5]

Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

Signs and symptoms

Roughly, cancer symptoms can be divided into three groups:

* Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice (yellowing the eyes and skin).
* Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
* Systemic symptoms: weight loss, poor appetite, fatigue and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.

Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.

Diagnosis

Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist, a type of physician (medical doctor) who specializes in the diagnosis of cancer and other diseases.

Investigation
Chest x-ray showing lung cancer in the left lung.

People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

Biopsy

A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.

The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of this patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist may perform on the tissue specimen. These tests may provide information about future behavior of the cancer (prognosis) and best treatment.

Treatment

Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.

Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.

Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.

Surgery

In theory, non-hematological cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.

Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.

Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.

Radiation therapy

Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.

Chemotherapy

Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.

The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoietic stem cells may be transplanted from a matched unrelated donor (MUD).

Targeted therapies

Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib.

Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.

Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors.[7]

Immunotherapy

Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.

Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.

Hormonal therapy

The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.

Angiogenesis inhibitors

Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors require to survive. Some, such as bevacizumab, have been approved and are in clinical use. One of the main problems with anti-angiogenesis drugs is that many factors stimulate blood vessel growth, in normal cells and cancer. Anti-angiogenesis drugs only target one factor, so the other factors continue to stimulate blood vessel growth. Other problems include route of administration, maintenance of stability and activity and targeting at the tumor vasculature.[8]

Symptom control

Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although doctors generally have the therapeutic skills to reduce pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.

Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.

Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures. Doctors have been reluctant to prescribe narcotics for pain in terminal cancer patients, for fear of contributing to addiction or suppressing respiratory function. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients.

Fatigue is a very common problem for cancer patients, and has only recently become important enough for oncologists to suggest treatment, even though it plays a significant role in many patients' quality of life.

Complementary and alternative

Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine.[9] "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine.[10] CAM use is common among people with cancer; a 2000 study found that 69% cancer patients had used at least one CAM therapy as part of their cancer treatment.[11] Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments which have been investigated and shown to be ineffective continue to be marketed and promoted.[12]

Treatment trials

Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.

Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.[13]

Prognosis

Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.

Emotional impact

Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.

Counseling can provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, peer counseling, bereavement, patient-to-patient, and sexuality.

Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research.

Causes

Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.

Chemical carcinogens

Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer and bladder cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes (see aneuploidy above).
The incidence of lung cancer is highly correlated with smoking. Source:NIH.
The incidence of lung cancer is highly correlated with smoking. Source:NIH.

Decades of research have demonstrated the strong association between tobacco use and cancers of many sites, making it perhaps the most important human carcinogen. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men.

Ionizing radiation

Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.

Infectious diseases

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.[14] The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral oncogene.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer.[15]

Hormonal imbalances

Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.

Immune system dysfunction

HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer.[16] Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.[17]

Heredity

Most forms of cancer are "sporadic", and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component, often a defective tumor suppressor allele. Famous examples are:

* certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
* tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
* Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors) due to mutations of p53
* Turcot syndrome (brain tumors and colonic polyposis)
* Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
* Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
* Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
* Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

Other causes

A few types of cancer in non-humans have been found to be caused by the tumor cells themselves. This phenomenon is seen in Sticker's sarcoma, also known as canine transmissible venereal tumor.[18] The closest known analogue to this in humans is individuals who have developed cancer from tumors hiding inside organ transplants.

Pathophysiology
Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.
Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetics

Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.

Oncogenes

Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[19] Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.[20]

Tumor suppressor genes

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.[21]

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.[22]

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.[23]

Cancer cell biology
Tissue can be organized in a continuous spectrum from normal to cancer.

Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Clonal evolution

The process by which normal tissue becomes malignant is a process of somatic evolution within the body[24]. Millions of years of biological evolution insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. Cancer cells undergo a process of natural selection, in that the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed[25]. This process is called clonal evolution. Tumors often continue to evolve in response to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.

Biological properties of cancer cells

In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:[26]

* Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
* Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
* Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
* Loss of capacity for senescence, leading to limitless replicative potential (immortality)
* Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
* Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
* Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).

The completion of these multiple steps would be a very rare event without :

* Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.

These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of Leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the P53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis.

