HYPERTENSION - FROM WIKIPEDIA, THE FREE ENCYCLOPEDIA

This article is about arterial hypertension. For other forms of hypertension, see Hypertension (disambiguation).
Hypertension
Classification and external resources

Automated arm blood pressure meter showing arterial hypertension (shown a systolic blood pressure 158 mmHg, diastolic blood pressure 99 mmHg and heart rate of 80 beats per minute)

ICD-9
401

OMIM
145500

DiseasesDB
6330

MedlinePlus
000468

MeSH
D006973

Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronicmedical condition in which the blood pressure in the arteries is elevated. Blood pressure is summarised by two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). This equals the maximum and minimum pressure, respectively. Normal blood pressure at rest is within the range of 100–140mmHg systolic (top reading) and 60–90mmHg diastolic (bottom reading). High blood pressure is said to be present if it is often at or above 140/90 mmHg.
Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as "primary hypertension" which means high blood pressure with no obvious underlying medical cause.[1] The remaining 5–10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system.
Hypertension puts strain on the heart, leading to hypertensive heart disease and coronary artery disease if not treated. Hypertension is also a major risk factor for stroke, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease. A moderately high arterial blood pressure is associated with a shortened life expectancy while mild elevation is not. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of health complications, although drug treatment is still often necessary in people for whom lifestyle changes are not enough or not effective.
Contents
•    1 Signs and symptoms
o    1.1 Secondary hypertension
o    1.2 Hypertensive crisis
o    1.3 Pregnancy
o    1.4 Children
•    2 Cause
o    2.1 Primary hypertension
o    2.2 Secondary hypertension
•    3 Pathophysiology
•    4 Diagnosis
o    4.1 Adults
o    4.2 Children
•    5 Prevention
•    6 Management
o    6.1 Lifestyle modifications
o    6.2 Medications
o    6.3 Elderly
o    6.4 Resistant hypertension
•    7 Epidemiology
o    7.1 Children
•    8 Prognosis
•    9 History
•    10 Society and culture
o    10.1 Awareness
o    10.2 Economics
•    11 Research
•    12 References
•    13 Further reading
•    14 External links
Signs and symptoms
Hypertension is rarely accompanied by any symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. A proportion of people with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as lightheadedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting episodes.[2] These symptoms, however, might be related to associated anxiety rather than the high blood pressure itself.[3]
On physical examination, hypertension may be suspected on the basis of the presence of hypertensive retinopathy detected by examination of the optic fundus found in the back of the eye using ophthalmoscopy.[4] Classically, the severity of the hypertensive retinopathy changes is graded from grade I–IV, although the milder types may be difficult to distinguish from each other.[4] Ophthalmoscopy findings may also give some indication as to how long a person has been hypertensive.[2]
Secondary hypertension
Main article: Secondary hypertension
Some additional signs and symptoms may suggest secondary hypertension, i.e. hypertension due to an identifiable cause such as kidney diseases or endocrine diseases. For example, truncal obesity, glucose intolerance, moon face, a "buffalo hump" and purple stretch marks suggest Cushing's syndrome.[5]Thyroid disease and acromegaly can also cause hypertension and have characteristic symptoms and signs.[5] An abdominal bruit may be an indicator of renal artery stenosis (a narrowing of the arteries supplying the kidneys), while decreased blood pressure in the lower extremities and/or delayed or absent femoral arterial pulses may indicate aortic coarctation (a narrowing of the aorta shortly after it leaves the heart). Labile or paroxysmal hypertension accompanied by headache, palpitations, pallor, and perspiration should prompt suspicions of pheochromocytoma.[5]
Hypertensive crisis
Main article: Hypertensive emergency
Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110—sometimes termed malignant or accelerated hypertension) is referred to as a "hypertensive crisis", as blood pressure at this level confers a high risk of complications. People with blood pressures in this range may have no symptoms, but are more likely to report headaches (22% of cases)[6] and dizziness than the general population.[2] Other symptoms accompanying a hypertensive crisis may include visual deterioration or breathlessness due to heart failure or a general feeling of malaise due to renal failure.[5] Most people with a hypertensive crisis are known to have elevated blood pressure, but additional triggers may have led to a sudden rise.[7]
A "hypertensive emergency", previously "malignant hypertension", is diagnosed when there is evidence of direct damage to one or more organs as a result of severely elevated blood pressure greater than 180 systolic or 120 diastolic.[8] This may include hypertensive encephalopathy, caused by brain swelling and dysfunction, and characterized by headaches and an altered level of consciousness (confusion or drowsiness). Retinal papilloedema and/or fundal hemorrhages and exudates are another sign of target organ damage. Chest pain may indicate heart muscle damage (which may progress to myocardial infarction) or sometimes aortic dissection, the tearing of the inner wall of the aorta. Breathlessness, cough, and the expectoration of blood-stained sputum are characteristic signs of pulmonary edema, the swelling of lung tissue due to left ventricular failure an inability of the left ventricle of the heart to adequately pump blood from the lungs into the arterial system.[7]Rapid deterioration of kidney function (acute kidney injury) and microangiopathic hemolytic anemia (destruction of blood cells) may also occur.[7] In these situations, rapid reduction of the blood pressure is mandated to stop ongoing organ damage.[7] In contrast there is no evidence that blood pressure needs to be lowered rapidly in hypertensive urgencies where there is no evidence of target organ damage and over aggressive reduction of blood pressure is not without risks.[5] Use of oral medications to lower the BP gradually over 24 to 48h is advocated in hypertensive urgencies.[7]
Pregnancy
Main article: Gestational hypertension
Hypertension occurs in approximately 8–10% of pregnancies.[5] Two blood pressure measurements six hours apart of greater than 140/90 mm Hg is considered diagnostic of hypertension in pregnancy.[9] Most women with hypertension in pregnancy have pre-existing primary hypertension, but high blood pressure in pregnancy may be the first sign of pre-eclampsia, a serious condition of the second half of pregnancy and puerperium.[5] Pre-eclampsia is characterised by increased blood pressure and the presence of protein in the urine.[5] It occurs in about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths globally.[5] Pre-eclampsia also doubles the risk of perinatal mortality.[5] Usually there are no symptoms in pre-eclampsia and it is detected by routine screening. When symptoms of pre-eclampsia occur the most common are headache, visual disturbance (often "flashing lights"), vomiting, epigastric pain, and edema. Pre-eclampsia can occasionally progress to a life-threatening condition called eclampsia, which is a hypertensive emergency and has several serious complications including vision loss, cerebral edema, seizures or convulsions, renal failure, pulmonary edema, and disseminated intravascular coagulation (a blood clotting disorder).[5][10]
Children
Failure to thrive, seizures, irritability, lack of energy, and difficulty breathing[11] can be associated with hypertension in neonates and young infants. In older infants and children, hypertension can cause headache, unexplained irritability, fatigue, failure to thrive, blurred vision, nosebleeds, and facial paralysis.[11][12]
Cause
Primary hypertension
Main article: Essential hypertension
Primary (essential) hypertension is the most common form of hypertension, accounting for 90–95% of all cases of hypertension.[1] In almost all contemporary societies, blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable.[13] Hypertension results from a complex interaction of genes and environmental factors. Numerous common genetic variants with small effects on blood pressure have been identified[14] as well as some rare genetic variants with large effects on blood pressure[15] but the genetic basis of hypertension is still poorly understood. Several environmental factors influence blood pressure. Lifestyle factors that lower blood pressure include reduced dietary salt intake,[16][17] increased consumption of fruits and low fat products (Dietary Approaches to Stop Hypertension (DASH diet)), exercise,[18]weight loss[19] and reduced alcohol intake.[20] Stress appears to play a minor role[3] with specific relaxation techniques not supported by the evidence.[21][22] The possible role of other factors such as caffeine consumption,[23] and vitamin D deficiency[24] are less clear cut. Insulin resistance, which is common in obesity and is a component of syndrome X (or the metabolic syndrome), is also thought to contribute to hypertension.[25] Recent studies have also implicated events in early life (for example low birth weight, maternal smoking and lack of breast feeding) as risk factors for adult essential hypertension,[26] although the mechanisms linking these exposures to adult hypertension remain obscure.[26]
Secondary hypertension
Main article: Secondary hypertension
Secondary hypertension results from an identifiable cause. Renal disease is the most common secondary cause of hypertension.[5] Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma.[5][27] Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive liquorice consumption and certain prescription medicines, herbal remedies and illegal drugs.[5][28]
Pathophysiology
Main article: Pathophysiology of hypertension


A diagram explaining factors affecting arterial pressure


Illustration depicting the effects of high blood pressure
In most people with established essential (primary) hypertension, increased resistance to blood flow (total peripheral resistance) accounts for the high pressure while cardiac output remains normal.[29] There is evidence that some younger people with prehypertension or 'borderline hypertension' have high cardiac output, an elevated heart rate and normal peripheral resistance, termed hyperkinetic borderline hypertension.[30] These individuals develop the typical features of established essential hypertension in later life as their cardiac output falls and peripheral resistance rises with age.[30] Whether this pattern is typical of all people who ultimately develop hypertension is disputed.[31] The increased peripheral resistance in established hypertension is mainly attributable to structural narrowing of small arteries and arterioles,[32] although a reduction in the number or density of capillaries may also contribute.[33] Hypertension is also associated with decreased peripheral venous compliance[34] which may increase venous return, increase cardiac preload and, ultimately, cause diastolic dysfunction. Whether increased active vasoconstriction plays a role in established essential hypertension is unclear.[35]
Pulse pressure (the difference between systolic and diastolic blood pressure) is frequently increased in older people with hypertension. This can mean that systolic pressure is abnormally high, but diastolic pressure may be normal or low — a condition termed isolated systolic hypertension.[36] The high pulse pressure in elderly people with hypertension or isolated systolic hypertension is explained by increased arterial stiffness, which typically accompanies aging and may be exacerbated by high blood pressure.[37]
Many mechanisms have been proposed to account for the rise in peripheral resistance in hypertension. Most evidence implicates either disturbances in renal salt and water handling (particularly abnormalities in the intrarenal renin-angiotensin system)[38] and/or abnormalities of the sympathetic nervous system.[39] These mechanisms are not mutually exclusive and it is likely that both contribute to some extent in most cases of essential hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension.[40][41]
Diagnosis
Typical tests performed
System    Tests
Renal
Microscopic urinalysis, proteinuria, BUN and/or creatinine

Endocrine
Serum sodium, potassium, calcium, TSH

Metabolic
Fasting blood glucose, HDL, LDL, and total cholesterol, triglycerides

Other    Hematocrit, electrocardiogram, and chest radiograph

Sources: Harrison's principles of internal medicine[42]others[43][44][45][46][47]

