Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of white blood cells. Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader group of diseases called hematological neoplasms.

Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms:

1. Acute leukemia is characterized by a rapid increase in the numbers of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children.
2. Chronic leukemia is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.

Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:

1. In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell.
2. In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

Combining these two classifications provides a total of four main categories. Within each of these four main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme.

1. Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older. Standard treatments involve chemotherapy and radiation. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.
2. Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 75%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.
3. Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The five-year survival rate is 40%. Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia.
4. Chronic myelogenous leukemia (CML) occurs mainly in adults. A very small number of children also develop this disease. Treatment is with imatinib (Gleevec in US, Glivec in Europe) or other drugs. The five-year survival rate is 90%. One subtype is chronic monocytic leukemia.
5. Hairy cell leukemia (HCL) is sometimes considered a subset of CLL, but does not fit neatly into this pattern. About 80% of affected people are adult men. There are no reported cases in young children. HCL is incurable, but easily treatable. Survival is 96% to 100% at ten years.
6. T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease. Despite its overall rarity, it is also the most common type of mature T cell leukemia; nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months.
7. Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.
8. Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV, it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally.

Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional. This could cause the patient's immune system to be unable to fight off a simple infection or to start attacking other body cells. Because leukemia prevents the immune system from working normally, some patients experience frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections.

Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor.

Some patients experience other symptoms, such as feeling sick, having fevers, chills, night sweats and other flu-like symptoms, or feeling fatigued. Some patients experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. All symptoms associated with leukemia can be attributed to other diseases. Consequently, leukemia is always diagnosed through medical tests.

The word leukemia, which means 'white blood', is derived from the disease's namesake high white blood cell counts that most leukemia patients have before treatment. The high number of white blood cells are apparent when a blood sample is viewed under a microscope. Frequently, these extra white blood cells are immature or dysfunctional. The excessive number of cells can also interfere with the level of other cells, causing a harmful imbalance in the blood count.

Some leukemia patients do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells which disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For an aleukemic patient, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.

No single known cause for all of the different types of leukemia exists. The known causes, which are not generally factors within the control of the average person, account for relatively few cases. The different leukemias likely have different causes.

Leukemia, like other cancers, results from somatic mutations in the DNA. Certain mutations produce leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances, and are likely to be influenced by genetic factors.

Among adults, the known causes are natural and artificial ionizing radiation, a few viruses such as Human T-lymphotropic virus, and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults. Cohort and case-control studies have linked exposure to some petrochemicals and hair dyes to the development of some forms of leukemia. A few cases of maternal-fetal transmission have been reported. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit.

Viruses have also been linked to some forms of leukemia. Experiments on mice and other mammals have demonstrated the relevance of retroviruses in leukemia, and human retroviruses have also been identified. The first human retrovirus identified was Human T-lymphotropic virus, or HTLV-1, is known to cause adult T-cell leukemia.

Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies. The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kind of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers.

In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia.

Whether non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power. They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause childhood leukemia. Exposure to significant ELF magnetic fields might result in twofold excess risk for leukemia for children exposed to these high levels of magnetic fields. However, the report also says that methodological weaknesses and biases in these studies have likely caused the risk to be overstated. No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated. Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization concludes that ELF exposure, if later proven to be causative, would account for just 100 to 2400 cases worldwide each year, representing 0.2 to 4.9% of the total incidence of childhood leukemia for that year (about 0.03 to 0.9% of all leukemias).

Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms, however, in rare cases blood tests may not show if a patient has leukemia, usually this is because the leukemia is in the early stages or has entered remission. A lymph node biopsy can be performed as well in order to diagnose certain types of leukemia in certain situations.

Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the patient. When concerns arise about visible damage due to leukemia, doctors may use an X-ray, MRI, or ultrasound. These can potentially view leukemia's effects on such body parts as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound). Finally, CT scans are rarely used to check lymph nodes in the chest.

Despite the use of these methods to diagnose whether or not a patient has leukemia, many people have not been diagnosed because many of the symptoms are vague, unspecific, and can refer to other diseases. For this reason, the American Cancer Society predicts that at least one-fifth of the people with leukemia have not yet been diagnosed.

Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia. SPRED1 gene mutations can be diagnosed with genetic sequencing.

Leukemia was first observed by pathologists Rudolf Virchow and John Hughes Bennett in 1845. Observing an abnormally large number of white blood cells in a blood sample from a patient, Virchow called the condition Leukämie in German, which he formed from the two Greek words leukos, meaning "white", and aima, meaning "blood". Around ten years after Virchow and Bennett's findings, pathologist Franz Ernst Christian Neumann found that one deceased leukemia patient's bone marrow was colored "dirty green-yellow" as opposed to the normal red. This finding allowed Neumann to conclude that a bone marrow problem was responsible for the abnormal blood of leukemia patients.

By 1900 leukemia was viewed as a family of diseases as opposed to a single disease. By 1947 Boston pathologist Sydney Farber believed from past experiments that aminopterin, a folic acid mimic, could potentially cure leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them actually were cured. This, however, led to further experiments.

In 1962, researchers Emil J. Freireich Jr. and Emil Frei III used combination chemotherapy to attempt to cure leukemia. The tests were successful with some patients surviving long after the tests.

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Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions (i.e. peritrichous). They are chemoorganotrophs, obtaining their energy from oxidation and reduction reactions using organic sources, and are facultative anaerobes. Most species produce hydrogen sulfide, which can readily be detected by growing them on media containing ferrous sulfate, such as TSI. Most isolates exist in two phases: a motile phase I and a nonmotile phase II. Cultures that are nonmotile upon primary culture may be switched to the motile phase using a Cragie tube.