Prevention

Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions). The epidemiological concept of "prevention" is usually defined as either primary prevention, for people who have not been diagnosed with a particular disease, or secondary prevention, aimed at reducing recurrence or complications of a previously diagnosed illness.

Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological trials and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.

About a third of the twelve most common cancers worldwide are due to nine potentially modifiable risk factors. Men with cancer are twice as likely as women to have a modifiable risk factor for their disease. The nine risk factors are tobacco smoking, excessive alcohol use, diet low in fruit and vegetables, limited physical exercise, human papillomavirus infection (unsafe sex), urban air pollution, domestic use of solid fuels, and contaminated injections (hepatitis B and C).[27]

Modifiable ("lifestyle") risk factors

Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men[28]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases, the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.

Every year, at least 200,000 people die worldwide from cancer related to their workplace.[29] Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces. Currently, most cancer deaths caused by occupational risk factors occur in the developed world.It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.[30]

See alcohol and cancer for more on that topic.

Diet

The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[31] Whether reducing obesity in a population also reduces cancer incidence is unknown.

Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.

Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer,[32] and reports that consumption of coffee is associated with a reduced risk of liver cancer.[33] Studies have linked consumption of grilled meat to an increased risk of stomach cancer,[34] colon cancer,[35] breast cancer,[36] and pancreatic cancer,[37] a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.

A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time.[38] These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.[39]

Recent studies have also demonstrated potential links between some forms of cancer and high consumption of refined sugars and other simple carbohydrates.[40][41][42][43][44] Although the degree of correlation and the degree of causality is still debated,[45][46][47] some organizations have in fact begun to recommend reducing intake of refined sugars and starches as part of their cancer prevention regemins.[48][49][50][51]

The WCRF/AICR Expert Report, Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective recommends (1) reducing intake of foods and drinks that promote weight gain, namely energy-dense foods and sugary drinks, (2) eating mostly foods of plant origin (3) limiting intake of red meat and avoiding processed meat, (4) limiting consumption of alcoholic beverages, and (5) reducing intake of salt and avoiding mouldy cereals (grains) or pulses (legumes).[52]

Vitamins

The idea that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.[53]

Epidemiological studies have shown that low vitamin D status is correlated to increased cancer risk.[54][55] However, the results of such studies need to be treated with caution, as they cannot show whether a correlation between two factors means that one causes the other (i.e. correlation does not imply causation).[56] The possibility that Vitamin D might protect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency).[57] This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group[58][59] estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.[60]

Results reported in the Journal of the American Medical Association (JAMA) in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.[61]

Chemoprevention
The neutrality of this section is disputed.
Please see the discussion on the talk page.(June 2008)
Please do not remove this message until the dispute is resolved.

The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances.

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.[62]

Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.[62]

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors.[63] The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients[64] and in the general population.[65][66] In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.

Genetic testing

Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery. Early identification of inherited genetic risk for cancer, along with cancer-preventing interventions such as surgery or enhanced surveillance, can be lifesaving for high-risk individuals.
Gene Cancer types Availability
BRCA1, BRCA2 Breast, ovarian, pancreatic Commercially available for clinical specimens
MLH1, MSH2, MSH6, PMS1, PMS2 Colon, uterine, small bowel, stomach, urinary tract Commercially available for clinical specimens

Vaccination

Considerable[weasel words] research effort is now devoted to the development of vaccines to prevent infection by oncogenic infectious agents, as well as to mount an immune response against cancer-specific epitopes) and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer.

As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines on the market as of October 2007 are Gardasil and Cervarix.

Screening

Cancer screening is an attempt to detect unsuspected cancers in an asymptomatic population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.

Screening for cancer can lead to earlier diagnosis in specific cases. Early diagnosis may lead to extended life, but may also falsely prolong the lead time to death through lead time bias or length time bias.

A number of different screening tests have been developed for different malignancies. Breast cancer screening can be done by breast self-examination, though this approach was discredited by a 2005 study in over 300,000 Chinese women. Screening for breast cancer with mammograms has been shown to reduce the average stage of diagnosis of breast cancer in a population. Stage of diagnosis in a country has been shown to decrease within ten years of introduction of mammographic screening programs. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened using a digital rectal exam along with prostate specific antigen (PSA) blood testing, though some authorities (such as the US Preventive Services Task Force) recommend against routinely screening all men.

Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.

Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.

For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.

Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma - a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations. Recent studies of CT scan-based screening for lung cancer in smokers have had equivocal results, and systematic screening is not recommended as of July 2007. Randomized clinical trials of plain-film chest X-rays to screen for lung cancer in smokers have shown no benefit for this approach.

Canine cancer detection has shown promise, but is still in the early stages of research.

Epidemiology
The risk of cancer rises with age

Cancer epidemiology is the study of the incidence of cancer as a way to infer possible trends and causes. The first such cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.

A founding paper of this discipline was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.

Cancer epidemiology must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A similar epidemiological concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient's longevity. This problem especially applies to prostate cancer and PSA screening.

Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.

State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is SEER, administered by the US Federal government. Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs and other institutions.

In some Western countries, such as the USA,[4] and the UK[74] cancer is overtaking cardiovascular disease as the leading cause of death. In many Third World countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; this is termed the epidemiologic transition in epidemiological terminology.

Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.

History
Typical macroscopic appearance of cancer. This invasive ductal carcinoma of the breast (pale area at the center) shows an oval tumor surrounded by spikes of whitish scar tissue in the surrounding yellow fatty tissue. The silhouette vaguely resembles a crab.
Typical macroscopic appearance of cancer. This invasive ductal carcinoma of the breast (pale area at the center) shows an oval tumor surrounded by spikes of whitish scar tissue in the surrounding yellow fatty tissue. The silhouette vaguely resembles a crab.

Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.[75]

Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name comes from the appearance of the cut surface of a solid malignant tumour, with the veins stretched on all sides as the animal the crab has its feet, whence it derives its name[76] (see picture). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.

Our oldest description and surgical treatment of cancer was discovered in Egypt and dates back to approximately 1600 B.C. The Papyrus describes 8 cases of ulcers of the breast that were treated by cauterization, with a tool called "the fire drill." The writing says about the disease, "There is no treatment."

Another very early surgical treatment for cancer was described in the 1020s by Avicenna (Ibn Sina) in The Canon of Medicine. He stated that the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor. He also recommended the use of cauterization for the area being treated if necessary.

In the 16th and 17th centuries, it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.[79]

With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874.[80] The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.

When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation came also the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.

Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of bomb victims in Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since WWII, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.

candidiasis reference

2008-07-12T13:08:00.000-07:00

Candidiasis, commonly called yeast infection or thrush, is a fungal infection (mycosis) of any of the Candida species, of which Candida albicans is the most common.[1][2]

Candidiasis encompasses infections that range from superficial, such as oral thrush and vaginitis, to systemic and potentially life-threatening diseases. Candida infections of the latter category are also referred to as candidemia and are usually confined to severely immunocompromised persons, such as cancer, transplant, and AIDS patients.

Superficial infections of skin and mucosal membranes by Candida causing local inflammation and discomfort are however common in many human populations.] While clearly attributable to the presence of the opportunistic pathogens of the genus Candida, candidiasis describes a number of different disease syndromes that often differ in their causes and outcomes

Manifestation

In immunocompetent persons, candidiasis is usually a very localized infection of the skin or mucosal membranes, including:[1]

* the oral cavity (oral thrush)
* the pharynx
* the esophagus
* the navel
* the intestines
* the urinary bladder
* the vagina

Candidiasis is a very common cause of vaginal irritation, or vaginitis, and can also occur on the male genitals. In immunocompromised patients, the Candida infection can affect the esophagus with the potential of becoming systemic, causing a much more serious condition, a fungemia called candidemia.[4][3]

Children, mostly between the ages of 3 and 9 years, can be affected by chronic mouth yeast infections, normally seen around the mouth as white patches. However, this is not a common condition.[citation needed]

Causes
Oral candidiasis on the tongue and soft palate.

Candida yeasts are usually present in most people, but uncontrolled multiplication resulting in disease symptoms is kept in check by other naturally occurring microorganisms, e.g., bacteria co-existing with the yeasts in the same locations, and by the human immune system.