Hypertension is diagnosed on the basis of a persistent high blood pressure. Traditionally, the National Institute of Clinical Excellence recommends three separate sphygmomanometer measurements at one monthly intervals.[48][49] The American Heart Association recommends at least three measurements on at least two separate health care visits.[50] An exception to this is those with very high blood pressure readings especially when there is poor organ function.[49] Initial assessment of the hypertensive people should include a complete history and physical examination. With the availability of 24-hour ambulatory blood pressure monitors and home blood pressure machines, the importance of not wrongly diagnosing those who have white coat hypertension has led to a change in protocols. In the United Kingdom, current best practice is to follow up a single raised clinic reading with ambulatory measurement, or less ideally with home blood pressure monitoring over the course of 7 days.[49]Pseudohypertension in the elderly or noncompressibility artery syndrome may also require consideration. This condition is believed to be due to calcification of the arteries resulting in abnormally high blood pressure readings with a blood pressure cuff while intra arterial measurements of blood pressure are normal.[51]
Once the diagnosis of hypertension has been made, physicians will attempt to identify the underlying cause based on risk factors and other symptoms, if present. Secondary hypertension is more common in preadolescent children, with most cases caused by renal disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension.[52] Laboratory tests can also be performed to identify possible causes of secondary hypertension, and to determine whether hypertension has caused damage to the heart, eyes, and kidneys. Additional tests for diabetes and high cholesterol levels are usually performed because these conditions are additional risk factors for the development of heart disease and may require treatment.[1]
Serum creatinine is measured to assess for the presence of kidney disease, which can be either the cause or the result of hypertension. Serum creatinine alone may overestimate glomerular filtration rate and recent guidelines advocate the use of predictive equations such as the Modification of Diet in Renal Disease (MDRD) formula to estimate glomerular filtration rate (eGFR).[53] eGFR can also provides a baseline measurement of kidney function that can be used to monitor for side effects of certain antihypertensive drugs on kidney function. Additionally, testing of urine samples for protein is used as a secondary indicator of kidney disease. Electrocardiogram (EKG/ECG) testing is done to check for evidence that the heart is under strain from high blood pressure. It may also show whether there is thickening of the heart muscle (left ventricular hypertrophy) or whether the heart has experienced a prior minor disturbance such as a silent heart attack. A chest X-ray or an echocardiogram may also be performed to look for signs of heart enlargement or damage to the heart.[5]
Adults
Classification (JNC7)[53]
Systolic pressure    Diastolic pressure
    mmHg
kPa
mmHg    kPa
Normal    90–119    12–15.9    60–79    8.0–10.5
High normal[54] or prehypertension
120–139    16.0–18.5    80–89    10.7–11.9
Stage 1 hypertension    140–159    18.7–21.2    90–99    12.0–13.2
Stage 2 hypertension    ≥160    ≥21.3    ≥100    ≥13.3
Isolated systolic
hypertension
≥140    ≥18.7    <90    <12.0
In people aged 18 years or older hypertension is defined as a systolic and/or a diastolic blood pressure measurement consistently higher than an accepted normal value (currently 139 mmHg systolic, 89 mmHg diastolic: see table —Classification (JNC7)). Lower thresholds are used (135 mmHg systolic or 85 mmHg diastolic) if measurements are derived from 24-hour ambulatory or home monitoring.[49] Recent international hypertension guidelines have also created categories below the hypertensive range to indicate a continuum of risk with higher blood pressures in the normal range. JNC7 (2003)[53] uses the term prehypertension for blood pressure in the range 120-139 mmHg systolic and/or 80-89 mmHg diastolic, while ESH-ESC Guidelines (2007)[55] and BHS IV (2004)[56] use optimal, normal and high normal categories to subdivide pressures below 140 mmHg systolic and 90 mmHg diastolic. Hypertension is also sub-classified: JNC7 distinguishes hypertension stage I, hypertension stage II, and isolated systolic hypertension. Isolated systolic hypertension refers to elevated systolic pressure with normal diastolic pressure and is common in the elderly.[53] The ESH-ESC Guidelines (2007)[55] and BHS IV (2004),[56] additionally define a third stage (stage III hypertension) for people with systolic blood pressure exceeding 179 mmHg or a diastolic pressure over 109 mmHg. Hypertension is classified as "resistant" if medications do not reduce blood pressure to normal levels.[53]
Children
Hypertension in neonates is rare, occurring in around 0.2 to 3% of neonates, and blood pressure is not measured routinely in the healthy newborn.[12] Hypertension is more common in high risk newborns. A variety of factors, such as gestational age, postconceptional age and birth weight needs to be taken into account when deciding if a blood pressure is normal in a neonate.[12]
Hypertension occurs quite commonly in children over the age of 3 years and adolescents (2-9% depending on age, sex and ethnicity)[57] and is associated with long term risks of ill-health.[58] Blood pressure rises with age in childhood and, in children, hypertension is defined as an average systolic or diastolic blood pressure on three or more occasions equal or higher than the 95th percentile appropriate for the sex, age and height of the child. High blood pressure must be confirmed on repeated visits however before characterizing a child as having hypertension.[58] Prehypertension in children has been defined as average systolic or diastolic blood pressure that is greater than or equal to the 90th percentile, but less than the 95th percentile.[58] In adolescents, it has been proposed that hypertension and pre-hypertension are diagnosed and classified using the same criteria as in adults.[58]
The value of routine screening for hypertension in children over the age of 3 years is debated.[59][60] In 2004 the National High Blood Pressure Education Program recommended that children aged 3 years and older have blood pressure measurement at least once at every health care visit[58] and the National Heart, Lung, Blood Institute’s and American Academy of Pediatrics made a similar recommendation.[61] However the American Academy of Family Physicians[62] support the view of the U.S. preventive Services Task Force that evidence is insufficient to determine the balance of benefits and harms of screening for hypertension in children and adolescents who do not have symptoms.[63]
Prevention
Much of the disease burden of high blood pressure is experienced by people who are not labelled as hypertensive.[56] Consequently, population strategies are required to reduce the consequences of high blood pressure and reduce the need for antihypertensive drug therapy. Lifestyle changes are recommended to lower blood pressure, before starting drug therapy. The 2004 British Hypertension Society guidelines[56] proposed the following lifestyle changes consistent with those outlined by the US National High BP Education Program in 2002[64] for the primary prevention of hypertension:
•    maintain normal body weight for adults (e.g. body mass index 20–25 kg/m2)
•    reduce dietary sodium intake to <100 mmol/ day (<6 g of sodium chloride or <2.4 g of sodium per day)
•    engage in regular aerobic physical activity such as brisk walking (≥30 min per day, most days of the week)
•    limit alcohol consumption to no more than 3 units/day in men and no more than 2 units/day in women
•    consume a diet rich in fruit and vegetables (e.g. at least five portions per day);
Effective lifestyle modification may lower blood pressure as much an individual antihypertensive drug. Combinations of two or more lifestyle modifications can achieve even better results.[56]
Management
Lifestyle modifications
The first line of treatment for hypertension is identical to the recommended preventive lifestyle changes[65] and includes dietary changes,[66] physical exercise, and weight loss. These have all been shown to significantly reduce blood pressure in people with hypertension.[67] Their potential effectiveness is similar to using a single medication.[54] If hypertension is high enough to justify immediate use of medications, lifestyle changes are still recommended in conjunction with medication.
Dietary change such as a low sodium diet is beneficial. A long term (more than 4 weeks) low sodium diet is effective in reducing blood pressure, both in people with hypertension and in people with normal blood pressure.[68] Also, the DASH diet, a diet rich in nuts, whole grains, fish, poultry, fruits and vegetables lowers blood pressure. A major feature of the plan is limiting intake of sodium, although the diet is also rich in potassium, magnesium, calcium, as well as protein.[69] Some programs aimed to reduce psychological stress such as biofeedback or transcendental meditation may be reasonable add-ons to other treatment to reduce hypertension. However several techniques such as yoga, relaxation and other forms of meditation do not appear to reduce blood pressure,[70] and, of the techniques with supportive evidence, there is limited information on whether the modest reduction in blood pressure results in prevention of cardiovascular disease.[70]
Several exercise regimes—including isometric resistance exercise, aerobic exercise, resistance exercise and device-guided breathing—may be useful in reducing blood pressure.[70]
Medications
See also: Comparison of international blood pressure guidelines
Several classes of medications, collectively referred to as antihypertensive drugs, are currently available for treating hypertension. Use should take into account the person's cardiovascular risk (including risk of myocardial infarction and stroke) as well as blood pressure readings, in order to gain a more accurate picture of the person's cardiovascular profile.[71] Evidence in those with mild hypertension (SBP less than 160 mmHg and /or DBP less than 100 mmHg) and no other health problems does not support a reduction in the risk of death or rate of health complications from medication treatment.[72] Medications are not recommended for people with prehypertension or high normal blood pressure.[54]
If drug treatment is initiated the Joint National Committee on High Blood Pressure (JNC-7)[53] recommends that the physician not only monitor for response to treatment but should also assess for any side effects resulting from the medication. Reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease.[73] For most people, recommendations are to reduce blood pressure to less than or equal to somewhere between 140/90 mmHg to 160/100 mmHg.[71][74] Attempting to achieve lower levels have not been shown to improve outcomes.[74] In those with diabetes or kidney disease some recommend levels below 120/80 mmHg;[71][75] however, these are not proven.[74] If the blood pressure goal is not met, a change in treatment should be made as therapeutic inertia is a clear impediment to blood pressure control.[76]
The best first line agent is disputed.[77] The Cochrane collaboration, World Health Organization and the United States guidelines supports low dose thiazide-based diuretic as first line treatment.[67][77][78][79] The UK guidelines emphasise calcium channel blockers (CCB) in preference for people over the age of 55 years or if of African or Caribbean family origin, with angiotensin converting enzyme inhibitors (ACE-I) used first line for younger people.[80] In Japan starting with any one of six classes of medications including: CCB, ACEI/ARB, thiazide diuretics, beta-blockers, and alpha-blockers is deemed reasonable, while in Canada and Europe all of these but alpha-blockers are recommended as options.[54][77]
Drug combinations
The majority of people require more than one drug to control their hypertension. In those with a systolic blood pressure greater than 160 mmHg or a diastolic blood pressure greater than 100 mmHg the American Heart Association recommends starting both a thiazide and an ACEI, ARB or CCB.[67] An ACEI and CCB combination can be used as well.[67]
Unacceptable combinations are non-dihydropyridine calcium blockers (such as verapamil or diltiazem) and beta-blockers, dual renin–angiotensin system blockade (e.g. angiotensin converting enzyme inhibitor + angiotensin receptor blocker), renin–angiotensin system blockers and beta-blockers, beta-blockers and centrally acting agents.[81] Combinations of an ACE-inhibitor or angiotensin II–receptor antagonist, a diuretic and an NSAID (including selective COX-2 inhibitors and non-prescribed drugs such as ibuprofen) should be avoided whenever possible due to a high documented risk of acute renal failure. The combination is known colloquially as a "triple whammy" in the Australian health industry.[65] Tablets containing fixed combinations of two classes of drugs are available and while convenient for the people, may be best reserved for those who have been established on the individual components.[82]
Elderly
Treating moderate to severe hypertension decreases death rates and cardiovascular morbidity and mortality in people aged 60 and older.[83] There are limited studies of people over 80 years old but a recent review concluded that antihypertensive treatment reduced cardiovascular deaths and disease, but did not significantly reduce total death rates.[83] The recommended BP goal is advised as <150/90 mm Hg with thiazide diuretic, CCB, ACEI, or ARB being the first line medication in the United States,[84] and in the revised UK guidelines calcium-channel blockers are advocated as first line with targets of clinic readings <150/90, or <145/85 on ambulatory or home blood pressure monitoring.[80]
Resistant hypertension
Resistant hypertension is defined as hypertension that remains above goal blood pressure in spite of using, at once, three antihypertensive agents belonging to different drug classes. Guidelines for treating resistant hypertension have been published in the UK[85] and US.[86] It has been proposed that a proportion of resistant hypertension may be the result of chronic high activity of the autonomic nervous system; this concept is known as "neurogenic hypertension".[87] Low adherence to treatment is an important causes of resistant hypertension.[88]
Epidemiology


Disability-adjusted life year for hypertensive heart disease per 100,000 inhabitants in 2004.[89]
  no data
  <110
  110-220
  220-330
  330-440
  440-550
  550-660      660-770
  770-880
  880-990
  990-1100
  1100-1600
  >1600
As of 2000, nearly one billion people or ~26% of the adult population of the world had hypertension.[90] It was common in both developed (333 million) and undeveloped (639 million) countries.[90] However rates vary markedly in different regions with rates as low as 3.4% (men) and 6.8% (women) in rural India and as high as 68.9% (men) and 72.5% (women) in Poland.[91] In Europe hypertension occurs in about 30-45% of people as of 2013.[54]
In 1995 it was estimated that 43 million people in the United States had hypertension or were taking antihypertensive medication, almost 24% of the adult United States population.[92] The prevalence of hypertension in the United States is increasing and reached 29% in 2004.[93][94] As of 2006 hypertension affects 76 million US adults (34% of the population) and African American adults have among the highest rates of hypertension in the world at 44%.[95] It is more common in blacks, Filipinos, and Native Americans and less in whites and Mexican Americans, rates increase with age, and is greater in the southeastern United States.[1][96] Hypertension is more common in men (though menopause tends to decrease this difference) and in those of low socioeconomic status.[1]
Children
Rates of high blood pressure in children and adolescent have increased in the last 20 years in the United States.[97] Most childhood hypertension, particularly in preadolescents, is secondary to an underlying disorder. Aside from obesity, kidney disease is the most common (60–70%) cause of hypertension in children. Adolescents usually have primary or essential hypertension, which accounts for 85–95% of cases.[98]
Prognosis
Main article: Complications of hypertension


Diagram illustrating the main complications of persistent high blood pressure
Hypertension is the most important preventable risk factor for premature death worldwide.[99] It increases the risk of ischemic heart disease[100]strokes,[5]peripheral vascular disease,[101] and other cardiovascular diseases, including heart failure, aortic aneurysms, diffuse atherosclerosis, and pulmonary embolism.[5] Hypertension is also a risk factor for cognitive impairment and dementia, and chronic kidney disease.[5] Other complications include hypertensive retinopathy and hypertensive nephropathy.[53]
History
Main article: History of hypertension


Image of veins from Harvey's Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus
Modern understanding of the cardiovascular system began with the work of physician William Harvey (1578–1657), who described the circulation of blood in his book "De motu cordis". The English clergyman Stephen Hales made the first published measurement of blood pressure in 1733.[102][103] Descriptions of hypertension as a disease came among others from Thomas Young in 1808 and especially Richard Bright in 1836.[102] The first report of elevated blood pressure in a person without evidence of kidney disease was made by Frederick Akbar Mahomed (1849–1884).[104] However hypertension as a clinical entity came into being in 1896 with the invention of the cuff-based sphygmomanometer by Scipione Riva-Rocci in 1896.[105] This allowed the measurement of blood pressure in the clinic. In 1905, Nikolai Korotkoff improved the technique by describing the Korotkoff sounds that are heard when the artery is ausculated with a stethoscope while the sphygmomanometer cuff is deflated.[103]
Historically the treatment for what was called the "hard pulse disease" consisted in reducing the quantity of blood by bloodletting or the application of leeches.[102] This was advocated by The Yellow Emperor of China, Cornelius Celsus, Galen, and Hippocrates.[102] In the 19th and 20th centuries, before effective pharmacological treatment for hypertension became possible, three treatment modalities were used, all with numerous side-effects: strict sodium restriction (for example the rice diet[102]), sympathectomy (surgical ablation of parts of the sympathetic nervous system), and pyrogen therapy (injection of substances that caused a fever, indirectly reducing blood pressure).[102][106] The first chemical for hypertension, sodium thiocyanate, was used in 1900 but had many side effects and was unpopular.[102] Several other agents were developed after the Second World War, the most popular and reasonably effective of which were tetramethylammonium chloride and its derivative hexamethonium, hydralazine and reserpine (derived from the medicinal plant Rauwolfia serpentina). A major breakthrough was achieved with the discovery of the first well-tolerated orally available agents. The first was chlorothiazide, the first thiazidediuretic and developed from the antibiotic sulfanilamide, which became available in 1958.[102][107] Subsequently beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors were developed as antihypertensive agents.
Society and culture
Awareness