Salmonella is closely related to the Escherichia genus and are found worldwide in cold- and warm-blooded animals (including humans), and in the environment. They cause illnesses like typhoid fever, paratyphoid fever, and the foodborne illness.

Salmonella is typically pronounced with the initial letter "L," although it is named for pathologist Daniel Elmer Salmon.

Salmonella infections are zoonotic and can be transferred between humans and nonhuman animals. Many infections are due to ingestion of contaminated food. A distinction is made between enteritis Salmonella and typhoid/paratyphoid Salmonella, where the latter — because of a special virulence factor and a capsule protein (virulence antigen) — can cause serious illness, such as Salmonella enterica subsp. enterica serovar Typhi. Salmonella typhi. is adapted to humans and does not occur in animals.

This is a group consisting of potentially all other serotypes (over a thousand) of the Salmonella bacterium, most of which have never been found in humans. These are encountered in various Salmonella species, most having never been linked to a specific host, and can also infect humans. It is therefore a zoonotic disease. The organism enters through the digestive tract and must be ingested in large numbers to cause disease in healthy adults. Gastric acidity is responsible for the destruction of the majority of ingested bacteria. The infection usually occurs as a result of massive ingestion of foods in which the bacteria are highly concentrated similarly to a culture medium. However, infants and young children are much more susceptible to infection, easily achieved by ingesting a small number of bacteria. It has been shown that, in infants, the contamination could be through inhalation of bacteria-laden dust. After a short incubation period of a few hours to one day, the germ multiplies in the intestinal lumen causing an intestinal inflammation with diarrhea that is often muco-purulent and bloody. In infants, dehydration can cause a state of severe toxicosis. The symptoms are usually mild. There is normally no sepsis, but it can occur exceptionally as a complication in weakened elderly patients (Hodgkin's disease, eg.). Extraintestinal localizations are possible, especially Salmonella meningitis in children, osteitis, etc. Enteritis Salmonella (e.g., Salmonella enterica subsp. enterica serovar enteritidis) can cause diarrhoea, which usually does not require antibiotic treatment. However, in people at risk such as infants, small children, the elderly, Salmonella infections can become very serious, leading to complications. If these are not treated, HIV patients and those with suppressed immunity can become seriously ill. Children with sickle cell anaemia who are infected with Salmonella may develop osteomyelitis.

Salmonella can survive for weeks outside a living body. They have been found in dried excrement after more than 2.5 years. Salmonella are not destroyed by freezing. Ultraviolet radiation and heat accelerate their demise; they perish after being heated to 55 °C (131 °F) for one hour, or to 60 °C (140 °F) for half an hour. To protect against Salmonella infection, it is recommended that food be heated for at least ten minutes at 75 °C (167 °F) so that the centre of the food reaches this temperature.

The AvrA toxin injected by the type three secretion system of Salmonella typhimurium works to inhibit the innate immune system by virtue of its serine/threonine acetyltransferase activity and requires binding to eukaryotic target cell phytic acid (IP6). This leaves the host more susceptible to infection. In a 2011 paper, Yale University School of Medicine researchers described in detail how Salmonella is able to make these proteins line up in just the right sequence to invade host cells. "These mechanisms present us with novel targets that might form the basis for the development of an entirely new class of anti-microbials," said Professor Dr. Jorge Galan, senior author of the paper and the Lucille P. Markey Professor of Microbial Pathogenesis and chair of the Section of Microbial Pathogenesis at Yale. In the new National Institutes of Health (NIH)-funded study, Galan and colleagues (Maria Lara-Tejero, Junya Kato, Samuel Wagner, and Xiaoyun Liu) identify what they call a bacterial sorting platform, which attracts needed proteins and lines them up in a specific order. If the proteins do not line up properly, Salmonella, as well as many other bacterial pathogens, cannot "inject" them into host cells to commandeer host cell functions, the lab has found. Understanding how this machine works raises the possibility that new therapies can be developed which disable this protein delivery machine and therefore thwart the ability of the bacterium to become pathogenic. The process would not kill the bacteria as most antibiotics do, but would cripple its ability to do harm. In theory, this means that bacteria such as Salmonella might not develop resistance to new therapies as quickly as they usually do to conventional antibiotics.

The genus Salmonella was named after Daniel Elmer Salmon, an American veterinary pathologist. While Theobald Smith was the actual discoverer of the type bacterium (Salmonella enterica var. choleraesuis) in 1885, Dr. Salmon was the administrator of the USDA research program, and thus the organism was named after him. Smith and Salmon had been searching for the cause of common hog cholera and proposed this organism as the causal agent. Later research, however, would show that this organism (now known as Salmonella enterica) rarely causes enteric symptoms in pigs, and was thus not the agent they were seeking (which was eventually shown to be a virus). However, related bacteria in the genus Salmonella were eventually shown to cause other important infectious diseases.

Salmonella nomenclature is complicated. Initially, each Salmonella species was named according to clinical considerations, e.g., Salmonella typhi-murium (mouse typhoid fever), S. cholerae-suis (hog cholera). After it was recognized that host specificity did not exist for many species, new strains (or serovar, short for serological variants) received species names according to the location at which the new strain was isolated. Later, molecular findings led to the hypothesis that Salmonella consisted of only one species, S. enterica, and the serovar were classified into six groups, two of which are medically relevant. But as this now formalized nomenclature is not in harmony with the traditional usage familiar to specialists in microbiology and infectologists, the traditional nomenclature is common. Currently, there are two recognized species: S. enterica and S. bongori, with six main subspecies: enterica (I), salamae (II), arizonae (IIIa), diarizonae (IIIb), houtenae (IV), and indica (VI). Historically, serotype (V) was bongori, which is now considered its own species. The serovar classification of Salmonella is based on the Kauffman-White classification scheme that permits serological varieties to be differentiated from each other. Newer methods for Salmonella typing and subtyping include genome-based methods such as pulsed field gel electrophoresis (PFGE), Multiple Loci VNTR Analysis (MLVA), Multilocus sequence typing (MLST) and (multiplex-) PCR-based methods.