In a study of 1009 women in New Zealand, Candida albicans was isolated from the vaginas of 19% of apparently healthy women. Carriers experienced few or no symptoms. However, external use of irritants (such as some detergents or douches) or internal disturbances (hormonal or physiological) can perturb the normal flora, constituting lactic acid bacteria, such as lactobacilli, and an overgrowth of yeast can result in noticeable symptoms.[citation needed] Pregnancy,[citation needed] the use of oral contraceptives,[citation needed] engaging in vaginal sex immediately and without cleansing after anal sex,[citation needed] and using lubricants containing glycerin have been found to be causally related to yeast infections.[citation needed] Diabetes mellitus and the use of antibiotics are also linked to an increased incidence of yeast infections.[citation needed] Diet has been found to be the cause in some animals. Hormone Replacement Therapy and infertility treatments may also be predisposing factors.[citation needed]

A weakened or undeveloped immune system or metabolic illnesses such as diabetes may predispose individuals to Candidiasis.[5] Diseases or conditions linked to candidiasis include HIV/AIDS, mononucleosis, cancer treatments, steroids, stress, and nutrient deficiency, among many others. Almost 15% of people with weakened immune systems develop a systemic illness caused by Candida species.[citation needed] In extreme cases, these superficial infections of the skin or mucous membranes may enter into the bloodstream and cause systemic Candida infections.

Antibiotic and steroid use are the most common reason for yeast overgrowth.[6] The former kills the bacteria which would otherwise help maintain Candida at safe levels, thus allowing the fungus to overgrow.

Since the Candida fungus thrives in warm, moist, and dark places, exposed areas with these conditions such as the mouth, skin folds, armpits, and vagina are more vulnerable.

In penile candidiasis, the causes include sexual intercourse with an infected party, low immunity, antibiotics, and diabetes. However, male yeast infection is less common, and the risk of getting it is only a fraction of that in women.[citation needed] However, yeast infection on the penis from direct contact via sexual intercourse with an infected woman is uncommon.

Symptoms

Symptoms include severe itching, burning, and soreness, irritation of the vagina and/or vulva, and a whitish or whitish-gray discharge, often with a curd-like appearance.

Many women mistake the symptoms of the more common bacterial vaginosis for a yeast infection. In a 2002 study published in the Journal of Obstetrics and Gynecology, only 33 percent of women who were self-treating for a yeast infection actually had a yeast infection. Instead, they had either bacterial vaginosis or a mixed-type infection.

In men, symptoms include red patchy sores near the head of the penis or on the foreskin, severe itching, and/or a burning sensation. Candidiasis of the penis can also have a white discharge, although uncommon. However, having no symptoms at all is common, and usually, a more severe form of the symptoms may emerge later.

Diagnosis

Medical professionals use two primary methods to diagnose yeast infections: microscopic examination and culturing.

For the culturing method, a sterile swab is rubbed on the infected skin surface. The swab is then rubbed across a culture medium. The medium is incubated for several days, during which time colonies of yeast and/or bacteria develop. The characteristics of the colonies provide a presumptive diagnosis of the organism that is causing symptoms.

Treatment

It is important to consider that Candida species are frequently part of the human body's normal oral and intestinal flora. Treatment with antibiotics can lead to eliminating the yeast's natural competitors for resources, and increase the severity of the condition.

In clinical settings, candidiasis is commonly treated with antimycotics—the antifungal drugs commonly used to treat candidiasis are topical clotrimazole, topical nystatin, fluconazole, and topical ketoconazole. For example, a one-time dose of fluconazole (as Diflucan 150-mg tablet taken orally) has been reported as being 90% effective in treating a vaginal yeast infection.[7] This dose is only effective for vaginal yeast infections, and other types of yeast infections may require different treatments. In severe infections (generally in hospitalized patients), amphotericin B, caspofungin, or voriconazole may be used. Local treatment may include vaginal suppositories or medicated douches. Gentian violet can be used for breastfeeding thrush, but pediatrician William Sears recommends using it sparingly,[8] since in large quantities it can cause mouth and throat ulcerations in nursing babies, and has been linked to mouth cancer in humans and to cancer in the digestive tract of other animals.[9]

While home remedies may offer relief in minor cases of infection, seeking medical attention may be necessary, especially if the extent of the infection cannot be judged accurately by the patient. For instance, oral thrush is visible only at the upper digestive tract, but it may be that the lower digestive tract is likewise colonized by Candida species.