Graph showing, prevalence of awareness, treatment and control of hypertension compared between the four studies of NHANES[93]
The World Health Organization has identified hypertension, or high blood pressure, as the leading cause of cardiovascularmortality. The World Hypertension League (WHL), an umbrella organization of 85 national hypertension societies and leagues, recognized that more than 50% of the hypertensive population worldwide are unaware of their condition.[108] To address this problem, the WHL initiated a global awareness campaign on hypertension in 2005 and dedicated May 17 of each year as World Hypertension Day (WHD). Over the past three years, more national societies have been engaging in WHD and have been innovative in their activities to get the message to the public. In 2007, there was record participation from 47 member countries of the WHL. During the week of WHD, all these countries – in partnership with their local governments, professional societies, nongovernmental organizations and private industries – promoted hypertension awareness among the public through several media and public rallies. Using mass media such as Internet and television, the message reached more than 250 million people. As the momentum picks up year after year, the WHL is confident that almost all the estimated 1.5 billion people affected by elevated blood pressure can be reached.[109]
Economics
High blood pressure is the most common chronic medical problem prompting visits to primary health care providers in USA. The American Heart Association estimated the direct and indirect costs of high blood pressure in 2010 as $76.6 billion.[95] In the US 80% of people with hypertension are aware of their condition, 71% take some antihypertensive medication, but only 48% of people aware that they have hypertension adequately control it.[95] Adequate management of hypertension can be hampered by inadequacies in the diagnosis, treatment, and/or control of high blood pressure.[110]Health care providers face many obstacles to achieving blood pressure control, including resistance to taking multiple medications to reach blood pressure goals. People also face the challenges of adhering to medicine schedules and making lifestyle changes. Nonetheless, the achievement of blood pressure goals is possible, and most importantly, lowering blood pressure significantly reduces the risk of death due to heart disease and stroke, the development of other debilitating conditions, and the cost associated with advanced medical care.[111][112]
Research
Main article: Renal sympathetic denervation
Selective radiofrequency ablation of the nerves supplying the kidneys, which employs a catheter-based device to cause thermal injury to the nerves surrounding the renal artery without affecting other sympathetic nerves, may lower blood pressure.[113] So far, major side effects have been relatively infrequent, although cases of renal artery dissection, femoral artery pseudoaneurysm, excessive decreases in blood pressure and heart rate are among the reported adverse effects.[113] It has been suggested that renal nerve ablation may have a role in the management of resistant hypertension but its long term efficacy and safety have not been evaluated.[113] However, a 2014 trial failed to confirm a beneficial effect.[114]
References
1.    Carretero OA, Oparil S (January 2000). "Essential hypertension. Part I: definition and etiology". Circulation101 (3): 329–35. doi:10.1161/01.CIR.101.3.329. PMID 10645931.
2.    Fisher ND, Williams GH (2005). "Hypertensive vascular disease". In Kasper DL, Braunwald E, Fauci AS, et al. Harrison's Principles of Internal Medicine (16th ed.). New York, NY: McGraw-Hill. pp. 1463–81. ISBN 0-07-139140-1.
3.    Marshall, IJ; Wolfe, CD; McKevitt, C (Jul 9, 2012). "Lay perspectives on hypertension and drug adherence: systematic review of qualitative research". BMJ (Clinical research ed.)345: e3953. doi:10.1136/bmj.e3953. PMC 3392078. PMID 22777025.
4.    Wong T, Mitchell P (February 2007). "The eye in hypertension". Lancet369 (9559): 425–35. doi:10.1016/S0140-6736(07)60198-6. PMID 17276782.
5.    O'Brien, Eoin; Beevers, D. G.; Lip, Gregory Y. H. (2007). ABC of hypertension. London: BMJ Books. ISBN 1-4051-3061-X.
6.    Papadopoulos DP, Mourouzis I, Thomopoulos C, Makris T, Papademetriou V (December 2010). "Hypertension crisis". Blood Press.19 (6): 328–36. doi:10.3109/08037051.2010.488052. PMID 20504242.
7.    Marik PE, Varon J (June 2007). "Hypertensive crises: challenges and management". Chest131 (6): 1949–62. doi:10.1378/chest.06-2490. PMID 17565029.
8.    Chobanian, AV; Bakris, GL; Black, HR; Cushman, WC; Green, LA; Izzo JL, Jr; Jones, DW; Materson, BJ; Oparil, S; Wright JT, Jr; Roccella, EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood, Institute; National High Blood Pressure Education Program Coordinating, Committee (Dec 2003). "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.". Hypertension42 (6): 1206–52. doi:10.1161/01.hyp.0000107251.49515.c2. PMID 14656957.
9.    Harrison's principles of internal medicine. (18th ed.). New York: McGraw-Hill. 2o11. pp. 55–61. ISBN 9780071748896.
10.    Gibson, Paul (July 30, 2009). "Hypertension and Pregnancy". eMedicine Obstetrics and Gynecology. Medscape. Retrieved 16 June 2009.
11.    Rodriguez-Cruz, Edwin; Ettinger, Leigh M (April 6, 2010). "Hypertension". eMedicine Pediatrics: Cardiac Disease and Critical Care Medicine. Medscape. Retrieved 16 June 2009.
12.    Dionne JM, Abitbol CL, Flynn JT (January 2012). "Hypertension in infancy: diagnosis, management and outcome". Pediatr. Nephrol.27 (1): 17–32. doi:10.1007/s00467-010-1755-z. PMID 21258818.
13.    Vasan, RS; Beiser, A; Seshadri, S; Larson, MG; Kannel, WB; D'Agostino, RB; Levy, D (2002-02-27). "Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study". JAMA: the Journal of the American Medical Association287 (8): 1003–10. doi:10.1001/jama.287.8.1003. PMID 11866648.
14.    Ehret GB, Munroe PB, Rice KM et al. (October 2011). "Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk". Nature478 (7367): 103–9. doi:10.1038/nature10405. PMC 3340926. PMID 21909115.
15.    Lifton, RP; Gharavi, AG, Geller, DS (2001-02-23). "Molecular mechanisms of human hypertension". Cell104 (4): 545–56. doi:10.1016/S0092-8674(01)00241-0. PMID 11239411.
16.    He, FJ; MacGregor, GA (June 2009). "A comprehensive review on salt and health and current experience of worldwide salt reduction programmes". Journal of Human Hypertension23 (6): 363–84. doi:10.1038/jhh.2008.144. PMID 19110538.
17.    He, FJ; Li, J; Macgregor, GA (Apr 3, 2013). "Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials". BMJ (Clinical research ed.)346: f1325. doi:10.1136/bmj.f1325. PMID 23558162.
18.    Dickinson HO, Mason JM, Nicolson DJ et al. (February 2006). "Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials". J. Hypertens.24 (2): 215–33. doi:10.1097/01.hjh.0000199800.72563.26. PMID 16508562.
19.    Haslam DW, James WP (2005). "Obesity". Lancet366 (9492): 1197–209. doi:10.1016/S0140-6736(05)67483-1. PMID 16198769.
20.    Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA et al. (2002). "Primary prevention of hypertension: Clinical and public health advisory from The National High Blood Pressure Education Program". JAMA288 (15): 1882–8. doi:10.1001/jama.288.15.1882. PMID 12377087.
21.    Dickinson, HO; Mason, JM; Nicolson, DJ; Campbell, F; Beyer, FR; Cook, JV; Williams, B; Ford, GA (February 2006). "Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials". Journal of hypertension24 (2): 215–33. doi:10.1097/01.hjh.0000199800.72563.26. PMID 16508562.
22.    Ospina MB, Bond K, Karkhaneh M et al. (June 2007). "Meditation practices for health: state of the research". Evid Rep Technol Assess (Full Rep) (155): 1–263. PMID 17764203.
23.    Mesas, AE; Leon-Muñoz, LM; Rodriguez-Artalejo, F; Lopez-Garcia, E (October 2011). "The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis". The American journal of clinical nutrition94 (4): 1113–26. doi:10.3945/ajcn.111.016667. PMID 21880846.
24.    Vaidya A, Forman JP (November 2010). "Vitamin D and hypertension: current evidence and future directions". Hypertension56 (5): 774–9. doi:10.1161/HYPERTENSIONAHA.109.140160. PMID 20937970.
25.    Sorof J, Daniels S (October 2002). "Obesity hypertension in children: a problem of epidemic proportions". Hypertension40 (4): 441–447. doi:10.1161/01.HYP.0000032940.33466.12. PMID 12364344. Retrieved 3 June 2009.
26.    Lawlor, DA; Smith, GD (May 2005). "Early life determinants of adult blood pressure". Current Opinion in Nephrology and Hypertension14 (3): 259–64. doi:10.1097/01.mnh.0000165893.13620.2b. PMID 15821420.
27.    Dluhy RG, Williams GH eds (1998). "Endocrine hypertension". In Wilson JD, Foster DW, Kronenberg HM. Williams textbook of endocrinology (9th ed.). Philadelphia ; Montreal: W.B. Saunders. pp. 729–49. ISBN 0721661521.
28.    Grossman E, Messerli FH (January 2012). "Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension". Am. J. Med.125 (1): 14–22. doi:10.1016/j.amjmed.2011.05.024. PMID 22195528.
29.    Conway J (April 1984). "Hemodynamic aspects of essential hypertension in humans". Physiol. Rev.64 (2): 617–60. PMID 6369352.
30.    Palatini P, Julius S (June 2009). "The role of cardiac autonomic function in hypertension and cardiovascular disease". Curr. Hypertens. Rep.11 (3): 199–205. doi:10.1007/s11906-009-0035-4. PMID 19442329.
31.    Andersson OK, Lingman M, Himmelmann A, Sivertsson R, Widgren BR (2004). "Prediction of future hypertension by casual blood pressure or invasive hemodynamics? A 30-year follow-up study". Blood Press.13 (6): 350–4. doi:10.1080/08037050410004819. PMID 15771219.
32.    Folkow B (April 1982). "Physiological aspects of primary hypertension". Physiol. Rev.62 (2): 347–504. PMID 6461865.
33.    Struijker Boudier HA, le Noble JL, Messing MW, Huijberts MS, le Noble FA, van Essen H (December 1992). "The microcirculation and hypertension". J Hypertens Suppl10 (7): S147–56. PMID 1291649.
34.    Safar ME, London GM (August 1987). "Arterial and venous compliance in sustained essential hypertension". Hypertension10 (2): 133–9. doi:10.1161/01.HYP.10.2.133. PMID 3301662.
35.    Schiffrin EL (February 1992). "Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture". Hypertension19 (2 Suppl): II1–9. doi:10.1161/01.HYP.19.2_Suppl.II1-a. PMID 1735561.
36.    Chobanian AV (August 2007). "Clinical practice. Isolated systolic hypertension in the elderly". N. Engl. J. Med.357 (8): 789–96. doi:10.1056/NEJMcp071137. PMID 17715411.
37.    Zieman SJ, Melenovsky V, Kass DA (May 2005). "Mechanisms, pathophysiology, and therapy of arterial stiffness". Arterioscler. Thromb. Vasc. Biol.25 (5): 932–43. doi:10.1161/01.ATV.0000160548.78317.29. PMID 15731494.
38.    Navar LG (December 2010). "Counterpoint: Activation of the intrarenal renin-angiotensin system is the dominant contributor to systemic hypertension". J. Appl. Physiol.109 (6): 1998–2000; discussion 2015. doi:10.1152/japplphysiol.00182.2010a. PMC 3006411. PMID 21148349.
39.    Esler M, Lambert E, Schlaich M (December 2010). "Point: Chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension". J. Appl. Physiol.109 (6): 1996–8; discussion 2016. doi:10.1152/japplphysiol.00182.2010. PMID 20185633.
40.    Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S (June 2009). "Endothelium-dependent contractions and endothelial dysfunction in human hypertension". Br. J. Pharmacol.157 (4): 527–36. doi:10.1111/j.1476-5381.2009.00240.x. PMC 2707964. PMID 19630832.
41.    Marchesi C, Paradis P, Schiffrin EL (July 2008). "Role of the renin-angiotensin system in vascular inflammation". Trends Pharmacol. Sci.29 (7): 367–74. doi:10.1016/j.tips.2008.05.003. PMID 18579222.
42.    Loscalzo, Joseph; Fauci, Anthony S.; Braunwald, Eugene; Dennis L. Kasper; Hauser, Stephen L; Longo, Dan L. (2008). Harrison's principles of internal medicine. McGraw-Hill Medical. ISBN 0-07-147691-1.
43.    Padwal RS, Hemmelgarn BR, Khan NA et al. (May 2009). "The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 1 – blood pressure measurement, diagnosis and assessment of risk". Canadian Journal of Cardiology25 (5): 279–86. doi:10.1016/S0828-282X(09)70491-X. PMC 2707176. PMID 19417858.
44.    Padwal RJ, Hemmelgarn BR, Khan NA et al. (June 2008). "The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 1 – blood pressure measurement, diagnosis and assessment of risk". Canadian Journal of Cardiology24 (6): 455–63. doi:10.1016/S0828-282X(08)70619-6. PMC 2643189. PMID 18548142.
45.    Padwal RS, Hemmelgarn BR, McAlister FA et al. (May 2007). "The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 1 – blood pressure measurement, diagnosis and assessment of risk". Canadian Journal of Cardiology23 (7): 529–38. doi:10.1016/S0828-282X(07)70797-3. PMC 2650756. PMID 17534459.
46.    Hemmelgarn BR, McAlister FA, Grover S et al. (May 2006). "The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part I – Blood pressure measurement, diagnosis and assessment of risk". Canadian Journal of Cardiology22 (7): 573–81. doi:10.1016/S0828-282X(06)70279-3. PMC 2560864. PMID 16755312.
47.    Hemmelgarn BR, McAllister FA, Myers MG et al. (June 2005). "The 2005 Canadian Hypertension Education Program recommendations for the management of hypertension: part 1- blood pressure measurement, diagnosis and assessment of risk". Canadian Journal of Cardiology21 (8): 645–56. PMID 16003448.
48.    North of England Hypertension Guideline Development Group (1 August 2004). "Frequency of measurements". Essential hypertension (NICE CG18). National Institute for Health and Clinical Excellence. p. 53. Retrieved 22 December 2011.
49.    National Clinical Guideline Centre (August 2011). "7 Diagnosis of Hypertension, 7.5 Link from evidence to recommendations". Hypertension (NICE CG 127). National Institute for Health and Clinical Excellence. p. 102. Retrieved 22 December 2011.
50.    Aronow, WS; Fleg, JL; Pepine, CJ; Artinian, NT; Bakris, G; Brown, AS; Ferdinand, KC; Ann Forciea, M; Frishman, WH; Jaigobin, C; Kostis, JB; Mancia, G; Oparil, S; Ortiz, E; Reisin, E; Rich, MW; Schocken, DD; Weber, MA; Wesley, DJ; Harrington, RA; Bates, ER; Bhatt, DL; Bridges, CR; Eisenberg, MJ; Ferrari, VA; Fisher, JD; Gardner, TJ; Gentile, F; Gilson, MF; Hlatky, MA; Jacobs, AK; Kaul, S; Moliterno, DJ; Mukherjee, D; Rosenson, RS; Stein, JH; Weitz, HH; Wesley, DJ (Jul–Aug 2011). "ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension.". Journal of the American Society of Hypertension : JASH5 (4): 259–352. PMID 21771565.
51.    Franklin, SS; Wilkinson, IB; McEniery, CM (February 2012). "Unusual hypertensive phenotypes: what is their significance?". Hypertension59 (2): 173–8. doi:10.1161/HYPERTENSIONAHA.111.182956. PMID 22184330.
52.    Luma GB, Spiotta RT (May 2006). "Hypertension in children and adolescents". Am Fam Physician73 (9): 1558–68. PMID 16719248.
53.    Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr. JL, Jones DW, Materson BJ, Oparil S, Wright Jr. JT, Roccella EJ (December 2003). "Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure". Hypertension (Joint National Committee On Prevention) 42 (6): 1206–52. doi:10.1161/01.HYP.0000107251.49515.c2. PMID 14656957.
54.    Giuseppe, Mancia; Fagard, R; Narkiewicz, K; Redon, J; Zanchetti, A; Bohm, M; Christiaens, T; Cifkova, R; De Backer, G; Dominiczak, A; Galderisi, M; Grobbee, DE; Jaarsma, T; Kirchhof, P; Kjeldsen, SE; Laurent, S; Manolis, AJ; Nilsson, PM; Ruilope, LM; Schmieder, RE; Sirnes, PA; Sleight, P; Viigimaa, M; Waeber, B; Zannad, F; Redon, J; Dominiczak, A; Narkiewicz, K; Nilsson, PM et al. (July 2013). "2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)". European heart journal34 (28): 2159–219. doi:10.1093/eurheartj/eht151. PMID 23771844.
55.    Mancia G, De Backer G, Dominiczak A et al. (September 2007). "2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension". J. Hypertens.25 (9): 1751–62. doi:10.1097/HJH.0b013e3282f0580f. PMID 17762635.
56.    Williams, B; Poulter, NR, Brown, MJ, Davis, M, McInnes, GT, Potter, JF, Sever, PS, McG Thom, S, British Hypertension, Society (March 2004). "Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV". Journal of Human Hypertension18 (3): 139–85. doi:10.1038/sj.jhh.1001683. PMID 14973512.
57.    Din-Dzietham R, Liu Y, Bielo MV, Shamsa F (September 2007). "High blood pressure trends in children and adolescents in national surveys, 1963 to 2002". Circulation116 (13): 1488–96. doi:10.1161/CIRCULATIONAHA.106.683243. PMID 17846287.
58.    National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (August 2004). "The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents". Pediatrics114 (2 Suppl 4th Report): 555–76. doi:10.1542/peds.114.2.S2.555. PMID 15286277.
59.    Chiolero, A; Bovet, P; Paradis, G (Mar 1, 2013). "Screening for elevated blood pressure in children and adolescents: a critical appraisal.". JAMA pediatrics167 (3): 266–73. doi:10.1001/jamapediatrics.2013.438. PMID 23303490.
60.    Daniels, SR.; Gidding, SS. (Mar 2013). "Blood pressure screening in children and adolescents: is the glass half empty or more than half full?". JAMA Pediatr167 (3): 302–4. doi:10.1001/jamapediatrics.2013.439. PMID 23303514.
61.    Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute (Dec 2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics. 128 Suppl 5: S213–56. doi:10.1542/peds.2009-2107C. PMID 22084329.
62.    http://www.aafp.org/patient-care/clinical-recommendations/all/hypertension.html
63.    Moyer, VA. (October 2013). "Screening for Primary Hypertension in Children and Adolescents: U.S. Preventive Services Task Force Recommendation Statement*". Annals of Internal Medicine159 (9): 613–9. doi:10.7326/0003-4819-159-9-201311050-00725. PMID 24097285.
64.    Whelton PK et al. (2002). "Primary prevention of hypertension. Clinical and public health advisory from the National High Blood Pressure Education Program". JAMA288 (15): 1882–1888. doi:10.1001/jama.288.15.1882. PMID 12377087.
65.    "NPS Prescribing Practice Review 52: Treating hypertension". NPS Medicines Wise. September 1, 2010. Retrieved 5 November 2010.
66.    Siebenhofer, A; Jeitler, K; Berghold, A; Waltering, A; Hemkens, LG; Semlitsch, T; Pachler, C; Strametz, R; Horvath, K (2011-09-07). "Long-term effects of weight-reducing diets in hypertensive patients". In Siebenhofer, Andrea. Cochrane Database of Systematic Reviews9 (9): CD008274. doi:10.1002/14651858.CD008274.pub2. PMID 21901719.
67.    Go, AS; Bauman, M; King, SM; Fonarow, GC; Lawrence, W; Williams, KA; Sanchez, E (Nov 15, 2013). "An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention". Hypertension63 (4): 878. doi:10.1161/HYP.0000000000000003. PMID 24243703.
68.    He, FJ; MacGregor, GA (2004). "Effect of longer-term modest salt reduction on blood pressure". In MacGregor, Graham A. Cochrane Database of Systematic Reviews (3): CD004937. doi:10.1002/14651858.CD004937. PMID 15266549.
69.    "Your Guide To Lowering Your Blood Pressure With DASH" (PDF). Retrieved 8 June 2009.
70.    Brook, RD; Appel, LJ; Rubenfire, M; Ogedegbe, G; Bisognano, JD; Elliott, WJ; Fuchs, FD; Hughes, JW; Lackland, DT; Staffileno, BA; Townsend, RR; Rajagopalan, S; American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Council on Nutrition, Physical, Activity (Jun 2013). "Beyond medications and diet: alternative approaches to lowering blood pressure: a scientific statement from the american heart association.". Hypertension61 (6): 1360–83. doi:10.1161/HYP.0b013e318293645f. PMID 23608661.
71.    Nelson, Mark. "Drug treatment of elevated blood pressure". Australian Prescriber (33): 108–112. Retrieved 11 August 2010.
72.    Diao, Diana; Wright JM; Cundiff DK; Gueyffier F (2012). "Pharmacotherapy for mild hypertension". Cochrane Database of Systematic Reviews (8). doi:10.1002/14651858.CD006742.pub2. CD006742.
73.    Law M, Wald N, Morris J (2003). "Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy". Health Technol Assess7 (31): 1–94. PMID 14604498.
74.    Arguedas, JA; Perez, MI; Wright, JM (Jul 8, 2009). "Treatment blood pressure targets for hypertension". In Arguedas, Jose Agustin. Cochrane Database of Systematic Reviews (3): CD004349. doi:10.1002/14651858.CD004349.pub2. PMID 19588353.
75.    Shaw, Gina (2009-03-07). "Prehypertension: Early-stage High Blood Pressure". WebMD. Retrieved 3 July 2009.
76.    Eni C. Okonofua; Kit N. Simpson; Ammar Jesri; Shakaib U. Rehman; Valerie L. Durkalski; Brent M. Egan (January 23, 2006). "Therapeutic Inertia Is an Impediment to Achieving the Healthy People 2010 Blood Pressure Control Goals". Hypertension47 (2006;47:345): 345–51. doi:10.1161/01.HYP.0000200702.76436.4b. PMID 16432045. Retrieved 22 November 2009.
77.    Klarenbach, SW; McAlister, FA, Johansen, H, Tu, K, Hazel, M, Walker, R, Zarnke, KB, Campbell, NR, Canadian Hypertension Education, Program (May 2010). "Identification of factors driving differences in cost effectiveness of first-line pharmacological therapy for uncomplicated hypertension". The Canadian journal of cardiology26 (5): e158–63. doi:10.1016/S0828-282X(10)70383-4. PMC 2886561. PMID 20485695.
78.    Wright JM, Musini VM (2009). "First-line drugs for hypertension". In Wright, James M. Cochrane Database of Systematic Reviews (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327.
79.    James, PA.; Oparil, S.; Carter, BL.; Cushman, WC.; Dennison-Himmelfarb, C.; Handler, J.; Lackland, DT.; Lefevre, ML. et al. (Dec 2013). "2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)". JAMA311 (5): 507–20. doi:10.1001/jama.2013.284427. PMID 24352797.
80.    National Institute Clinical Excellence (August 2011). "1.5 Initiating and monitoring antihypertensive drug treatment, including blood pressure targets". GC127 Hypertension: Clinical management of primary hypertension in adults. Retrieved 23 December 2011.
81.    Sever PS, Messerli FH (October 2011). "Hypertension management 2011: optimal combination therapy". Eur. Heart J.32 (20): 2499–506. doi:10.1093/eurheartj/ehr177. PMID 21697169.
82.    "2.5.5.1 Angiotensin-converting enzyme inhibitors". British National Formulary. No. 62. September 2011.
83.    Musini VM, Tejani AM, Bassett K, Wright JM (2009). "Pharmacotherapy for hypertension in the elderly". In Musini, Vijaya M. Cochrane Database of Systematic Reviews (4): CD000028. doi:10.1002/14651858.CD000028.pub2. PMID 19821263.
84.    James, Paul A.; Oparil, Suzanne; Carter, Barry L.; Cushman, William C.; Dennison-Himmelfarb, Cheryl; Handler, Joel; Lackland, Daniel T.; LeFevre, Michael L.; MacKenzie, Thomas D.; Ogedegbe, Olugbenga; Smith, Sidney C.; Svetkey, Laura P.; Taler, Sandra J.; Townsend, Raymond R.; Wright, Jackson T.; Narva, Andrew S.; Ortiz, Eduardo (18 December 2013). "2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults". JAMA311 (5): 507–20. doi:10.1001/jama.2013.284427. PMID 24352797.
85.    "CG34 Hypertension - quick reference guide" (PDF). National Institute for Health and Clinical Excellence. 28 June 2006. Retrieved 4 March 2009.
86.    Calhoun DA, Jones D, Textor S et al. (June 2008). "Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research". Hypertension51 (6): 1403–19. doi:10.1161/HYPERTENSIONAHA.108.189141. PMID 18391085.
87.    Zubcevic J, Waki H, Raizada MK, Paton JF (June 2011). "Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension". Hypertension57 (6): 1026–33. doi:10.1161/HYPERTENSIONAHA.111.169748. PMC 3105900. PMID 21536990.
88.    Santschi, V; Chiolero, A; Burnier, M (Nov 2009). "Electronic monitors of drug adherence: tools to make rational therapeutic decisions.". Journal of hypertension27 (11): 2294–5; author reply 2295. doi:10.1097/hjh.0b013e328332a501. PMID 20724871.
89.    "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved 11 November 2009.
90.    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J (2005). "Global burden of hypertension: analysis of worldwide data". Lancet365 (9455): 217–23. doi:10.1016/S0140-6736(05)17741-1. PMID 15652604.
91.    Kearney PM, Whelton M, Reynolds K, Whelton PK, He J (January 2004). "Worldwide prevalence of hypertension: a systematic review". J. Hypertens.22 (1): 11–9. doi:10.1097/00004872-200401000-00003. PMID 15106785.
92.    Burt VL, Whelton P, Roccella EJ et al. (March 1995). "Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991". Hypertension25 (3): 305–13. doi:10.1161/01.HYP.25.3.305. PMID 7875754. Retrieved 5 June 2009.
93.    Burt VL, Cutler JA, Higgins M et al. (July 1995). "Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991". Hypertension26 (1): 60–9. doi:10.1161/01.HYP.26.1.60. PMID 7607734. Retrieved 5 June 2009.
94.    Ostchega Y, Dillon CF, Hughes JP, Carroll M, Yoon S (July 2007). "Trends in hypertension prevalence, awareness, treatment, and control in older U.S. adults: data from the National Health and Nutrition Examination Survey 1988 to 2004". Journal of the American Geriatrics Society55 (7): 1056–65. doi:10.1111/j.1532-5415.2007.01215.x. PMID 17608879.
95.    Lloyd-Jones D, Adams RJ, Brown TM et al. (February 2010). "Heart disease and stroke statistics--2010 update: a report from the American Heart Association". Circulation121 (7): e46–e215. doi:10.1161/CIRCULATIONAHA.109.192667. PMID 20019324.
96.    "Culture-Specific of Health Risk". Stanford. Retrieved 12 April 2014.
97.    Falkner B (May 2009). "Hypertension in children and adolesents: epidemiology and natural history". Pediatr. Nephrol.25 (7): 1219–24. doi:10.1007/s00467-009-1200-3. PMC 2874036. PMID 19421783.
98.    Luma GB, Spiotta RT (May 2006). "Hypertension in children and adolescents". Am Fam Physician73 (9): 1558–68. PMID 16719248.
99.    "Global health risks: mortality and burden of disease attributable to selected major risks". World Health Organization. 2009. Retrieved 10 February 2012.
100.    Lewington S, Clarke R, Qizilbash N, Peto R, Collins R (December 2002). "Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies". Lancet360 (9349): 1903–13. doi:10.1016/S0140-6736(02)11911-8. PMID 12493255.
101.    Singer DR, Kite A (June 2008). "Management of hypertension in peripheral arterial disease: does the choice of drugs matter?". European Journal of Vascular and Endovascular Surgery35 (6): 701–8. doi:10.1016/j.ejvs.2008.01.007. PMID 18375152.
102.    Esunge PM (October 1991). "From blood pressure to hypertension: the history of research". J R Soc Med84 (10): 621. PMC 1295564. PMID 1744849.
103.    Kotchen TA (October 2011). "Historical trends and milestones in hypertension research: a model of the process of translational research". Hypertension58 (4): 522–38. doi:10.1161/HYPERTENSIONAHA.111.177766. PMID 21859967.
104.    Swales JD, ed. (1995). Manual of hypertension. Oxford: Blackwell Science. pp. xiii. ISBN 0-86542-861-1.
105.    Postel-Vinay N, ed. (1996). A century of arterial hypertension 1896–1996. Chichester: Wiley. p. 213. ISBN 0-471-96788-2.
106.    Dustan HP, Roccella EJ, Garrison HH (September 1996). "Controlling hypertension. A research success story". Arch. Intern. Med.156 (17): 1926–35. doi:10.1001/archinte.156.17.1926. PMID 8823146.
107.    Novello FC, Sprague JM (1957). "Benzothiadiazine dioxides as novel diuretics". J. Am. Chem. Soc.79 (8): 2028. doi:10.1021/ja01565a079.
108.    Chockalingam A (May 2007). "Impact of World Hypertension Day". Canadian Journal of Cardiology23 (7): 517–9. doi:10.1016/S0828-282X(07)70795-X. PMC 2650754. PMID 17534457.
109.    Chockalingam A (June 2008). "World Hypertension Day and global awareness". Canadian Journal of Cardiology24 (6): 441–4. doi:10.1016/S0828-282X(08)70617-2. PMC 2643187. PMID 18548140.
110.    Alcocer L, Cueto L (June 2008). "Hypertension, a health economics perspective". Therapeutic Advances in Cardiovascular Disease2 (3): 147–55. doi:10.1177/1753944708090572. PMID 19124418. Retrieved 20 June 2009.
111.    William J. Elliott (October 2003). "The Economic Impact of Hypertension". The Journal of Clinical Hypertension5 (4): 3–13. doi:10.1111/j.1524-6175.2003.02463.x. PMID 12826765.
112.    Coca A (2008). "Economic benefits of treating high-risk hypertension with angiotensin II receptor antagonists (blockers)". Clinical Drug Investigation28 (4): 211–20. doi:10.2165/00044011-200828040-00002. PMID 18345711.
113.    Gulati, V.; White, WB. (August 2013). "Review of the state of renal nerve ablation for patients with severe and resistant hypertension". J Am Soc Hypertens7 (6): 484–93. doi:10.1016/j.jash.2013.07.003. PMID 23953998.
114.    "Medtronic Announces U.S. Renal Denervation Pivotal Trial Fails to Meet Primary Efficacy Endpoint While Meeting Primary Safety Endpoint". Medtronic. Retrieved 10 January 2014.
Further reading
Typhoid fever
From Wikipedia, the free encyclopedia
This article is about typhoid fever. For a disease with a similar name, see typhus. For a related disease which is caused by two different bacteria, see Paratyphoid fever.
Typhoid fever
Classification and external resources