Serovar Typhimurium has considerable diversity and may be very old. The majority of the isolates belong to a single clonal complex. Isolates are divided into phage types, but some phage types do not have a single origin as determined using mutational changes. Phage type DT104 is heterogeneous and represented in multiple sequence types, with its multidrug-resistant variant being the most successful and causing epidemics in many parts of the world.

Serovar Typhi is relatively young compared to Typhimurium, and probably originated approximately 30,000-50,000 years ago.

Sources of infection

1. Infected food, often gaining an unusual color, odor, or chewiness, that is then introduced into the stream of commerce;
2. Poor kitchen hygiene, especially problematic in institutional kitchens and restaurants because this can lead to a significant outbreak;
3. Excretions from either sick or infected but apparently clinically healthy people and animals (especially endangered are caregivers and animals);
4. Polluted surface water and standing water (such as in shower hoses or unused water dispensers);
5. Unhygienically thawed fowl (the meltwater contains many bacteria);
6. An association with reptiles (pet tortoises, snakes, and frogs, but primarily aquatic turtles) is well described.

Salmonella bacteria can survive several weeks in a dry environment and several months in water; thus, they are frequently found in polluted water, contamination from the excrement of carrier animals being particularly important. Aquatic vertebrates, notably birds and reptiles, are important vectors of Salmonella. Poultry, cattle, and sheep frequently being agents of contamination, salmonella can be found in food, especially in milk, meats and sometimes in eggs which have cracks.

About 142,000 (reported) Americans are infected each year with Salmonella enteritidis from chicken eggs, and about 30 die. The shell of the egg may be contaminated with Salmonella by faeces or environment, or its interior (yolk) may be contaminated by penetration of the bacteria through the porous shell or from a hen whose infected ovaries contaminate the egg during egg formation. Nevertheless, such interior egg yolk contamination is theoretically unlikely. Even under natural conditions, the rate of infection was found to be very small (0.6% in a study of naturally-contaminated eggs and 3.0% among artificially- and heavily-infected hens). A recent analysis of death certificates in the United States identified a total of 1,316 Salmonella-related deaths between the years 1990 to 2006. These were predominately among older adults and those who were immunocompromised.

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Ovarian cancer is a cancerous growth arising from different parts of the ovary.

Most (>90%) ovarian cancers are classified as "epithelial" and were believed to arise from the surface (epithelium) of the ovary. However, recent evidence suggests that the Fallopian tube could also be the source of some ovarian cancers. Since the ovaries and tubes are closely related to each other, it is hypothesized that these cells can mimic ovarian cancer. Other types arise from the egg cells (germ cell tumor) or supporting cells (sex cord/stromal).

In 2004, in the United States, 25,580 new cases were diagnosed and 16,090 women died of ovarian cancer. The risk increases with age and decreases with pregnancy. Lifetime risk is about 1.6%, but women with affected first-degree relatives have a 5% risk. Women with a mutated BRCA1 or BRCA2 gene carry a risk between 25% and 60% depending on the specific mutation. Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of death from gynecological cancer.

In early stages ovarian cancer is associated with abdominal distension.

10-year relative survival ranges from 84.1% in stage IA to 10.4% in stage IIIC.

Ovarian cancer causes non-specific symptoms. Early diagnosis would result in better survival, on the assumption that stage I and II cancers progress to stage III and IV cancers (but this has not been proven). Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid (ascites) in the abdominal cavity.

Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound. The diagnosis must be confirmed with surgery to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis) and look for cancer cells in the abdominal fluid. Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.

In most cases, the cause of ovarian cancer remains unknown. Older women, and in those who have a first or second degree relative with the disease, have an increased risk. Hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1 and BRCA2, but also in genes for hereditary nonpolyposis colorectal cancer). Infertile women and those with a condition called endometriosis, those who have never been pregnant and those who use postmenopausal estrogen replacement therapy are at increased risk. Use of combined oral contraceptive pills is a protective factor. The risk is also lower in women who have had their uterine tubes blocked surgically (tubal ligation).

Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis.

1. Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer. It includes serous tumour, endometrioid tumor and mucinous cystadenocarcinoma.
2. Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
3. Germ cell tumor accounts for approximately 30% of ovarian tumors but only 5% of ovarian cancers, because most germ cell tumors are teratomas and most teratomas are benign (see Teratoma). Germ cell tumor tends to occur in young women and girls. The prognosis depends on the specific histology of germ cell tumor, but overall is favorable.
4. Mixed tumors, containing elements of more than one of the above classes of tumor histology.

The exact cause is usually unknown. The risk of developing ovarian cancer appears to be affected by several factors. The more children a woman has, the lower her risk of ovarian cancer. Early age at first pregnancy, older age of final pregnancy and the use of low dose hormonal contraception have also been shown to have a protective effect. Ovarian cancer is reduced in women after tubal ligation.