Treating candidiasis solely with medication may not give desired results, and other underlying causes require consideration. For example, oral candidiasis can also be the sign of a more serious condition, such as HIV infection or other immunodeficiency diseases. Following the health tips at vulvovaginal health can help prevent vaginal candidiasis.

It is possible for Candida Albicans to develop a resistance to the drugs used to treat it, as seen from research done[10] involving fluconazole, one of the drugs that is used to treat Candidiasis. In this case, the recurring infection would have to use a different prescription, and it is possible that resistance is slowly built to many of the available medications used to treat the yeast infection.

Babies with diaper rash should have their diaper areas kept clean, dry, and exposed to air as much as possible. Sugars assist the overgrowth of yeast, possibly explaining the increased prevalence of yeast infections in patients with diabetes mellitus, as noted above. As many Candida spp. reside in the digestive tract, dietary changes may be effective for preventing or during a Candida infection. Due to its requirement for readily-fermentable carbon sources, such as mono- or dimeric sugars (e.g., sucrose, glucose, lactose) and starch, avoiding foods that contain these nutrients in high abundance may help to prevent excessive Candida growth.

History and taxonomic classification

The genera Candida, species albicans was described by botanist Christine Marie Berkhout. She described the fungus in her doctoral thesis, at the University of Utrecht in 1923. Over the years, the classification of the genera and species has evolved. Obsolete names for this genus include Mycotorula and Torulopsis. The species has also been known in the past as Monilia albicans and Oidium albicans. The current classification is nomen conservandum, which means the name is authorized for use by the International Botanical Congress (IBC).

Alternative views

Alternative medicine proponents frequently diagnose people with "systemic candidiasis" using methods not deemed valid by mainstream conventional medicine. Belief in widespread "systemic candidiasis" was promoted by a book published by Dr. William Crook,[11] which hypothesized that a variety of common symptoms such as fatigue, PMS, sexual dysfunction, asthma, psoriasis, digestive and urinary problems, multiple sclerosis, and muscle pain, could be caused by subclinical infections of Candida albicans.[citation needed] Crook suggested a variety of remedies to treat these symptoms, ranging from dietary modification to colonic irrigation. With the exception of the few dietary studies in the Urinary tract infection section conventional medicine has not used most of these alternatives, since there is limited scientific evidence to prove their effectiveness, or that subclinical "systemic candidiasis" is a viable diagnosis

cataracts reference

2008-07-12T13:06:00.000-07:00

A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light. Early in the development of age-related cataract the power of the lens may be increased, causing near-sightedness (myopia), and the gradual yellowing and opacification of the lens may reduce the perception of blue colours. Cataracts typically progress slowly to cause vision loss and are potentially blinding if untreated.[1]

A senile cataract, occurring in the aged, is characterized by an initial opacity in the lens, subsequent swelling of the lens and final shrinkage with complete loss of transparency.[2] Moreover, with time the cataract cortex liquefies to form a milky white fluid in a Morgagnian cataract, which can cause severe inflammation if the lens capsule ruptures and leaks. Untreated, the cataract can cause phacomorphic glaucoma. Very advanced cataracts with weak zonules are liable to dislocation anteriorly or posteriorly. Such spontaneous posterior dislocations (akin to the historical surgical procedure of couching) in ancient times were regarded as a blessing from the heavens, because some perception of light was restored in the cataractous patients.

Cataract derives from the Latin cataracta meaning "waterfall" and the Greek kataraktes and katarrhaktes, from katarassein meaning "to dash down" (kata-, "down"; arassein, "to strike, dash". As rapidly running water turns white, the term may later have been used metaphorically to describe the similar appearance of mature ocular opacities. In Latin, cataracta had the alternate meaning "portcullis",[4] so it is also possible that the name came about through the sense of "obstruction". Early Persian physicians called the term nazul-i-ah, or 'descent of the water' - vulgarised into waterfall disease or cataract - believing such blindness to be caused by an outpouring of corrupt humour into the eye.[5] In dialect English a cataract is called a pearl, as in "pearl eye" and "pearl-eyed".