Rose spots on the chest of a patient with typhoid fever due to the bacterium Salmonella Typhi

ICD-10
A01.0

ICD-9
002

DiseasesDB
27829

MedlinePlus
001332

MeSH
D014435


Typhoid fever — also known simply as typhoid[1] — is a common worldwide bacterial disease transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica enterica, serovar Typhi.[2]
The disease has received various names, such as gastric fever, enteric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever and pythogenic fever. The name typhoid means "resembling typhus" and comes from the neuropsychiatric symptoms common to typhoid and typhus.[3] Despite this similarity of their names, typhoid fever and typhus are distinct diseases and are caused by different species of bacteria.[4]
The impact of this disease fell sharply in the developed world with the application of 20th-century sanitation techniques.[citation needed]
Contents
•    1 Signs and symptoms
•    2 Transmission
•    3 Diagnosis
•    4 Prevention
•    5 Treatment
o    5.1 Surgery
o    5.2 Resistance
•    6 Epidemiology
•    7 History
o    7.1 Development of vaccination
o    7.2 Notable cases
•    8 See also
•    9 References
•    10 Further reading
•    11 External links
Signs and symptoms
Classically, the course of untreated typhoid fever is divided into four individual stages, each lasting approximately one week. Over the course of these stages, the patient becomes exhausted and emaciated.[5]
•    In the first week, the temperature rises slowly, and fever fluctuations are seen with relative bradycardia (Faget sign), malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases, and abdominal pain is also possible. There is a decrease in the number of circulating white blood cells (leukopenia) with eosinopenia and relative lymphocytosis; blood cultures are positive for Salmonella typhi or paratyphi. The Widal test is negative in the first week.[citation needed]
•    In the second week of the infection, the patient lies prostrate with high fever in plateau around 40 °C (104 °F) and bradycardia (sphygmothermic dissociation or Faget sign), classically with a dicrotic pulse wave. Delirium is frequent, often calm, but sometimes agitated. This delirium gives to typhoid the nickname of "nervous fever". Rose spots appear on the lower chest and abdomen in around a third of patients. There are rhonchi in lung bases.
The abdomen is distended and painful in the right lower quadrant, where borborygmi can be heard. Diarrhea can occur in this stage: six to eight stools in a day, green, comparable to pea soup, with a characteristic smell. However, constipation is also frequent. The spleen and liver are enlarged (hepatosplenomegaly) and tender, and there is elevation of liver transaminases. The Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage.
(The major symptom of this fever is that the fever usually rises in the afternoon up to the first and second week.)
•    In the third week of typhoid fever, a number of complications can occur:
o    Intestinal haemorrhage due to bleeding in congested Peyer's patches; this can be very serious but is usually not fatal.
o    Intestinal perforation in the distal ileum: this is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicaemia or diffuse peritonitis sets in.
o    Encephalitis
o    Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects.
o    Metastatic abscesses, cholecystitis, endocarditis and osteitis
o    The fever is still very high and oscillates very little over 24 hours. Dehydration ensues, and the patient is delirious (typhoid state). One third of affected individuals develop a macular rash on the trunk.
o    Platelet count goes down slowly and risk of bleeding rises.
•    By the end of third week, the fever starts subsiding (defervescence). This carries on into the fourth and final week.
Transmission
The bacterium that causes typhoid fever may be spread through poor hygiene habits and public sanitation conditions, and sometimes also by flying insects feeding on feces. Public education campaigns encouraging people to wash their hands after defecating and before handling food are an important component in controlling spread of the disease. According to statistics from the United States Centers for Disease Control and Prevention (CDC), the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the U.S.A.
Diagnosis
Diagnosis is made by any blood, bone marrow or stoolcultures and with the Widal test (demonstration of salmonella antibodies against antigensO-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and cultures of the blood and stool.[6]
The Widal test is time-consuming, and often, when a diagnosis is reached, it is too late to start an antibiotic regimen.
The term enteric fever is a collective term that refers to severe typhoid and paratyphoid.[7]
Prevention
Main article: Typhoid vaccine


Doctor administering a typhoid vaccination at a school in San Augustine County, Texas, 1943


A 1939 conceptual illustration showing various ways that typhoid bacteria can contaminate a water well (center)
Sanitation and hygiene are the critical measures that can be taken to prevent typhoid. Typhoid does not affect animals, and therefore, transmission is only from human to human. Typhoid can only spread in environments where human feces or urine are able to come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to prevent typhoid.
There are two vaccines licensed for use for the prevention of typhoid:[8] the live, oral Ty21a vaccine (sold as Vivotif by Crucell Switzerland AG) and the injectable Typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). Both are 50% to 80% protective and are recommended for travellers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form. There exists an older, killed-whole-cell vaccine that is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use because it has a higher rate of side effects (mainly pain and inflammation at the site of the injection).[8]
Treatment
The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general.
Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin.[7][9] Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice.[10][11][12]Cefixime is a suitable oral alternative.[13][14]
Typhoid fever, when properly treated, is not fatal in most cases. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin and ciprofloxacin, have been commonly used to treat typhoid fever in microbiology (Baron S et al.). Treatment of the disease with antibiotics reduces the case-fatality rate to approximately 1%.[15]
When untreated, typhoid fever persists for three weeks to a month. Death occurs in between 10% and 30% of untreated cases.[16] In some communities, however, case-fatality rates may reach as high as 47%.[citation needed]
Surgery
Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Small-bowel resection is indicated for patients with multiple perforations.
If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is not always successful in eradicating the carrier state because of persisting hepatic infection.
Resistance
Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, and these agents have not been used as first–line treatment for almost twenty years.[citation needed] Typhoid that is resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid).
Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are therefore moving away from using ciprofloxacin as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. For these patients, the recommended first line treatment is ceftriaxone. It has also been suggested that azithromycin is better at treating typhoid in resistant populations than both fluoroquinolone drugs and ceftriaxone.[9] Azithromycin significantly reduces relapse rates compared with ceftriaxone.
There is a separate problem with laboratory testing for reduced susceptibility to ciprofloxacin: current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to ciprofloxacin (MIC 0.125–1.0 mg/l) would not be picked up by this method.[17] It is not certain how this problem can be solved, because most laboratories around the world (including the West) are dependent on disk testing and cannot test for MICs.
Epidemiology