The relationship between use of oral contraceptives and ovarian cancer was shown in a summary of results of 45 case-control and prospective studies. Cumulatively these studies show a protective effect for ovarian cancers. Women who used oral contraceptives for 10 years had about a 60% reduction in risk of ovarian cancer. (risk ratio .42 with statistical significant confidence intervals given the large study size, not unexpected). This means that if 250 women took oral contraceptives for 10 years, 1 ovarian cancer would be prevented. This is by far the largest epidemiological study to date on this subject (45 studies, over 20,000 women with ovarian cancer and about 80,000 controls).

The link to the use of fertility medication, such as Clomiphene citrate, has been controversial. An analysis in 1991 raised the possibility that use of drugs may increase the risk of ovarian cancer. Several cohort studies and case-control studies have been conducted since then without demonstrating conclusive evidence for such a link. It will remain a complex topic to study as the infertile population differs in parity from the "normal" population.

Ovarian cancer at its early stages(I/II) is difficult to diagnose until it spreads and advances to later stages (III/IV). This is because most symptoms are non-specific and thus of little use in diagnosis.

When an ovarian malignancy is included in the list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolyte test should be obtained in all patients.

The serum BHCG level should be measured in any female in whom pregnancy is a possibility. In addition, serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) should be measured in young girls and adolescents with suspected ovarian tumors because the younger the patient, the greater the likelihood of a malignant germ cell tumor.

A blood test called CA-125 is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. However, this is the only widely-used marker currently available.

Current research is looking at ways to combine tumor markers proteomics along with other indicators of disease (i.e. radiology and/or symptoms) to improve accuracy. The challenge in such an approach is that the very low population prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results (i.e. performing surgical procedures in which cancer is not found intra-operatively). However, the contributions of proteomics are still in the early stages and require further refining. Current studies on proteomics mark the beginning of a paradigm shift towards individually tailored therapy.

A pelvic examination and imaging including CT scan and trans-vaginal ultrasound are essential. Physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic examination can include a rectovaginal component for better palpation of the ovaries. For very young patients, magnetic resonance imaging may be preferred to rectal and vaginal examination.

To definitively diagnose ovarian cancer, a surgical procedure to take a look into the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas will be removed and sent for microscopic analysis. Fluid from the abdominal cavity can also be analysed for cancerous cells. If there is cancer, this procedure can also determine its spread (which is a form of tumor staging).

Surgical treatment may be sufficient for malignant tumors that are well-differentiated and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors that are confined to the ovary. For patients with advanced disease a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.

Surgery is the preferred treatment and is frequently necessary to obtain a tissue specimen for differential diagnosis via its histology. Surgery performed by a specialist in gynecologic oncology usually results in an improved result. Improved survival is attributed to more accurate staging of the disease and a higher rate of aggressive surgical excision of tumor in the abdomen by gynecologic oncologists as opposed to general gynecologists and general surgeons.

The type of surgery depends upon how widespread the cancer is when diagnosed (the cancer stage), as well as the presumed type and grade of cancer. The surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), the fallopian tubes (salpingectomy), and the uterus (hysterectomy). For some very early tumors (stage 1, low grade or low-risk disease), only the involved ovary and fallopian tube will be removed (called a "unilateral salpingo-oophorectomy," USO), especially in young females who wish to preserve their fertility.

In advanced malignancy, where complete resection is not feasible, as much tumor as possible is removed (debulking surgery). In cases where this type of surgery is successful (i.e. < 1 cm in diameter of tumor is left behind ["optimal debulking"]), the prognosis is improved compared to patients where large tumor masses (> 1 cm in diameter) are left behind. Minimally invasive surgical techniques may facilitate the safe removal of very large (greater than 10 cm) tumors with fewer complications of surgery.

Chemotherapy has been a general standard of care for ovarian cancer for decades, although with highly variable protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. This depends on the histology of the tumor; some kinds of tumor (particularly teratoma) are not sensitive to chemotherapy. In some cases, there may be reason to perform chemotherapy first, followed by surgery.

For patients with stage IIIC epithelial ovarian adenocarcinomas who have undergone successful optimal debulking, a recent clinical trial demonstrated that median survival time is significantly longer for patient receiving intraperitoneal (IP) chemotherapy. Patients in this clinical trial reported less compliance with IP chemotherapy and fewer than half of the patients received all six cycles of IP chemotherapy. Despite this high "drop-out" rate, the group as a whole (including the patients that didn't complete IP chemotherapy treatment) survived longer on average than patients who received intravenous chemotherapy alone.

Some specialists believe the toxicities and other complications of IP chemotherapy will be unnecessary with improved IV chemotherapy drugs currently being developed.

Although IP chemotherapy has been recommended as a standard of care for the first-line treatment of ovarian cancer, the basis for this recommendation has been challenged.

Radiation therapy is not effective for advanced stages because when vital organs are in the radiation field, a high dose cannot be safely delivered. Radiation therapy is then commonly avoided in such stages as the vital organs may not be able to withstand the problems associated with these ovarian cancer treatments.

Ovarian cancer usually has a poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning that most cases are not diagnosed until they have reached advanced stages. More than 60% of women presenting with this cancer already have stage III or stage IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, included the uterus, urinary bladder, bowel and the lining of the bowel wall omentum forming new tumor growths before cancer is even suspected.

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Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye (see uveal melanoma). Melanoma can occur in any part of the body that contains melanocytes.

Melanoma is less common than other skin cancers. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer. Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among Caucasians living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe. According to a WHO report about 48,000 melanoma related deaths occur worldwide per year.

The treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy. The chance of a cure is greatest when the tumor is discovered while it is still small and thin, and can be entirely removed surgically.

Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.

The earliest stage of melanoma starts when the melanocytes begin to grow out of control. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, and the tumour is less than 1mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage then it can usually be completely removed with surgery.

When the tumour cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis - the behaviour of the cells changes dramatically.

The next step in the evolution is the invasive verical growth phase, which is a confusing term, however it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The Breslow's depth of the lesion is usually less than 1 mm (0.04 in), the Clark level is usually 2.

The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumour thickness is usually more than 1 mm (0.04 in), and the tumour involves the deeper parts of the dermis.

The host elicits an immunological reaction against the tumour (during the VGP), which is judged by the presence and activity of the TILs (tumour infiltrating lymphocytes). These cells sometimes completely destroy the primary tumour, this is called regression, which is the latest stage of the melanoma development. In certain cases the primary tumour is completely destroyed and only the metastatic tumour is discovered.

In some cases, melanoma runs in families. Several different genes have been identified as increasing the risk of developing melanoma. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively low risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition Xeroderma Pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant.

Familial melanoma is genetically heterogeneous, and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma. The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a — a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) — which has been localised to the p21 region of human chromosome 9.

Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene.

Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.

In addition to identifying high-risk patients, researchers want to identify high-risk lesions within a given patient. Many new technologies, such as optical coherence tomography (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy and fluorescently tagged antibodies are also proving to be valuable diagnostic tools.

Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.

Early signs of melanoma are changes to the shape or color of existing moles or in the case of nodular melanoma the appearance of a new lump anywhere on the skin (such lesions should be referred without delay to a dermatologist). At later stages, the mole may itch, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDE":

* Asymmetry

* Borders (irregular)

* Color (variegated), and

* Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)

* Evolving over time

These classifications do not however apply to the most dangerous form of melanoma nodular melanoma which has its own classifications:

• Elevated above the skin surface
• Firm to the touch
• Growing.

Metastatic melanoma may cause non-specific paraneoplastic symptoms including loss of appetite, nausea, vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma.

There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals. To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" mnemonic below), to be aware of moles and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.

A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":

• Asymmetrical skin lesion.
• Border of the lesion is irregular.
• Color: melanomas usually have multiple colors.
• Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.
• Enlarging: Enlarging or evolving

A weakness in this system is the D. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and all melanomas were malignant on day 1 of growth, which is merely a dot. An astute physician will examine all abnormal moles, including ones less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms among laypeople and sometimes even physicians. An experienced doctor can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy.

Some will advocate the system "ABCDE",[18] with E for evolution. Certainly moles which change and evolve will be a concern. Alternatively, some will refer to E as elevation. Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas are detected in the very early stage, or in-situ stage, before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.

However, Nodular melanomas do not fulfill these criteria, having their own mnemonic "EFG":

• Elevated: the lesion is raised above the surrounding skin.
• Firm: the nodule is solid to the touch.
• Growing: the nodule is increasing in size.

A recent and novel method of melanoma detection is the "Ugly Duckling Sign" It is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person's skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and further professional exam is required. The "Little Red Riding Hood" sign suggests that individuals with fair skin and light colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care and caution should be rendered when examining such individuals as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble non-melanomas or are considered to be "wolves in sheep clothing". These fair skinned individuals often have lightly pigmented or amelanotic melanomas which will not present easy-to-observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope (dermatoscopy) very difficult.

People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma.

Moles that are irregular in color or shape are often treated as candidates of melanoma. Following a visual examination and a dermatoscopic exam, or an in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. If the mole is malignant, the mole and an area around it need excision.

The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma. Amelanotic melanomas and melanomas arising in fair skinned individuals (see the "Little Red Riding Hood" sign) are very difficult to detect as they fail to show many of the characteristics in the ABCD rule, break the "Ugly Duckling" sign, and are very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.

Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up of high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (being possible with the use of any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use sunscreens with an SPF rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of sunscreen to prevent melanoma. This controversy is well discussed in numerous review articles, and is refuted by most dermatologists. This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB. See Sunscreen controversy for further references and discussions. Tanning, once believed to help prevent skin cancers, actually can lead to an increased incidence of melanomas. Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.

A good rule of thumb for decreasing ultraviolet light exposure is to avoid the sun between the hours of 9 a.m. and 3 p.m. or avoid the sun when your shadow is shorter than your height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.

Almost all melanomas start with altering the color and appearance of normal-looking skin. This area may be a dark spot or an abnormal new mole. Other melanomas form from a mole or freckle that is already present in the skin. It can be difficult to distinguish between a melanoma and a normal mole. When looking for danger signs in pigmented lesions of the skin a few simple rules are often used. The “ABCDE” list, the "ugly duckling sign", and the "red riding hood" rule are defined and discussed under the heading "Detection" earlier in this article.

“Melanoma Monday” is the kick-off of May Melanoma Month with special activities nationally and locally. Also known as National Skin Self-Examination Day. People are encouraged to examine their skin for skin cancer. Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.

In research setting other therapies, such as adoptive cell therapy or gene therapy, may be tested. Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US have been used in advanced (metastatic) melanoma with moderate success. The first treatment involves adoptive cell therapy using immune cells isolated from a patient's own melanoma tumor (TIL). These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL Therapy following lymphodepletion can result in complete responses in highly pretreated patients. The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.

A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.

About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggest that B-Raf inhibitors including Plexxicon(R) can lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. Large clinical trials are underway to more fully evaluate the efficacy and potency of B-Raf inhibitors. Sutent may be effective for patients with metastatic melanoma.

Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.

John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806. The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease).