Causes

Cataracts develop from a variety of reasons, including long-term ultraviolet exposure, exposure to radiation, secondary effects of diseases such as diabetes, hypertension and advanced age; they are usually a result of denaturation of lens proteins. Genetic factors are often a cause of congenital cataracts and positive family history may also play a role in predisposing someone to cataracts at an earlier age, a phenomenon of "anticipation" in pre-senile cataracts. Cataracts may also be produced by eye injury or physical trauma. A study among Icelandair pilots showed commercial airline pilots as three times more likely to develop cataracts than people with non-flying jobs. This is thought to be caused by excessive exposure to radiation coming from outer space.[7] Cataracts are also unusually common in persons exposed to infrared radiation, such as glassblowers who suffer from "exfoliation syndrome". Exposure to microwave radiation can cause cataracts.

Cataracts may be partial or complete, stationary or progressive, hard or soft.

Some drugs can induce cataract development, such as Corticosteroids[8] and Ezetimibe[citation needed] and Seroquel.

There are various types of cataract, e.g. nuclear, cortical, mature, hypermature. Cataracts are also classified by their location, e.g. posterior (classically due to steroid use[8][9]) and anterior (common (senile) cataract related to aging).

Epidemiology

Age-related cataract is responsible for 48% of world blindness, which represents about 18 million people, according to the World Health Organization (WHO).[10] In many countries surgical services are inadequate, and cataracts remain the leading cause of blindness. As populations age, the number of people with cataracts is growing. Cataracts are also an important cause of low vision in both developed and developing countries. Even where surgical services are available, low vision associated with cataracts may still be prevalent, as a result of long waits for operations and barriers to surgical uptake, such as cost, lack of information and transportation problems.

In the United States, age-related lenticular changes have been reported in 42% of those between the ages of 60% of those between the ages 65 and 74,[12] and 91% of those between the ages of 75 and 85.

Cataract surgery

When a cataract is "ripe" (sufficiently developed to be removed by surgery), the most effective and common treatment is to make an incision (capsulotomy) into the capsule of the cloudy lens in order to surgically remove the lens. There are two types of eye surgery that can be used to remove cataracts: extra-capsular (extracapsular cataract extraction, or ECCE) and intra-capsular (intracapsular cataract extraction, or ICCE).

Extra-capsular (ECCE) surgery consists of removing the lens but leaving the majority of the lens capsule intact. High frequency sound waves (phacoemulsification) are sometimes used to break up the lens before extraction.

Intra-capsular (ICCE) surgery involves removing the entire lens of the eye, including the lens capsule, but it is rarely performed in modern practice.

In either extra-capsular surgery or intra-capsular surgery, the cataractous lens is removed and replaced with a plastic lens (an intraocular lens implant) which stays in the eye permanently.

Cataract operations are usually performed using a local anaesthetic and the patient is allowed to go home the same day. Recent improvements in intraocular technology now allow cataract patients to choose a multifocal lens to create a visual environment in which they are less dependent on glasses. Under some medical systems multifocal lenses cost extra. Traditional intraocular lenses are monofocal.

Complications are possible after cataract surgery, including endophthalmitis, posterior capsular opacification and retinal detachment.

In ICCE there is the issue of the Jack in the box phenomenon where the patient has to wear aphakic glasses - alternatives include contact lenses but these can prove to be high maintenance, particularly in dusty areas.