Incidence of typhoid fever
♦ Strongly endemic
♦ Endemic
♦ Sporadic cases
An estimated 16–33 million cases of typhoid fever occur annually. Its incidence is highest in children and young adults between 5 and 19 years old.[16] These cases as of 2010 caused about 190,000 deaths up from 137,000 in 1990.[18] Historically, in the pre-antibiotic era, the case fatality rate of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%.[19]
History
Around 430–424 BC, a devastating plague, which some believe to have been typhoid fever, killed one third of the population of Athens, including their leader Pericles. The balance of power shifted from Athens to Sparta, ending the Golden Age of Pericles that had marked Athenian dominance in the Greek ancient world. The ancient historian Thucydides also contracted the disease, but he survived to write about the plague. His writings are the primary source on this outbreak and modern academics and medical scientists consider epidemic typhus the most likely cause. In 2006 a study detected DNA sequences similar to those of the bacterium responsible for typhoid fever in dental pulp extracted from a burial pit dated to the time of the outbreak.[20]


Mary Mallon ("Typhoid Mary") in a hospital bed (foreground). She was forcibly quarantined as a carrier of typhoid fever in 1907 for three years and then again from 1915 until her death in 1938.
The cause of the plague has long been disputed and other scientists have disputed the findings, citing serious methodologic flaws in the dental pulp-derived DNA study.[21] The disease is most commonly transmitted through poor hygiene habits and public sanitation conditions; during the period in question, the whole population of Attica was besieged within the Long Walls and lived in tents.
Some historians believe that the English colony of Jamestown, Virginia, died out from typhoid. Typhoid fever killed more than 6000 settlers between 1607 and 1624.[22]
During the American Civil War, 81,360 Union soldiers died of typhoid or dysentery.[23] In the late 19th century, the typhoid fever mortality rate in Chicago averaged 65 per 100,000 people a year. The worst year was 1891, when the typhoid death rate was 174 per 100,000 people.[24]
The most notorious carrier of typhoid fever—but by no means the most destructive—was Mary Mallon, also known as Typhoid Mary. In 1907, she became the first American carrier to be identified and traced. She was a cook in New York. She is closely associated with fifty-three cases and three deaths.[25] Public health authorities told Mary to give up working as a cook or have her gall bladder removed. Mary quit her job but returned later under a false name. She was detained and quarantined after another typhoid outbreak. She died of pneumonia after 26 years in quarantine.
Development of vaccination
During the course of treatment of a typhoid outbreak in a local village in 1838, English country doctor William Budd, realised that the "poisons" involved in infectious diseases multiplied in the intestines of the sick, were present in their excretions, and could then be transmitted to the healthy through their consumption of contaminated water.[26] He proposed strict isolation as a method for containing such outbreaks in the future.[27] The medical and scientific communities did not identify the role of microorganisms in infectious disease until the work of Louis Pasteur.


Almroth Edward Wright, developed the first effective typhoid vaccine.
In 1880 Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid. In 1884 pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings, and the organism was given names such as Eberth's bacillus, Eberthella typhi and Gaffky-Eberth bacillus. Today the bacillus that causes typhoid fever goes by the scientific name of Salmonella enterica enterica, serovar Typhi.
The British bacteriologist Almroth Edward Wright first developed an effective typhoid vaccine at the Army Medical School in Netley, Hampshire. It was introduced in 1896 and used successfully during the Boer War.[28] At that time typhoid often killed more soldiers at war than were lost due to enemy combat. He further developed his vaccine at a newly opened research department at St Mary's Hospital Medical School in London from 1902, where he established a method for measuring protective substances (opsonin) in human blood.
Citing the example of the Second Boer War, during which many soldiers died from easily preventable diseases, Wright convinced the British Army that 10 million vaccines should be produced for the troops being sent to the Western Front, thereby saving up to half a million lives during the War.[29] The British Army was the only combatant at the outbreak of the war to be fully immunized against the bacteria, which meant that for the first time, casualties due to combat exceeded those from disease.[8]
In 1909, Frederick F. Russell, a U.S. Army physician, adopted Wright's typhoid vaccine for use with the US Army and two years later his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military.[30]


Lizzie van Zyl was a child inmate in a British-run concentration camp in South Africa who died from typhoid fever during the Boer War (1899–1902).
Most developed countries saw declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1908, the chlorination of drinking water was a significant step in the control of typhoid fever in the U.S. The first permanent disinfection of drinking water in the U.S. occurred on the Jersey City, New Jersey water supply. Credit for the decision to build the chlorination system has been given to John L. Leal[31] The chlorination facility was designed by George W. Fuller.[32] Antibiotics were introduced in clinical practice in 1942, greatly reducing mortality. Today, the incidence of typhoid fever in developed countries is around 5 cases per 1,000,000 people per year.
A notable outbreak occurred in Aberdeen, Scotland in 1964. This was due to contaminated tinned meat sold at the city's branch of the William Low chain of stores. No fatalities resulted.
An outbreak in the Democratic Republic of Congo in 2004–05 recorded more than 42,000 cases and 214 deaths.[16]
Notable cases
•    Roger Sherman, one of the Founding Fathers of the United States died of typhoid fever in 1793.
•    Gerard Manley Hopkins, English poet, died of typhoid fever in 1889.[33]
•    Typhoid Mary, accused of spreading typhoid fever
•    Dr HJH 'Tup' Scott, captain of the 1886 Australian cricket team that toured England, died of typhoid in 1910.[34]
•    Wilbur Wright, the older of the two Wright Brothers, died of typhoid on May 30, 1912.
•    Arnold Bennett, English novelist, died in 1932 of typhoid, two months after drinking a glass of water in a Paris hotel to prove it was safe.[35]
•    Hakaru Hashimoto, Japanese medical scientist, died of typhoid fever in 1934.[36]
•    Heath Bell, a relief pitcher for the San Diego Padres acquired typhoid on a 2010 trip to Fiji but survived.[37]
•    Louisa May Alcott, author of Little Women acquired typhoid while being a nurse at a hospital in Washington, D.C. but survived.
•    Major Gonville Bromhead, who fought in the Battle of Rorke's Drift, depicted in the film Zulu, died of typhoid fever in India in 1891.
See also
•    Herxheimer reaction
•    Kauffman-White classification
References
1.    ^MedlinePlus EncyclopediaTyphoid fever
2.    ^Salmonella and Salmonellosis. Textbookofbacteriology.net. Retrieved on 2014-05-12.
3.    ^ Oxford English Dictionary. typhoid, adj. and n. and typhus, n. Online version March 2011. Retrieved May 2011.
4.    ^ Cunha BA (March 2004). "Osler on typhoid fever: differentiating typhoid from typhus and malaria". Infect. Dis. Clin. North Am.18 (1): 111–25. doi:10.1016/S0891-5520(03)00094-1. PMID 15081508.
5.    ^"Typhoid". Merriam Webster Dictionary. Retrieved 2013-06-24.
6.    ^ Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
7.    ^ ab Parry CM, Beeching NJ (2009). "Treatment of enteric fever". BMJ338: b1159–b1159. doi:10.1136/bmj.b1159. PMID 19493937.
8.    ^ abc Fraser A, Goldberg E, Acosta CJ, Paul M, Leibovici L (2007). "Vaccines for preventing typhoid fever". In Fraser, Abigail. Cochrane Database Syst Rev (3): CD001261. doi:10.1002/14651858.CD001261.pub2. PMID 17636661.
9.    ^ ab Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA (2011). "Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)". In Bhutta, Zulfiqar A. Cochrane Database Syst Rev (10): CD004530. doi:10.1002/14651858.CD004530.pub4. PMID 21975746.
10.    ^ Soe GB, Overturf GD (1987). "Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins". Rev Infect Dis (The University of Chicago Press) 9 (4): 719–36. doi:10.1093/clinids/9.4.719. JSTOR 4454162. PMID 3125577.
11.    ^ Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall EJ, Rowe B, Hyams KC (1993). "Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever". Eur J Clin Microbiol Infect Dis12 (12): 907–910. doi:10.1007/BF01992163. PMID 8187784.
12.    ^ Dutta P, Mitra U, Dutta S, De A, Chatterjee MK, Bhattacharya SK (2001). "Ceftriaxone therapy in ciprofloxacin treatment failure typhoid fever in children". Indian J Med Res113: 210–3. PMID 11816954.
13.    ^ Bhutta ZA, Khan IA, Molla AM (1994). "Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone". Pediatr Infect Dis J13 (11): 990–993. doi:10.1097/00006454-199411000-00010. PMID 7845753.
14.    ^ Cao XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM (1999). "A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group". Pediatr Infect Dis J18 (3): 245–8. PMID 10093945.
15.    ^Diarrhoeal Diseases (Updated February 2009). World Health Organization
16.    ^ abc"Typhoid Fever". World Health Organization. Retrieved 2007-08-28.
17.    ^ Cooke FJ, Wain J, Threlfall EJ (2006). "Fluoroquinolone resistance in Salmonella typhi (letter)". Brit Med J333 (7563): 353–354. doi:10.1136/bmj.333.7563.353-b. PMC 1539082. PMID 16902221.
18.    ^ Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.". Lancet380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
19.    ^Heymann, David L., ed. (2008), Control of Communicable Diseases Manual, Washington, D.C.: American Public Health Association, pg 665. ISBN 978-0-87553-189-2.
20.    ^ Papagrigorakis MJ, Yapijakis C, Synodinos PN, Baziotopoulou-Valavani E (2006). "DNA examination of ancient dental pulp incriminates typhoid fever as a probable cause of the Plague of Athens". Int J Infect Dis10 (3): 206–214. doi:10.1016/j.ijid.2005.09.001. PMID 16412683.
21.    ^ Shapiro B, Rambaut A, Gilbert MT (2006). "No proof that typhoid caused the Plague of Athens (a reply to Papagrigorakis et al.)". Int J Infect Dis10 (4): 334–335. doi:10.1016/j.ijid.2006.02.006. PMID 16730469.
22.    ^ Byrne, Joseph Patrick (2008). Encyclopedia of Pestilence, Pandemics, and Plagues: A-M. ABC-CLIO. p. 190. ISBN 0-313-34102-8.
23.    ^ "Armies of pestilence: the effects of pandemics on history". James Clarke & Co. (2004). p.191. ISBN 0-227-17240-X
24.    ^"1900 Flow of Chicago River Reversed". Chicago Timeline. Chicago Public Library. Archived from the original on 2007-03-07. Retrieved 2007-02-08.
25.    ^"Nova: The Most Dangerous Woman in America".
26.    ^ Asimov, Asimov's Biographical Encyclopedia of Science and Technology 2nd Revised edition
27.    ^ Aronson SM (1995). "William Budd and typhoid fever". Rhode Island medicine78 (11): 310. PMC 1279260. PMID 8547718.
28.    ^"Sir Almroth Edward Wright". Encyclopaedia Britannica.
29.    ^"Library and Archive Catalogue". Royal Society. Retrieved 1 November 2010.
30.    ^USAMRMC: 50 Years of Dedication to the Warfighter 1958 – 2008. U.S. Army Medical Research & Material Command (2008). 2008. p. 5. ASIN B003WYKJNY.
31.    ^ Leal, John L. (1909). "The Sterilization Plant of the Jersey City Water Supply Company at Boonton, N.J." Proceedings American Water Works Association. pp. 100–9.
32.    ^ Fuller, George W. (1909). "Description of the Process and Plant of the Jersey City Water Supply Company for the Sterilization of the Water of the Boonton Reservoir." Proceedings American Water Works Association. 110-34.
33.    ^ Ruggles, Eleanor (1944) Gerard Manley Hopkins: a life. Norton.
34.    ^ Scott, Belinda F.. (1910-09-23) Biography – Henry James Herbert Scott – Australian Dictionary of Biography. Adbonline.anu.edu.au. Retrieved on 2014-05-12.
35.    ^"Straw for Silence". The Spectator (F.C. Westley) 203. 1959. ISSN 0038-6952. OCLC 1766325. Retrieved March 16, 2011.
36.    ^Hakaru Hashimoto#Biography
37.    ^"Heath Bell Recovering After Bout With Typhoid Fever on Vacation". aolnews.com. 2011. Retrieved 17 October 2011.
Malaria
From Wikipedia, the free encyclopedia
Malaria
Classification and external resources

A Plasmodium in the form that enters humans and other vertebrates from the saliva of female mosquitoes (a sporozoite) traverses the cytoplasm of a mosquito midgut epithelial cell.
ICD-10
B50-B54

ICD-9
084

OMIM
248310

DiseasesDB
7728

MedlinePlus
000621

MeSH
C03.752.250.552

Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans (a type of unicellular microorganism) of the genus Plasmodium. Commonly, the disease is transmitted by a bite from an infected female Anopheles mosquito, which introduces the organisms from its saliva into a person's circulatory system. In the blood, the parasites travel to the liver to mature and reproduce. Malaria causes symptoms that typically include fever and headache, which in severe cases can progress to coma or death.
Five species of Plasmodium can infect and be transmitted by humans. The vast majority of deaths are caused by P. falciparum and P. vivax, while P. ovale, and P. malariae cause a generally milder form of malaria that is rarely fatal. The zoonotic species P. knowlesi, prevalent in Southeast Asia, causes malaria in macaques but can also cause severe infections in humans. Malaria is common in tropical and subtropical regions because rainfall, warm temperatures, and stagnant waters provide an environment ideal for mosquito larvae. Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests. Modern techniques that use the polymerase chain reaction to detect the parasite's DNA have also been developed, but these are not widely used in malaria-endemic areas due to their cost and complexity.
Disease transmission can be reduced by preventing mosquito bites by using mosquito nets and insect repellents, or with mosquito-control measures such as spraying insecticides and draining standing water. Despite a need, no effective vaccine exists, although efforts to develop one are ongoing. Several medications are available to prevent malaria in travellers to malaria-endemic countries. A number of antimalarial medications are available in those who have the disease. Severe malaria is treated with intravenous or intramuscularquinine or, since the mid-2000s, the artemisinin derivative artesunate, which is better than quinine in both children and adults and is given in combination with a second anti-malarial such as mefloquine. Resistance has developed to several antimalarial drugs; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and emerging resistance to artemisinin has become a problem in some parts of Southeast Asia.
The disease is widespread in tropical and subtropical regions in a broad band around the equator, including much of Sub-Saharan Africa, Asia, and the Americas. The World Health Organization estimates that in 2010, there were 219 million documented cases of malaria. That year, the disease killed between 660,000 and 1.2 million people,[1] many of whom were children in Africa. The actual number of deaths is not known with certainty, data is unavailable in many rural areas, and many cases are undocumented. Malaria is commonly associated with poverty and may also be a major hindrance to economic development.
Contents
•    1 Signs and symptoms
o    1.1 Complications
•    2 Cause
o    2.1 Life cycle
o    2.2 Recurrent malaria
•    3 Pathophysiology
o    3.1 Genetic resistance
o    3.2 Liver dysfunction
•    4 Diagnosis
o    4.1 Classification
•    5 Prevention
o    5.1 Mosquito control
o    5.2 Other methods
o    5.3 Medications
•    6 Treatment
o    6.1 Resistance
•    7 Prognosis
•    8 Epidemiology
•    9 History
•    10 Society and culture
o    10.1 Economic impact
o    10.2 Counterfeit and substandard drugs
o    10.3 War
o    10.4 Eradication efforts
•    11 Research
•    12 Other animals
•    13 References
o    13.1 Cited literature
•    14 Further reading
•    15 External links
Signs and symptoms