The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for benefit depends upon the early removal of the disease ...' More than one and a half centuries later this situation remains largely unchanged.

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Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms (endotherms). Most E. coli strains are harmless, but some, such as serotype O157:H7, can cause serious food poisoning in humans, and are occasionally responsible for product recalls. The harmless strains are part of the normal flora of the gut, and can benefit their hosts by producing vitamin K2, and by preventing the establishment of pathogenic bacteria within the intestine.

E. coli bacteria are not always confined to the intestine, and their ability to survive for brief periods outside the body makes them ideal indicator organisms to test environmental samples for fecal contamination. The bacterium can also be grown easily, and its genetics are comparatively simple and easily manipulated or duplicated through a process of metagenics, making it one of the best-studied prokaryotic model organisms, and an important species in biotechnology and microbiology.

E. coli was discovered by German pediatrician and bacteriologist Theodor Escherich in 1885, and is now classified as part of the Enterobacteriaceae family of gamma-proteobacteria.

E. coli is Gram-negative, facultative anaerobic and non-sporulating. Cells are typically rod-shaped, and are about 2.0 micrometres (μm) long and 0.5 μm in diameter, with a cell volume of 0.6 – 0.7 (μm)3. It can live on a wide variety of substrates. E. coli uses mixed-acid fermentation in anaerobic conditions, producing lactate, succinate, ethanol, acetate and carbon dioxide. Since many pathways in mixed-acid fermentation produce hydrogen gas, these pathways require the levels of hydrogen to be low, as is the case when E. coli lives together with hydrogen-consuming organisms, such as methanogens or sulphate-reducing bacteria.

Optimal growth of E. coli occurs at 37°C (98.6°F) but some laboratory strains can multiply at temperatures of up to 49°C (120.2°F). Growth can be driven by aerobic or anaerobic respiration, using a large variety of redox pairs, including the oxidation of pyruvic acid, formic acid, hydrogen and amino acids, and the reduction of substrates such as oxygen, nitrate, dimethyl sulfoxide and trimethylamine N-oxide.

Strains that possess flagella can swim and are motile. The flagella have a peritrichous arrangement.

E. coli and related bacteria possess the ability to transfer DNA via bacterial conjugation, transduction or transformation, which allows genetic material to spread horizontally through an existing population. This process led to the spread of the gene encoding shiga toxin from Shigella to E. coli O157:H7, carried by a bacteriophage.

As more is known about certain organisms, such as genetic information, the taxonomic classification of species is changed to reflect the advance in knowledge, however in the case of Escherichia coli due to its medical importance, this has not occurred (namely split into several genera/species) and remains one of the most diverse bacterial species: only 20% of the genome is common to all strains. In fact, from the evolutionary point of view, the members of genus Shigella (dysenteriae, flexneri, boydii, sonnei) are actually E. coli strains "in disguise" (i.e. E.coli is paraphyletic to the genus).

A strain of E. coli is a sub-group within the species that has unique characteristics that distinguish it from other E. coli strains. These differences are often detectable only at the molecular level; however, they may result in changes to the physiology or lifecycle of the bacterium. For example, a strain may gain pathogenic capacity, the ability to use a unique carbon source, the ability to take upon a particular ecological niche or the ability to resist antimicrobial agents. Different strains of E. coli are often host-specific, making it possible to determine the source of faecal contamination in environmental samples. For example, knowing which E. coli strains are present in a water sample allows researchers to make assumptions about whether the contamination originated from a human, another mammal or a bird.

A common subdivison system of E.coli, but not based on evolutionary relatedness, is by serotype, which is based on major surface antigens (O antigen: part of lipopolysaccharide layer; H: flagellin; K antigen: capsule), e.g. O157:H7) (NB: K-12, the common laboratory strain is not a serotype.)

New strains of E. coli evolve through the natural biological process of mutation and through horizontal gene transfer. Some strains develop traits that can be harmful to a host animal. These virulent strains typically cause a bout of diarrhoea that is unpleasant in healthy adults and is often lethal to children in the developing world. More virulent strains, such as O157:H7 cause serious illness or death in the elderly, the very young or the immunocompromised.

E. coli is the type species of the genus and the neotype strain is ATCC 11775, also known as NCTC 9001, which is pathogenic to chickens and has a O1:K1:H7 serotype. However, in most studies either O157:H7 or K-12 MG1655 or K-12 W3110 are used as a representative E.coli.

Transmission of pathogenic E. coli often occurs via faecal-oral transmission. Common routes of transmission include: unhygienic food preparation, farm contamination due to manure fertilization, irrigation of crops with contaminated greywater or raw sewage, feral pigs on cropland, or direct consumption of sewage-contaminated water. Dairy and beef cattle are primary reservoirs of E. coli O157:H7, and they can carry it asymptomatically and shed it in their faeces. Food products associated with E. coli outbreaks include cucumber, raw ground beef, raw seed sprouts or spinach, raw milk, unpasteurized juice, unpasteurized cheese and foods contaminated by infected food workers via faecal-oral route.

According to the U.S. Food and Drug Administration, the faecal-oral cycle of transmission can be disrupted by cooking food properly, preventing cross-contamination, instituting barriers such as gloves for food workers, instituting health care policies so food industry employees seek treatment when they are ill, pasteurization of juice or dairy products and proper hand washing requirements.

Shiga toxin-producing E. coli (STEC), specifically serotype O157:H7, have also been transmitted by flies, as well as direct contact with farm animals, petting zoo animals, and airborne particles found in animal-rearing environments.