Prevention

Although cataracts have no scientifically proven prevention, it is sometimes said that wearing ultraviolet-protecting sunglasses may slow the development of cataracts.[13][14] Regular intake of antioxidants (such as vitamin A, C and E) is theoretically helpful, but taking them as a supplement has been shown to have no benefit.[15]

Recent research

Although statins are known for their ability to lower lipids, they are also believed to have antioxidant qualities. It is believed that oxidative stress plays a role in the development of nuclear cataracts, which are the most common type of age-related cataract. To explore the relationship between nuclear cataracts and statin use, a group of researchers took a group of 1299 patients who were at risk of developing nuclear cataracts and gave some of them statins. Their results suggest that statin use in a general population may be associated with a lower risk of developing nuclear cataract disease.[16]

Research is scant and mixed but weakly positive for the nutrients lutein and zeaxanthin. Bilberry extract shows promise in rat models [21][22] and in clinical studies.[23]

Types of cataracts
Bilateral cataracts in an infant due to Congenital rubella syndrome, courtesy CDC
Bilateral cataracts in an infant due to Congenital rubella syndrome, courtesy CDC

The following is a classification of the various types of cataracts. This is not comprehensive and other unusual types may be noted.

* Classified by etiology

* Age-related cataract

* Immature Senile Cataract (IMSC) - partially opaque lens, disc view hazy
* Mature Senile Cataract (MSC) - Completely opaque lens, no disc view
* Hypermature Senile Cataract (HMSC) - Liquefied cortical matter: Morgagnian Cataract

* Congenital cataract

* Sutural cataract
* Lamellar cataract
* Zonular cataract
* Total cataract

* Secondary cataract

Slit lamp photo of Anterior capsular opacification visible a few months after implantation of Intraocular lens in eye, magnified view
Slit lamp photo of Anterior capsular opacification visible a few months after implantation of Intraocular lens in eye, magnified view

* Drug-induced cataract (e.g. Corticosteroids)

* Traumatic cataract

* Blunt trauma (capsule usually intact)
* Penetrating trauma (capsular rupture & leakage of lens material - calls for an emergency surgery for extraction of lens and leaked material to minimize further damage)

* Classified by location of opacity within lens structure (However, mixed morphology is quite commonly seen, e.g. PSC with nuclear changes & cortical spokes of cataract)

* Anterior cortical cataract
* Anterior polar cataract
* Anterior subcapsular cataract

Slit lamp photo of Posterior capsular opacification visible a few months after implantation of Intraocular lens in eye, seen on retroillumination
Slit lamp photo of Posterior capsular opacification visible a few months after implantation of Intraocular lens in eye, seen on retroillumination

* Nuclear cataract - Grading correlates with hardness & difficulty of surgical removal

* 1 - Grey
* 2 - Yellow
* 3 - Amber
* 4 - Brown/Black (Note: "Black cataract" translated in some languages (like Hindi) refers to Glaucoma, not the color of the lens nucleus)

* Posterior cortical cataract
* Posterior polar cataract (importance lies in higher risk of complication - posterior capsular tears during surgery)
* Posterior subcapsular cataract (PSC) (clinically common)

* After-cataract - posterior capsular opacification subsequent to a successful extracapsular cataract surgery (usually within 3 months - 2 years) with or without IOL implantation. Requires a quick & painless office procedure with Nd:YAG laser capsulotomy to restore optical clarity.

Associations with systemic conditions

* Chromosomal disorders

* Alport's syndrome
* Cri-du-chat syndrome
* Conradi's syndrome
* Myotonic dystrophy
* Patau's syndrome
* Schmid-Fraccaro syndrome
* Trisomy 18 (Edward's syndrome)
* Turner's syndrome

* Disease of the skin and mucous membranes

* Atopic dermatitis
* Basal-cell nevus syndrome
* Ichthyosis
* Pemphigus

* Metabolic and nutrition diseases

* Aminoaciduria (Lowe's syndrome)
* Diabetes mellitus
* Fabry's disease
* Galactosemia / Galactosemic Cataract
* Homocystinuria
* Hypervitaminosis D
* Hyperparathyroidism
* Hypothyroidism
* Mucopolysaccharidoses
* Wilson's disease

* Infectious diseases

* Congenital

* Congential herpes simplex
* Congenital syphilis
* Cytomegalic inclusion disease
* Rubella

* Others

* Cysticercosis
* Leprosy
* Onchocerciasis
* Toxoplasmosis

* Toxic substances introduced systemically

* Corticosteroids
* Haloperidol
* Miotics
* Triparanol