Main symptoms of malaria[2]
The signs and symptoms of malaria typically begin 8–25 days following infection;[2] however, symptoms may occur later in those who have taken antimalarial medications as prevention.[3] Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms,[4] and can resemble other conditions such as septicemia, gastroenteritis, and viral diseases.[3] The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.[5]
The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae. P. falciparuminfection can cause recurrent fever every 36–48 hours or a less pronounced and almost continuous fever.[6]
Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection.[4] Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.[4]
Complications
There are several serious complications of malaria. Among these is the development of respiratory distress, which occurs in up to 25% of adults and 40% of children with severe P. falciparum malaria. Possible causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary oedema, concomitant pneumonia, and severe anaemia. Although rare in young children with severe malaria, acute respiratory distress syndrome occurs in 5–25% of adults and up to 29% of pregnant women.[7]Coinfection of HIV with malaria increases mortality.[8] Renal failure is a feature of blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine.[4]
Infection with P. falciparum may result in cerebral malaria, a form of severe malaria that involves encephalopathy. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.[9] Splenomegaly, severe headache, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur.[4]
Malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,[10] particularly in P. falciparum infection, but also with P. vivax.[11]
Cause
Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi.[12][13] Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%).[3] Although P. falciparum traditionally accounts for the majority of deaths,[14] recent evidence suggests that P. vivax malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of P. falciparum infection.[15]P. vivax proportionally is more common outside of Africa.[16] There have been documented human infections with several species of Plasmodium from higher apes; however, with the exception of P. knowlesi—a zoonotic species that causes malaria in macaques[13]—these are mostly of limited public health importance.[17]
Climate change is likely to affect malaria transmission, but the severity and geographic distribution of such effects is currently uncertain.[18][19]
Life cycle


The life cycle of malaria parasites. A mosquito causes an infection by a bite. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.
In the life cycle of Plasmodium, a female Anopheles mosquito (the definitive host) transmits a motile infective form (called the sporozoite) to a vertebrate host such as a human (the secondary host), thus acting as a transmission vector. A sporozoite travels through the blood vessels to liver cells (hepatocytes), where it reproduces asexually (tissue schizogony), producing thousands of merozoites. These infect new red blood cells and initiate a series of asexual multiplication cycles (blood schizogony) that produce 8 to 24 new infective merozoites, at which point the cells burst and the infective cycle begins anew.[20]
Other merozoites develop into immature gametocytes, which are the precursors of male and female gametes. When a fertilised mosquito bites an infected person, gametocytes are taken up with the blood and mature in the mosquito gut. The male and female gametocytes fuse and form a ookinete—a fertilized, motile zygote. Ookinetes develop into new sporozoites that migrate to the insect's salivary glands, ready to infect a new vertebrate host. The sporozoites are injected into the skin, in the saliva, when the mosquito takes a subsequent blood meal.[21]
Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar, and thus do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal.[22] Malaria parasites can also be transmitted by blood transfusions, although this is rare.[23]
Recurrent malaria
Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either recrudescence, relapse, or reinfection. Recrudescence is when symptoms return after a symptom-free period. It is caused by parasites surviving in the blood as a result of inadequate or ineffective treatment.[24] Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozoites in liver cells. Relapse commonly occurs between 8–24 weeks and is commonly seen with P. vivax and P. ovale infections.[3]P. vivax malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite.[25] Reinfection means the parasite that caused the past infection was eliminated from the body but a new parasite was introduced. Reinfection cannot readily be distinguished from recrudescence, although recurrence of infection within two weeks of treatment for the initial infection is typically attributed to treatment failure.[26] People may develop some immunity when exposed to frequent infections.[27]
Pathophysiology
Further information: Plasmodium falciparum biology


Micrograph of a placenta from a stillbirth due to maternal malaria. H&E stain. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites
Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.[28]
After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle.[28] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[29]
Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.[28]
Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections,[25] although their existence in P. ovale is uncertain.[30]
The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen.[31] The blockage of the microvasculature causes symptoms such as in placental malaria.[32] Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.[33]
Genetic resistance
Main article: Genetic resistance to malaria
According to a 2005 review, due to the high levels of mortality and morbidity caused by malaria—especially the P. falciparum species—it has placed the greatest selective pressure on the human genome in recent history. Several genetic factors provide some resistance to it including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells.[34][35]
The impact of sickle cell trait on malaria immunity illustrates some of the evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a defect in the hemoglobin molecule in the blood. Instead of retaining the biconcave shape of a normal red blood cell, the modified hemoglobin S molecule causes the cell to sickle or distort into a curved shape. Due to the sickle shape, the molecule is not as effective in taking or releasing oxygen. Infection causes red cells to sickle more, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are homozygous (with two copies of the abnormal hemoglobin beta allele) have sickle-cell anaemia, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria. Although the shorter life expectancy for those with the homozygous condition would not sustain the trait's survival, the trait is preserved because of the benefits provided by the heterozygous form.[35][36]
Liver dysfunction
Liver dysfunction as a result of malaria is uncommon and usually only occurs in those with other liver condition such as viral hepatitis or chronic liver disease. The syndrome is sometimes called malarial hepatitis.[37] While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.[37]
Diagnosis
Main article: Diagnosis of malaria


The blood film is the gold standard for malaria diagnosis.


Ring-forms and gametocytes of Plasmodium falciparum in human blood
Owing to the non-specific nature of the presentation of symptoms, diagnosis of malaria in non-endemic areas requires a high degree of suspicion, which might be elicited by any of the following: recent travel history, enlarged spleen, fever, low number of platelets in the blood, and higher-than-normal levels of bilirubin in the blood combined with a normal level of white blood cells.[3]
Malaria is usually confirmed by the microscopic examination of blood films or by antigen-based rapid diagnostic tests (RDT).[38][39] Microscopy is the most commonly used method to detect the malarial parasite—about 165 million blood films were examined for malaria in 2010.[40] Despite its widespread usage, diagnosis by microscopy suffers from two main drawbacks: many settings (especially rural) are not equipped to perform the test, and the accuracy of the results depends on both the skill of the person examining the blood film and the levels of the parasite in the blood. The sensitivity of blood films ranges from 75–90% in optimum conditions, to as low as 50%. Commercially available RDTs are often more accurate than blood films at predicting the presence of malaria parasites, but they are widely variable in diagnostic sensitivity and specificity depending on manufacturer, and are unable to tell how many parasites are present.[40]
In regions where laboratory tests are readily available, malaria should be suspected, and tested for, in any unwell person who has been in an area where malaria is endemic. In areas that cannot afford laboratory diagnostic tests, it has become common to use only a history of fever as the indication to treat for malaria—thus the common teaching "fever equals malaria unless proven otherwise". A drawback of this practice is overdiagnosis of malaria and mismanagement of non-malarial fever, which wastes limited resources, erodes confidence in the health care system, and contributes to drug resistance.[41] Although polymerase chain reaction-based tests have been developed, they are not widely used in areas where malaria is common as of 2012, due to their complexity.[3]
Classification
Malaria is classified into either "severe" or "uncomplicated" by the World Health Organization (WHO).[3] It is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated.[42]
•    Decreased consciousness
•    Significant weakness such that the person is unable to walk
•    Inability to feed
•    Two or more convulsions
•    Low blood pressure (less than 70 mmHg in adults and 50 mmHg in children)
•    Breathing problems
•    Circulatory shock
•    Kidney failure or hemoglobin in the urine
•    Bleeding problems, or hemoglobin less than 50 g/L (5 g/dL)
•    Pulmonary oedema
•    Blood glucose less than 2.2 mmol/L (40 mg/dL)
•    Acidosis or lactate levels of greater than 5 mmol/L
•    A parasite level in the blood of greater than 100,000 per microlitre (µL) in low-intensity transmission areas, or 250,000 per µL in high-intensity transmission areas
Cerebral malaria is defined as a severe P. falciparum-malaria presenting with neurological symptoms, including coma (with a Glasgow coma scale less than 11, or a Blantyre coma scale greater than 3), or with a coma that lasts longer than 30 minutes after a seizure.[43]
Prevention


An Anopheles stephensi mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). This mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence.
Methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. There is no vaccine for malaria. The presence of malaria in an area requires a combination of high human population density, high anopheles 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 eventually disappear from that area, as happened in North America, Europe and parts of the 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. Furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing population density, making it economically unfeasible in some areas.[44]
Prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the initial costs required are out of reach of many of the world's poorest people. There is a wide difference in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. For example, in China—whose government in 2010 announced a strategy to pursue malaria elimination in the Chinese provinces—the required investment is a small proportion of public expenditure on health. In contrast, a similar program in Tanzania would cost an estimated one-fifth of the public health budget.[45]
Mosquito control
Further information: Mosquito control


Man spraying kerosene oil in standing water, Panama Canal Zone 1912


Walls where indoor residual spraying of DDT has been applied. The mosquitoes remain on the wall until they fall down dead on the floor.
Vector control refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. For individual protection, the most effective insect repellents are based on DEET or picaridin.[46] Insecticide-treated mosquito nets (ITNs) and indoor residual spraying (IRS) have been shown to be highly effective in preventing malaria among children in areas where malaria is common.[47][48] Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.[49]


Mosquito nets create a protective barrier against malaria-carrying mosquitoes that bite at night.
Mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net.[50] Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa.[51] About 13% of households in Sub-Saharan countries own ITNs.[52] In 2000, 1.7 million (1.8%) African children living in stable malaria-endemic conditions were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs in 2007, leaving 89.6 million children unprotected.[53] An increased percentage of African households (31%) are estimated to own at least one ITN in 2008. Most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. A recommended practice for usage is to hang a large "bed net" above the center of a bed to drape over it completely with the edges tucked in. Pyrethroid-treated nets and long-lasting insecticide-treated nets offer the best protection, and are most effective when used from dusk to dawn.[54]
Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquito rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite.[55] As of 2006, the World Health Organization recommends 12 insecticides in IRS operations, including DDT and the pyrethroids cyfluthrin and deltamethrin.[56] This public health use of small amounts of DDT is permitted under the Stockholm Convention, which prohibits its agricultural use.[57] One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS.[58]
There are a number of other methods to reduce mosquito bites and slow the spread of malaria. Efforts to decrease mosquito larva by decreasing the availability of open water in which they develop or by adding substances to decrease their development is effective in some locations.[59] Electronic mosquito repellent devices which make very high frequency sounds that are supposed to keep female mosquitoes away, do not have supporting evidence.[60]
Other methods
Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world.[61] Recognizing the disease in the early stages can stop the disease from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.[62]Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants,[63] and in preschool children where transmission is seasonal.[64]
June has been marked as Anti-malaria month by National Vector Borne Disease Control Programme (NVBDCP) of India with an objective to increase multisectoral collaboration and community involvement in malaria control.[65][66]
Medications
Main article: Malaria prophylaxis
There are a number of drugs that can help prevent malaria while travelling in areas where it exists. Most of these drugs are also sometimes used in treatment. Chloroquine may be used where the parasite is still sensitive.[67] Because most Plasmodium is resistant to one or more medications, one of three medications—mefloquine (Lariam), doxycycline (available generically), or the combination of atovaquone and proguanil hydrochloride (Malarone)—is frequently needed.[67] Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is associated with death, suicide, and neurological and psychiatric symptoms.[67]
The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before arriving and continue taking them for four weeks after leaving (with the exception of atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward).[68] The use of preventative drugs is seldom practical for those who reside in areas where malaria exists, and their use is usually only in short-term visitors and travellers. This is due to the cost of the drugs, side effects from long-term use, and the difficulty in obtaining anti-malarial drugs outside of wealthy nations.[69] The use of preventative drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance.[70]
Treatment
Malaria is treated with antimalarial medications; the ones used depends on the type and severity of the disease. While medications against fever are commonly used, their effects on outcomes are not clear.[71]
Uncomplicated malaria may be treated with oral medications. The most effective treatment for P. falciparum infection is the use of artemisinins in combination with other antimalarials (known as artemisinin-combination therapy, or ACT), which decreases resistance to any single drug component.[72] These additional antimalarials include: amodiaquine, lumefantrine, mefloquine or sulfadoxine/pyrimethamine.[73] Another recommended combination is dihydroartemisinin and piperaquine.[74][75] ACT is about 90% effective when used to treat uncomplicated malaria.[51] To treat malaria during pregnancy, the WHO recommends the use of quinine plus clindamycin early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters).[76] In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.[77][78]
Infection with P. vivax, P. ovale or P. malariae is usually treated without the need for hospitalization. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) as well as clearance of liver forms with primaquine.[79]
Recommended treatment for severe malaria is the intravenous use of antimalarial drugs. For severe malaria, artesunate is superior to quinine in both children and adults.[80] Treatment of severe malaria involves supportive measures that are best done in a critical care unit. This includes the management of high fevers and the seizures that may result from it. It also includes monitoring for poor breathing effort, low blood sugar, and low blood potassium.[14]
Resistance
Drug resistance poses a growing problem in 21st century malaria treatment. Resistance is now common against all classes of antimalarial drugs save the artemisinins.[81] Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world.[82] Malaria strains found on the Cambodia-Thailand border are resistant to combination therapies that include artemisinins, and may therefore be untreatable.[83] Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype.[84] Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand and Vietnam.[85]
Prognosis


Disability-adjusted life year for malaria per 100,000 inhabitants in 2004
   no data
   <10
   0–100
   100–500
   500–1000
  1000–1500
  1500–2000      2000–2500
  2500–2750
  2750–3000
  3000–3250
  3250–3500
   ≥3500
When properly treated, people with malaria can usually expect a complete recovery.[86] However, severe malaria can progress extremely rapidly and cause death within hours or days.[87] In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment.[3] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[88]Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to Salmonella bacteria and the Epstein–Barr virus.[89]
During childhood, malaria causes anemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria.[88] Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy.[90] Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.[88]
Epidemiology


Distribution of malaria in the world:[91]♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria
The WHO estimates that in 2010 there were 219 million cases of malaria resulting in 660,000 deaths.[3][92] Others have estimated the number of cases at between 350 and 550 million for falciparum malaria[93] and deaths in 2010 at 1.24 million[94] up from 1.0 million deaths in 1990.[95] The majority of cases (65%) occur in children under 15 years old.[94] About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly.[10] There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States.[7] About 900 people died from the disease in Europe between 1993 and 2003.[46] Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO, deaths attributable to malaria in 2010 were reduced by over a third from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.[51]
Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur.[96] An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66).[97] A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali.[94] The Malaria Atlas Project aims to map global endemic levels of malaria, providing a means with which to determine the global spatial limits of the disease and to assess disease burden.[98][99] This effort led to the publication of a map of P. falciparum endemicity in 2010.[100] As of 2010, about 100 countries have endemic malaria.[92][101] Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease.[46]
The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.[102] Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, providing them with the environment they need for continuous breeding.[103] In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall.[104] Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes.[105] In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.[106]
History
Main article: History of malaria
Although the parasite responsible for P. falciparum malaria has been in existence for 50,000–100,000 years, the population size of the parasite did not increase until about 10,000 years ago, concurrently with advances in agriculture[107] and the development of human settlements. Close relatives of the human malaria parasites remain common in chimpanzees. Some evidence suggests that the P. falciparum malaria may have originated in gorillas.[108]
References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.[109] Malaria may have contributed to the decline of the Roman Empire,[110] and was so pervasive in Rome that it was known as the "Roman fever".[111] Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along the Tiber River. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, runoff from agriculture, and drainage problems from road construction led to the increase of standing water.[112]