Urinary tract infection

Uropathogenic E. coli (UPEC) is responsible for approximately 90% of urinary tract infections (UTI) seen in individuals with ordinary anatomy. In ascending infections, fecal bacteria colonize the urethra and spread up the urinary tract to the bladder as well as to the kidneys (causing pyelonephritis), or the prostate in males. Because women have a shorter urethra than men, they are 14 times more likely to suffer from an ascending UTI.

Uropathogenic E. coli use P fimbriae (pyelonephritis-associated pili) to bind urinary tract endothelial cells and colonize the bladder. These adhesins specifically bind D-galactose-D-galactose moieties on the P blood-group antigen of erythrocytes and uroepithelial cells. Approximately 1% of the human population lacks this receptor, and its presence or absence dictates an individual's susceptibility to E. coli urinary tract infections. Uropathogenic E. coli produce alpha- and beta-hemolysins, which cause lysis of urinary tract cells.

UPEC can evade the body's innate immune defences (e.g. the complement system) by invading superficial umbrella cells to form intracellular bacterial communities (IBCs). They also have the ability to form K antigen, capsular polysaccharides that contribute to biofilm formation. Biofilm-producing E. coli are recalcitrant to immune factors and antibiotic therapy, and are often responsible for chronic urinary tract infections. K antigen-producing E. coli infections are commonly found in the upper urinary tract.

Descending infections, though relatively rare, occur when E. coli cells enter the upper urinary tract organs (kidneys, bladder or ureters) from the blood stream.

Bacterial infections are usually treated with antibiotics. However, the antibiotic sensitivities of different strains of E. coli vary widely. As Gram-negative organisms, E. coli are resistant to many antibiotics that are effective against Gram-positive organisms. Antibiotics which may be used to treat E. coli infection include amoxicillin, as well as other semisynthetic penicillins, many cephalosporins, carbapenems, aztreonam, trimethoprim-sulfamethoxazole, ciprofloxacin, nitrofurantoin and the aminoglycosides.

Antibiotic resistance is a growing problem. Some of this is due to overuse of antibiotics in humans, but some of it is probably due to the use of antibiotics as growth promoters in animal feeds. A study published in the journal Science in August 2007 found the rate of adaptative mutations in E. coli is "on the order of 10−5 per genome per generation, which is 1,000 times as high as previous estimates," a finding which may have significance for the study and management of bacterial antibiotic resistance.

Antibiotic-resistant E. coli may also pass on the genes responsible for antibiotic resistance to other species of bacteria, such as Staphylococcus aureus, through a process called horizontal gene transfer. E. coli bacteria often carry multiple drug-resistance plasmids, and under stress, readily transfer those plasmids to other species. Indeed, E. coli is a frequent member of biofilms, where many species of bacteria exist in close proximity to each other. This mixing of species allows E. coli strains that are piliated to accept and transfer plasmids from and to other bacteria. Thus, E. coli and the other enterobacteria are important reservoirs of transferable antibiotic resistance.

Researchers have actively been working to develop safe, effective vaccines to lower the worldwide incidence of E. coli infection. In March 2006, a vaccine eliciting an immune response against the E. coli O157:H7 O-specific polysaccharide conjugated to recombinant exotoxin A of Pseudomonas aeruginosa (O157-rEPA) was reported to be safe in children two to five years old. Previous work had already indicated it was safe for adults. A phase III clinical trial to verify the large-scale efficacy of the treatment is planned.

In 2006, Fort Dodge Animal Health (Wyeth) introduced an effective, live, attenuated vaccine to control airsacculitis and peritonitis in chickens. The vaccine is a genetically modified avirulent vaccine that has demonstrated protection against O78 and untypeable strains.

In January 2007, the Canadian biopharmaceutical company Bioniche announced it has developed a cattle vaccine which reduces the number of O157:H7 shed in manure by a factor of 1000, to about 1000 pathogenic bacteria per gram of manure.

In April 2009, a Michigan State University researcher announced he had developed a working vaccine for a strain of E. coli. Mahdi Saeed, professor of epidemiology and infectious disease in MSU's colleges of Veterinary Medicine and Human Medicine, has applied for a patent for his discovery and has made contact with pharmaceutical companies for commercial production.

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The Texas Animal Health Commission has been inundated with calls on the neurological equine herpes virus, ranging from people wanting to know if they should cancel an equine event to when are updates available.

The following are definitions for EHV-1 and EHM, derived from the United States Department of Agriculture’s Animal and Plants Health Inspection Service website at www.aphis.usda.gov:

• Suspected EHV-1 case: An exposed horse with a fever – a temperature greater than 101.5 degrees Fahrenheit – during the monitoring period.

• Confirmed EHV-1 case: A suspect EHV-1 case whose infection is laboratory confirmed by virus isolation and/or polymerase chain reaction (PCR) detection of the virus, or a four-fold change in titer on the serum neutralization test using paired sera.

• Suspect EHM case: An exposed horse exhibiting signs of central nervous system (CNS) dysfunction, including most commonly posterior incoordination, weakness, recumbency with inability to rise or bladder atony.

• Confirmed EHM case: A suspect EHM case testing positive for EHV-1 by virus isolation and/or PCR assay on nasal swab or blood (buffy coat). In cases of sudden death or where the horse dies as a result of neurological complications, the postmortem lesions are consistent with those of myeloencephalopathy and EHV-1 has been isolated, detected by PCR, or demonstrated by immunohistochemical examination of the CNS.

• Non-clinical EHV-1 case: (It is not recommended to test exposed non-clinical horses). An exposed horse with no clinical signs (no fever and non-neurologic) testing positive for EHV-1 by virus isolation and/or PCR assay on nasal swab or blood (buffy coat).