British doctor Ronald Ross received the Nobel Prize for Physiology or Medicine in 1902 for his work on malaria.
The term malaria originates from MedievalItalian: mala aria — "bad air"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland.[113] Malaria was once common in most of Europe and North America,[114] where it is no longer endemic,[115] though imported cases do occur.[116]
Scientific studies on malaria made their first significant advance in 1880, when Charles Louis Alphonse Laveran—a French army doctor working in the military hospital of Constantine in Algeria—observed parasites inside the red blood cells of infected people for the first time. He therefore proposed that malaria is caused by this organism, the first time a protist was identified as causing disease.[117] For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. A year later, Carlos Finlay, a Cuban doctor treating people with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans.[118] This work followed earlier suggestions by Josiah C. Nott,[119] and work by Sir Patrick Manson, the "father of tropical medicine", on the transmission of filariasis.[120]
In April 1894, a Scottish physician Sir Ronald Ross visited Sir Patrick Manson at his house on Queen Anne Street, London. This visit was the start of four years of collaboration and fervent research that culminated in 1898 when Ross, who was working in the Presidency General Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes. He thus proved that the mosquito was the vector for malaria in humans by showing that certain mosquito species transmit malaria to birds. He isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.[121] For this work, Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.[122] The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900. Its recommendations were implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against the disease.[123]
The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona to control fever. Its effectiveness against malaria was found and the Jesuits introduced the treatment to Europe around 1640; by 1677, it was included in the London Pharmacopoeia as an antimalarial treatment.[124] It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.[125][126]


Artemisia annua, source of the antimalarial drug artemisin
Quinine become the predominant malarial medication until the 1920s, when other medications began to be developed. In the 1940s, chloroquine replaced quinine as the treatment of both uncomplicated and severe malaria until resistance supervened, first in Southeast Asia and South America in the 1950s and then globally in the 1980s.[127] Artemisinins, discovered by Chinese scientist Tu Youyou and colleagues in the 1970s from the plant Artemisia annua, became the recommended treatment for P. falciparum malaria, administered in combination with other antimalarials as well as in severe disease.[128]
Plasmodium vivax was used between 1917 and the 1940s for malariotherapy—deliberate injection of malaria parasites to induce fever to combat certain diseases such as tertiary syphilis. In 1917, the inventor of this technique, Julius Wagner-Jauregg, received the Nobel Prize in Physiology or Medicine for his discoveries. The technique was dangerous, killing about 15% of patients, so it is no longer in use.[129]
The first pesticide used for indoor residual spraying was DDT.[130] Although it was initially used exclusively to combat malaria, its use quickly spread to agriculture. In time, pest control, rather than disease control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s.[57] Before DDT, malaria was successfully eliminated or controlled in tropical areas like Brazil and Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by applying the highly toxic arsenic compound Paris Green to places with standing water.[131]
Malaria vaccines have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-attenuated sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans.[132]
Society and culture
See also: World Malaria Day
Economic impact


Malaria clinic in Tanzania
Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to economic development.[133][134] Although tropical regions are most affected, malaria's furthest influence reaches into some temperate zones that have extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.[135]
A comparison of average per capita GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives a fivefold difference ($1,526 USD versus $8,268 USD). In the period 1965 to 1990, countries where malaria was common had an average per capita GDP that increased only 0.4% per year, compared to 2.4% per year in other countries.[136]
Poverty can increase the risk of malaria, since those in poverty do not have the financial capacities to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.[137] The disease has a heavy burden in some countries, where it may be responsible for 30–50% of hospital admissions, up to 50% of outpatient visits, and up to 40% of public health spending.[138]
Cerebral malaria is one of the leading causes of neurological disabilities in African children.[90] Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery.[88] Consequently, severe and cerebral malaria have far-reaching socioeconomic consequences that extend beyond the immediate effects of the disease.[139]
Counterfeit and substandard drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia,[140]China,[141]Indonesia, Laos, Thailand, and Vietnam, and are an important cause of avoidable death in those countries.[142] The WHO said that studies indicate that up to 40% of artesunate-based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries.[143] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.[144]
Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging.[145] A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.[1]
War