Ramirez said TAHC keeps track of the official data in Texas of EHV-1 cases.

“We are the source [for the data],” she said, adding that she hopes media sources direct individuals “to get our updates and not rely on hearsay.”

She said the TAHC has not modified entry requirements into Texas and suggests individuals check with specific states on entry requirements.

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Malaria is a mosquito-borne infectious disease of humans caused by eukaryotic protists of the genus Plasmodium. It is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa, Asia and the Americas. Malaria is very prevalent in these regions because they have significant amounts of rain fall and consistent hot temperatures. These warm, consistent temperatures and moisture provide mosquitos with the environment they need to breed continuously. The disease results from the multiplication of malaria parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases progressing to coma, and death.

Four species of Plasmodium can infect and be transmitted by humans. Severe disease is largely caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae is generally a milder disease that is rarely fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans.

Malaria transmission can be reduced by preventing mosquito bites by distribution of inexpensive mosquito nets and insect repellents, or by mosquito-control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs. Although many are under development, the challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is still to be met. Two drugs are also available to prevent malaria in travellers to malaria-endemic countries (prophylaxis).

A variety of antimalarial medications are available. In the last 5 years, treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin derivative artesunate which is superior to quinine in both children and adults. Resistance has developed to several antimalarial drugs, most notably chloroquine.

Each year, there are more than 225 million cases of malaria, killing around 781,000 people each year according to the World Health Organisation's 2010 World Malaria Report, 2.23% of deaths worldwide. The majority of deaths are of young children in sub-Saharan Africa. Ninety percent of malaria-related deaths occur in sub-Saharan Africa. Malaria is commonly associated with poverty, and can indeed be a cause of poverty and a major hindrance to economic development.

Signs and symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three days for P. malariae. P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable. Cerebral malaria is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.

Severe malaria is almost exclusively caused by P. falciparum infection, and usually arises 6–14 days after infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care and treatment. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.

Cause

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. P. falciparum is the most common cause of infection, and is also responsible for about 90% of the deaths from malaria. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi, P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.

Malaria parasites contain apicoplasts, an organelle usually found in plants, complete with their own functioning genomes. These apicoplast are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio-synthesis. To date, 466 proteins have been found to be produced by apicoplasts and these are now being looked at as possible targets for novel anti-malarial drugs.

Prevention

Methods used in order to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication and the prevention of mosquito bites.

The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favours the parasite's reproduction. Many countries are seeing an increasing number of imported malaria cases owing to extensive travel and migration.

Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year.

A 2008 study that examined international financing of malaria control found large regional variations in the levels of average annual per capita funding ranging from US$0.01 in Myanmar to US$147 in Suriname. The study found 34 countries where the funding was less than US$1 per capita, including 16 countries where annual malaria support was less than US$0.5. The 16 countries included 710 million people or 50% of the global population exposed to the risks of malaria transmission, including seven of the poorest countries in Africa (Côte d'Ivoire, Republic of the Congo, Chad, Mali, Democratic Republic of the Congo, Somalia, and Guinea) and two of the most densely populated stable endemic countries in the world (Indonesia and India).

Brazil, Eritrea, India, and Vietnam, unlike many other developing nations, have successfully reduced the malaria burden. Common success factors have included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.

Medications

Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Modern drugs used include mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride (Malarone). Doxycycline and the atovaquone and proguanil combination are the best tolerated with mefloquine associated with higher rates of neurological and psychiatric symptoms. The choice of which drug to use depends on which drugs the parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards). Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Quinine was used historically, however the development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the 20th century reduced its use. Today, quinine is not generally used for prophylaxis. The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of partial immunity.

Treatment

When properly treated, a patient with malaria can expect a complete recovery. The treatment of malaria depends on the severity of the disease; whether patients who can take oral drugs have to be admitted depends on the assessment and the experience of the clinician. Uncomplicated malaria is treated with oral drugs. The most effective strategy for P. falciparum infection recommended by WHO is the use of artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, in order to avoid the development of drug resistance against artemisinin-based therapies.

Severe malaria requires the parenteral administration of antimalarial drugs. Until recently the most used treatment for severe malaria was quinine but artesunate has been shown to be superior to quinine in both children and adults. Treatment of severe malaria also involves supportive measures.

Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.

It is advised to be cautious diagnosing and treating without the presence of a headache, as it is possible that the patient has dengue; not malaria.

History

Malaria has infected humans for over 50,000 years, and Plasmodium may have been a human pathogen for the entire history of the species. Close relatives of the human malaria parasites remain common in chimpanzees. Some new evidence suggests that the most virulent strain of human malaria may have originated in gorillas.

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China. Malaria may have contributed to the decline of the Roman Empire, and was so pervasive in Rome that it was known as the "Roman fever". The term malaria originates from Medieval Italian: mala aria — "bad air"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.

Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns.

Prevention

An early effort at malaria prevention occurred in 1896, just before the mosquito malaria link was confirmed in India by a British physician, Ronald Ross. An 1896 Uxbridge malaria outbreak prompted health officer, Dr. Leonard White, to write a report to the Massachusetts State Board of Health, which led to study of mosquito-malaria links, and the first efforts for malaria prevention. Massachusetts State pathologist Theobald Smith, asked that White's son collect mosquito specimens for further analysis, and that citizens 1) add screens to windows, and 2) drain collections of water. Carlos Finlay was also engaged in mosquito related research, and mosquito borne disease theory, in the 1880s in Cuba, basing his work on the study of Yellow Fever.

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