World War II poster
Throughout history, the contraction of malaria has played a prominent role in the fates of government rulers, nation-states, military personnel, and military actions.[146] In 1910, Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book titled The Prevention of Malaria that included a chapter titled "The Prevention of Malaria in War." The chapter's author, Colonel C. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role that malaria has historically played during wars: "The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era. ... It is probably the case that many of the so-called camp fevers, and probably also a considerable proportion of the camp dysentery, of the wars of the sixteenth, seventeenth and eighteenth centuries were malarial in origin."[147]
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.[148] According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."[149]
Significant financial investments have been made to procure existing and create new anti-malarial agents. During World War I and World War II, inconsistent supplies of the natural anti-malaria drugs cinchona bark and quinine prompted substantial funding into research and development of other drugs and vaccines. American military organizations conducting such research initiatives include the Navy Medical Research Center, Walter Reed Army Institute of Research, and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.[150]
Additionally, initiatives have been founded such as Malaria Control in War Areas (MCWA), established in 1942, and its successor, the Communicable Disease Center (now known as the Centers for Disease Control and Prevention, or CDC) established in 1946. According to the CDC, MCWA "was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic".[151]
Eradication efforts
Several notable attempts are being made to eliminate the parasite from sections of the world, or to eradicate it worldwide. In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization plans to dissolve if that goal is accomplished.[152] Several malaria vaccines are in clinical trials, which are intended to provide protection for children in endemic areas and reduce the speed of transmission of the disease. As of 2012, The Global Fund to Fight AIDS, Tuberculosis and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria.[153] The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market.[154] Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict the spread of malaria based on the availability of habitat of malaria-carrying parasites.[98] The Malaria Policy Advisory Committee (MPAC) of the World Health Organization (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination".[155] In November 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with the long-term goal of malaria eradication.[156]
Malaria has been successfully eliminated or greatly reduced in certain areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions. Several factors contributed, such as the draining of wetland breeding grounds for agriculture and other changes in water management practices, and advances in sanitation, including greater use of glass windows and screens in dwellings.[157] Malaria was eliminated from most parts of the USA in the early 20th century by such methods, and the use of the pesticideDDT and other means eliminated it from the remaining pockets in the South in the 1950s.[158] (see National Malaria Eradication Program) In Suriname, the disease has been cleared from its capital city and coastal areas through a three-pronged approach initiated by the Global Malaria Eradication program in 1955, involving: vector control through the use of DDT and IRS; regular collection of blood smears from the population to identify existing malaria cases; and providing chemotherapy to all affected individuals.[159]Bhutan is pursuing an aggressive malaria elimination strategy, and has achieved a 98.7% decline in microscopy-confirmed cases from 1994 to 2010. In addition to vector control techniques such as IRS in high-risk areas and thorough distribution of long-lasting ITNs, factors such as economic development and increasing access to health services have contributed to Bhutan's successes in reducing malaria incidence.[160]
Research
See also: Malaria vaccine
Immunity (or, more accurately, tolerance) to P. falciparum malaria does occur naturally, but only in response to years of repeated infection.[27] An individual can be protected from a P. falciparum infection if they receive about a thousand bites from mosquitoes that carry a version of the parasite rendered non-infective by a dose of X-rayirradiation.[161] An effective vaccine is not yet available for malaria, although several are under development.[162] The highly polymorphic nature of many P. falciparum proteins results in significant challenges to vaccine design. Vaccine candidates that target antigens on gametes, zygotes, or ookinetes in the mosquito midgut aim to block the transmission of malaria. These transmission-blocking vaccines induce antibodies in the human blood; when a mosquito takes a blood meal from a protected individual, these antibodies prevent the parasite from completing its development in the mosquito.[163] Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have been inadequate on their own.[164] For example, SPf66 was tested extensively in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective.[165] Several potential vaccines targeting the pre-erythrocytic stage of the parasite's life cycle are being developed, with RTS,S as the leading candidate;[161] it is expected to be licensed in 2015.[89] A US biotech company, Sanaria, is developing a pre-erythrocytic attenuated vaccine called PfSPZ that uses whole sporozoites to induce an immune response.[166] In 2006, the Malaria Vaccine Advisory Committee to the WHO outlined a "Malaria Vaccine Technology Roadmap" that has as one of its landmark objectives to "develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than one year" by 2015.[167]
Malaria parasites contain apicoplasts, organelles usually found in plants, complete with their own genomes. These apicoplasts are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, such as fatty acid biosynthesis. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel anti-malarial drugs.[168]
With the onset of drug-resistant Plasmodium parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid adducts, which are taken up by the parasite and ultimately interfere with its ability to create several essential B vitamins.[169][170] Antimalarial drugs using synthetic metal-basedcomplexes are attracting research interest.[171][172]
A non-chemical vector control strategy involves genetic manipulation of malaria mosquitoes. Advances in genetic engineering technologies make it possible to introduce foreign DNA into the mosquito genome and either decrease the lifespan of the mosquito, or make it more resistant to the malaria parasite. Sterile insect technique is a genetic control method whereby large numbers of sterile males mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eliminate the target population.[50]
Genomics is now central to malaria research. With the sequencing of P. falciparum, one of its vectors Anopheles gambiae, and the human genome, the genetics of all three organisms in the malaria lifecycle can be studied.[173] Another new application of genetic technology is the ability to produce genetically modified mosquitoes that do not transmit malaria, potentially allowing biological control of malaria transmission.[174]
Researchers are encouraged by the findings of a study that commenced in 2002 involving the monitoring of the lives of 1,000 Tanzanian children. The study is one of many being explored in 2014 in the race to find a malaria vaccine.[175]
Other animals
Nearly 200 parasitic Plasmodium species have been identified that infect birds, reptiles, and other mammals,[176] and about 30 species naturally infect non-human primates.[177] Some of the malaria parasites that affect non-human primates (NHP) serve as model organisms for human malarial parasites, such as P. coatneyi (a model for P. falciparum) and P. cynomolgi (P. vivax). Diagnostic techniques used to detect parasites in NHP are similar to those employed for humans.[178] Malaria parasites that infect rodents are widely used as models in research, such as P. berghei.[179]Avian malaria primarily affects species of the order Passeriformes, and poses a substantial threat to birds of Hawaii, the Galapagos, and other archipelagoes. The parasite P. relictum is known to play a role in limiting the distribution and abundance of endemic Hawaiian birds. Global warming is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.[180]
References
1.    Nayyar GML, Breman JG, Newton PN, Herrington J (2012). "Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa". Lancet Infectious Diseases12 (6): 488–96. doi:10.1016/S1473-3099(12)70064-6. PMID 22632187.
2.    Fairhurst RM, Wellems TE (2010). "Chapter 275. Plasmodium species (malaria)". In Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases2 (7th ed.). Philadelphia, Pennsylvania: Churchill Livingstone/Elsevier. pp. 3437–3462. ISBN 978-0-443-06839-3.
3.    Nadjm B, Behrens RH (2012). "Malaria: An update for physicians". Infectious Disease Clinics of North America26 (2): 243–59. doi:10.1016/j.idc.2012.03.010. PMID 22632637.
4.    Bartoloni A, Zammarchi L (2012). "Clinical aspects of uncomplicated and severe malaria". Mediterranean Journal of Hematology and Infectious Diseases4 (1): e2012026. doi:10.4084/MJHID.2012.026. PMC 3375727. PMID 22708041. 
5.    Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME (2006). "Malarial retinopathy: A newly established diagnostic sign in severe malaria". American Journal of Tropical Medicine and Hygiene75 (5): 790–7. PMC 2367432. PMID 17123967. 
6.    Ferri FF (2009). "Chapter 332. Protozoal infections". Ferri's Color Atlas and Text of Clinical Medicine. Elsevier Health Sciences. p. 1159. ISBN 978-1-4160-4919-7.
7.    Taylor WR, Hanson J, Turner GD, White NJ, Dondorp AM (2012). "Respiratory manifestations of malaria". Chest142 (2): 492–505. doi:10.1378/chest.11-2655. PMID 22871759. 
8.    Korenromp E, Williams B, de Vlas S, Gouws E, Gilks C, Ghys P, Nahlen B (2005). "Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa". Emerging Infectious Diseases11 (9): 1410–9. doi:10.3201/eid1109.050337. PMC 3310631. PMID 16229771. 
9.    Beare NA, Lewallen S, Taylor TE, Molyneux ME (2011). "Redefining cerebral malaria by including malaria retinopathy". Future Microbiology6 (3): 349–55. doi:10.2217/fmb.11.3. PMC 3139111. PMID 21449844. 
10.    Hartman TK, Rogerson SJ, Fischer PR (2010). "The impact of maternal malaria on newborns". Annals of Tropical Paediatrics30 (4): 271–82. doi:10.1179/146532810X12858955921032. PMID 21118620.
11.    Rijken MJ, McGready R, Boel ME, Poespoprodjo R, Singh N, Syafruddin D, Rogerson S, Nosten F (2012). "Malaria in pregnancy in the Asia-Pacific region". Lancet Infectious Diseases12 (1): 75–88. doi:10.1016/S1473-3099(11)70315-2. PMID 22192132.
12.    Mueller I, Zimmerman PA, Reeder JC (2007). "Plasmodium malariae and Plasmodium ovale—the "bashful" malaria parasites". Trends in Parasitology23 (6): 278–83. doi:10.1016/j.pt.2007.04.009. PMC 3728836. PMID 17459775.
13.    Collins WE (2012). "Plasmodium knowlesi: A malaria parasite of monkeys and humans". Annual Review of Entomology57: 107–21. doi:10.1146/annurev-ento-121510-133540. PMID 22149265.
14.    Sarkar PK, Ahluwalia G, Vijayan VK, Talwar A (2009). "Critical care aspects of malaria". Journal of Intensive Care Medicine25 (2): 93–103. doi:10.1177/0885066609356052. PMID 20018606.
15.    Baird JK (2013). "Evidence and implications of mortality associated with acute Plasmodium vivax malaria". Clinical Microbiology Reviews26 (1): 36–57. doi:10.1128/CMR.00074-12. PMC 3553673. PMID 23297258.
16.    Arnott A, Barry AE, Reeder JC (2012). "Understanding the population genetics of Plasmodium vivax is essential for malaria control and elimination". Malaria Journal11: 14. doi:10.1186/1475-2875-11-14. PMC 3298510. PMID 22233585. 
17.    Collins WE, Barnwell JW (2009). "Plasmodium knowlesi: finally being recognized". Journal of Infectious Diseases199 (8): 1107–8. doi:10.1086/597415. PMID 19284287. 
18.    Parham PE, Christiansen-Jucht C, Pople D, Michael E (2011). "Understanding and Modelling the Impact of Climate Change on Infectious Diseases". InTech– Progress and Future Challenges. in Climate Change. Blanco J, Kheradmand H (eds) ISBN 978-9533074115: 43–66.
19.    "Climate Change And Infectious Diseases". CLIMATE CHANGE AND HUMAN HEALTH - RISK AND RESPONSES. World Health Organization.
20.    Schlagenhauf-Lawlor 2008, pp. 70–1
21.    Cowman AF, Berry D, Baum J (2012). "The cellular and molecular basis for malaria parasite invasion of the human red blood cell". Journal of Cell Biology198 (6): 961–71. doi:10.1083/jcb.201206112. PMC 3444787. PMID 22986493. 
22.    Arrow KJ, Panosian C, Gelband H, Institute of Medicine (U.S.). Committee on the Economics of Antimalarial Drugs (2004). Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. National Academies Press. p. 141. ISBN 978-0-309-09218-0.
23.    Owusu-Ofori AK, Parry C, Bates I (2010). "Transfusion-transmitted malaria in countries where malaria is endemic: A review of the literature from sub-Saharan Africa". Clinical Infectious Diseases51 (10): 1192–8. doi:10.1086/656806. PMID 20929356. 
24.    WHO 2010, p. vi
25.    White NJ (2011). "Determinants of relapse periodicity in Plasmodium vivax malaria". Malaria Journal10: 297. doi:10.1186/1475-2875-10-297. PMC 3228849. PMID 21989376. 
26.    WHO 2010, p. 17
27.    Tran TM, Samal B, Kirkness E, Crompton PD (2012). "Systems immunology of human malaria". Trends in Parasitology28 (6): 248–57. doi:10.1016/j.pt.2012.03.006. PMC 3361535. PMID 22592005.
28.    Bledsoe GH (2005). "Malaria primer for clinicians in the United States". Southern Medical Journal98 (12): 1197–204; quiz 1205, 1230. doi:10.1097/01.smj.0000189904.50838.eb. PMID 16440920.
29.    Vaughan AM, Aly AS, Kappe SH (2008). "Malaria parasite pre-erythrocytic stage infection: Gliding and hiding". Cell Host & Microbe4 (3): 209–18. doi:10.1016/j.chom.2008.08.010. PMC 2610487. PMID 18779047. 
30.    Richter J, Franken G, Mehlhorn H, Labisch A, Häussinger D (2010). "What is the evidence for the existence of Plasmodium ovale hypnozoites?". Parasitology Research107 (6): 1285–90. doi:10.1007/s00436-010-2071-z. PMID 20922429.
31.    Tilley L, Dixon MW, Kirk K (2011). "The Plasmodium falciparum-infected red blood cell". International Journal of Biochemistry and Cell Biology43 (6): 839–42. doi:10.1016/j.biocel.2011.03.012. PMID 21458590.
32.    Mens PF, Bojtor EC, Schallig HDFH (2012). "Molecular interactions in the placenta during malaria infection". European Journal of Obstetrics & Gynecology and Reproductive Biology152 (2): 126–32. doi:10.1016/j.ejogrb.2010.05.013. PMID 20933151.
33.    Rénia L, Wu Howland S, Claser C, Charlotte Gruner A, Suwanarusk R, Hui Teo T, Russell B, Ng LF (2012). "Cerebral malaria: mysteries at the blood-brain barrier". Virulence3 (2): 193–201. doi:10.4161/viru.19013. PMC 3396698. PMID 22460644. 
34.    Kwiatkowski DP (2005). "How malaria has affected the human genome and what human genetics can teach us about malaria". American Journal of Human Genetics77 (2): 171–92. doi:10.1086/432519. PMC 1224522. PMID 16001361. 
35.    Hedrick PW (2011). "Population genetics of malaria resistance in humans". Heredity107 (4): 283–304. doi:10.1038/hdy.2011.16. PMC 3182497. PMID 21427751. 
36.    Weatherall DJ (2008). "Genetic variation and susceptibility to infection: The red cell and malaria". British Journal of Haematology141 (3): 276–86. doi:10.1111/j.1365-2141.2008.07085.x. PMID 18410566.
37.    Bhalla A, Suri V, Singh V (2006). "Malarial hepatopathy". Journal of Postgraduate Medicine52 (4): 315–20. PMID 17102560. 
38.    Abba K, Deeks JJ, Olliaro P, Naing CM, Jackson SM, Takwoingi Y, Donegan S, Garner P (2011). "Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries". In Abba, Katharine. Cochrane Database of Systematic Reviews (7): CD008122. doi:10.1002/14651858.CD008122.pub2. PMID 21735422.
39.    Kattenberg JH, Ochodo EA, Boer KR, Schallig HD, Mens PF, Leeflang MM (2011). "Systematic review and meta-analysis: Rapid diagnostic tests versus placental histology, microscopy and PCR for malaria in pregnant women". Malaria Journal10: 321. doi:10.1186/1475-2875-10-321. PMC 3228868. PMID 22035448. 
40.    Wilson ML (2012). "Malaria rapid diagnostic tests". Clinical Infectious Diseases54 (11): 1637–41. doi:10.1093/cid/cis228. PMID 22550113.
41.    Perkins MD, Bell DR (2008). "Working without a blindfold: The critical role of diagnostics in malaria control". Malaria Journal1 (Suppl 1): S5. doi:10.1186/1475-2875-7-S1-S5. PMC 2604880. PMID 19091039. 
42.    WHO 2010, p. 35
43.    WHO 2010, p. v
44.    World Health Organization (1958). "Malaria" (PDF). The First Ten Years of the World Health Organization. World Health Organization. pp. 172–87.
45.    Sabot O, Cohen JM, Hsiang MS, Kahn JG, Basu S, Tang L, Zheng B, Gao Q, Zou L, Tatarsky A, Aboobakar S, Usas J, Barrett S, Cohen JL, Jamison DT, Feachem RG (2010). "Costs and financial feasibility of malaria elimination". Lancet376 (9752): 1604–15. doi:10.1016/S0140-6736(10)61355-4. PMC 3044845. PMID 21035839.
46.    Kajfasz P (2009). "Malaria prevention". International Maritime Health60 (1–2): 67–70. PMID 20205131. 
47.    Lengeler C (2004). "Insecticide-treated bed nets and curtains for preventing malaria". In Lengeler, Christian. Cochrane Database of Systematic Reviews (2): CD000363. doi:10.1002/14651858.CD000363.pub2. PMID 15106149.
48.    Tanser FC, Lengeler C, Sharp BL (2010). "Indoor residual spraying for preventing malaria". In Lengeler, Christian. Cochrane Database of Systematic Reviews (4): CD006657. doi:10.1002/14651858.CD006657.pub2. PMID 20393950.
49.    Palmer, J. "WHO gives indoor use of DDT a clean bill of health for controlling malaria". WHO.
50.    Raghavendra K, Barik TK, Reddy BP, Sharma P, Dash AP (2011). "Malaria vector control: From past to future". Parasitology Research108 (4): 757–79. doi:10.1007/s00436-010-2232-0. PMID 21229263. 
51.    Howitt P, Darzi A, Yang GZ, Ashrafian H, Atun R, Barlow J, Blakemore A, Bull AM, Car J, Conteh L, Cooke GS, Ford N, Gregson SA, Kerr K, King D, Kulendran M, Malkin RA, Majeed A, Matlin S, Merrifield R, Penfold HA, Reid SD, Smith PC, Stevens MM, Templeton MR, Vincent C, Wilson E (2012). "Technologies for global health". The Lancet380 (9840): 507–35. doi:10.1016/S0140-6736(12)61127-1. PMID 22857974.
52.    Miller JM, Korenromp EL, Nahlen BL, W Steketee R (2007). "Estimating the number of insecticide-treated nets required by African households to reach continent-wide malaria coverage targets". Journal of the American Medical Association297 (20): 2241–50. doi:10.1001/jama.297.20.2241. PMID 17519414. 
53.    Noor AM, Mutheu JJ, Tatem AJ, Hay SI, Snow RW (2009). "Insecticide-treated net coverage in Africa: mapping progress in 2000–07". Lancet373 (9657): 58–67. doi:10.1016/S0140-6736(08)61596-2. PMC 2652031. PMID 19019422.
54.    Schlagenhauf-Lawlor 2008, pp. 215
55.    Enayati A, Hemingway J (2010). "Malaria management: Past, present, and future". Annual Review of Entomology55: 569–91. doi:10.1146/annurev-ento-112408-085423. PMID 19754246.
56.    (PDF) Indoor Residual Spraying: Use of Indoor Residual Spraying for Scaling Up Global Malaria Control and Elimination. WHO Position Statement (Report). World Health Organization. 2006.
57.    van den Berg H (2009). "Global status of DDT and its alternatives for use in vector control to prevent disease". Environmental Health Perspectives117 (11): 1656–63. doi:10.1289/ehp.0900785. PMC 2801202. PMID 20049114.
58.    Pates H, Curtis C (2005). "Mosquito behaviour and vector control". Annual Review of Entomology50: 53–70. doi:10.1146/annurev.ento.50.071803.130439. PMID 15355233.
59.    Tusting, LS; Thwing, J; Sinclair, D; Fillinger, U; Gimnig, J; Bonner, KE; Bottomley, C; Lindsay, SW (Aug 29, 2013). "Mosquito larval source management for controlling malaria.". The Cochrane database of systematic reviews8: CD008923. doi:10.1002/14651858.CD008923.pub2. PMID 23986463.
60.    Enayati AA, Hemingway J, Garner P. (2007). "Electronic mosquito repellents for preventing mosquito bites and malaria infection" (PDF). In Enayati, Ahmadali. Cochrane Database of Systematic Reviews (2): CD005434. doi:10.1002/14651858.CD005434.pub2. PMID 17443590.
61.    Lalloo DG, Olukoya P, Olliaro P (2006). "Malaria in adolescence: Burden of disease, consequences, and opportunities for intervention". Lancet Infectious Diseases6 (12): 780–93. doi:10.1016/S1473-3099(06)70655-7. PMID 17123898.
62.    Mehlhorn H, ed. (2008). "Disease Control, Methods". Encyclopedia of Parasitology (3rd ed.). Springer. pp. 362–6. ISBN 978-3-540-48997-9.
63.    Bardají A, Bassat Q, Alonso PL, Menéndez C (2012). "Intermittent preventive treatment of malaria in pregnant women and infants: making best use of the available evidence". Expert Opinion on Pharmacotherapy13 (12): 1719–36. doi:10.1517/14656566.2012.703651. PMID 22775553.
64.    Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringanje C (2012). "Intermittent preventive treatment for malaria in children living in areas with seasonal transmission". In Meremikwu, Martin M. Cochrane Database of Systematic Reviews2 (2): CD003756. doi:10.1002/14651858.CD003756.pub4. PMID 22336792. 
65.    Lal, S; Phukan, PK; Sharma, SN; Dhillon, GP; Kaul, SM; Saxena, NB (Jun 1998). "'Anti-malaria month'--a step forward in multisectoral collaboration and community involvement in malaria control.". The Journal of communicable diseases30 (2): 93–101. PMID 9914675.
66.    Anti-Malaria month campaign: Operational guide. National Vector Borne Disease Control Programme (NVBDCP). Retrieved 19 January 2014.
67.    Jacquerioz FA, Croft AM (2009). "Drugs for preventing malaria in travellers". In Jacquerioz FA. Cochrane Database of Systematic Reviews (4): CD006491. doi:10.1002/14651858.CD006491.pub2. PMID 19821371. 
68.    Freedman DO (2008). "Clinical practice. Malaria prevention in short-term travelers". New England Journal of Medicine359 (6): 603–12. doi:10.1056/NEJMcp0803572. PMID 18687641. 
69.    Fernando SD, Rodrigo C, Rajapakse S (2011). "Chemoprophylaxis in malaria: Drugs, evidence of efficacy and costs". Asian Pacific Journal of Tropical Medicine4 (4): 330–36. doi:10.1016/S1995-7645(11)60098-9. PMID 21771482.
70.    Turschner S, Efferth T (2009). "Drug resistance in Plasmodium: Natural products in the fight against malaria". Mini Reviews in Medicinal Chemistry9 (2): 206–14. doi:10.2174/138955709787316074. PMID 19200025.
71.    Meremikwu MM, Odigwe CC, Akudo Nwagbara B, Udoh EE (2012). "Antipyretic measures for treating fever in malaria". In Meremikwu, Martin M. Cochrane Database of Systematic Reviews9: CD002151. doi:10.1002/14651858.CD002151.pub2. PMID 22972057.
72.    Kokwaro G (2009). "Ongoing challenges in the management of malaria". Malaria Journal8 (Suppl 1): S2. doi:10.1186/1475-2875-8-S1-S2. PMC 2760237. PMID 19818169. 
73.    WHO 2010, pp. 75–86
74.    WHO 2010, p. 21
75.    Keating GM (2012). "Dihydroartemisinin/piperaquine: A review of its use in the treatment of uncomplicated Plasmodium falciparum malaria". Drugs72 (7): 937–61. doi:10.2165/11203910-000000000-00000. PMID 22515619.
76.    Manyando C, Kayentao K, D'Alessandro U, Okafor HU, Juma E, Hamed K (2011). "A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy". Malaria Journal11: 141. doi:10.1186/1475-2875-11-141. PMC 3405476. PMID 22548983. 
77.    O'Brien C, Henrich PP, Passi N, Fidock DA (2011). "Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum". Current Opinion in Infectious Diseases24 (6): 570–7. doi:10.1097/QCO.0b013e32834cd3ed. PMC 3268008. PMID 22001944. 
78.    Fairhurst RM, Nayyar GM, Breman JG, Hallett R, Vennerstrom JL, Duong S, Ringwald P, Wellems TE, Plowe CV, Dondorp AM (2012). "Artemisinin-resistant malaria: research challenges, opportunities, and public health implications". American Journal of Tropical Medicine and Hygiene87 (2): 231–41. doi:10.4269/ajtmh.2012.12-0025. PMC 3414557. PMID 22855752. 
79.    Waters NC, Edstein MD (2012). "8-Aminoquinolines: Primaquine and tafenoquine". In Staines HM, Krishna S (eds). Treatment and Prevention of Malaria: Antimalarial Drug Chemistry, Action and Use. Springer. pp. 69–93. ISBN 978-3-0346-0479-6.
80.    Sinclair D, Donegan S, Isba R, Lalloo DG (2012). "Artesunate versus quinine for treating severe malaria". In Sinclair, David. Cochrane Database of Systematic Reviews6: CD005967. doi:10.1002/14651858.CD005967.pub4. PMID 22696354.
81.    White NJ (2004). "Antimalarial drug resistance". J. Clin. Invest.113 (8): 1084–92. doi:10.1172/JCI21682. PMC 385418. PMID 15085184.
82.    White NJ (2008). "Qinghaosu (artemisinin): the price of success". Science.320 (5874): 330–334. doi:10.1126/science.1155165. PMID 18420924.
83.    Wongsrichanalai C, Meshnick SR (2008). "Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia–Thailand border". Emerging Infectious Diseases14 (5): 716–9. doi:10.3201/eid1405.071601. PMC 2600243. PMID 18439351.
84.    Dondorp AM, Yeung S, White L, Nguon C, Day NPJ, Socheat D, von Seidlein L (2010). "Artemisinin resistance: current status and scenarios for containment". Nature Reviews Microbiology8 (4): 272–80. doi:10.1038/nrmicro2331. PMID 20208550.
85.    World Health Organization (2013). "Q&A on artemisinin resistance". WHO malaria publications.
86.    "Frequently Asked Questions (FAQs): If I get malaria, will I have it for the rest of my life?". US Centers for Disease Control and Prevention. February 8, 2010. Retrieved 2012-05-14.
87.    Trampuz A, Jereb M, Muzlovic I, Prabhu R (2003). "Clinical review: Severe malaria". Critical Care7 (4): 315–23. doi:10.1186/cc2183. PMC 270697. PMID 12930555. 
88.    Fernando SD, Rodrigo C, Rajapakse S (2010). "The 'hidden' burden of malaria: Cognitive impairment following infection". Malaria Journal9: 366. doi:10.1186/1475-2875-9-366. PMC 3018393. PMID 21171998. 
89.    Riley EM, Stewart VA (2013). "Immune mechanisms in malaria: New insights in vaccine development". Nature Medicine19 (2): 168–78. doi:10.1038/nm.3083. PMID 23389617.
90.    Idro R, Marsh K, John CC, Newton CRJ (2010). "Cerebral malaria: Mechanisms of brain injury and strategies for improved neuro-cognitive outcome". Pediatric Research68 (4): 267–74. doi:10.1203/PDR.0b013e3181eee738. PMC 3056312. PMID 20606600. 
91.    "Malaria". US Centers for Disease Control and Prevention. April 15, 2010. Retrieved 2012-05-02.
92.    (PDF) World Malaria Report 2012 (Report). World Health Organization.
93.    Olupot-Olupot P, Maitland, K (2013). "Management of severe malaria: Results from recent trials". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 764: 241–50. doi:10.1007/978-1-4614-4726-9_20. ISBN 978-1-4614-4725-2. PMID 23654072.
94.    Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD (2012). "Global malaria mortality between 1980 and 2010: A systematic analysis". Lancet379 (9814): 413–31. doi:10.1016/S0140-6736(12)60034-8. PMID 22305225.
95.    Lozano R, et al. (2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010". Lancet380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
96.    Layne SP. "Principles of Infectious Disease Epidemiology" (PDF). EPI 220. UCLA Department of Epidemiology. Archived from the original on 2006-02-20. Retrieved 2007-06-15.
97.    Provost C (April 25, 2011). "World Malaria Day: Which countries are the hardest hit? Get the full data". The Guardian. Retrieved 2012-05-03.
98.    Guerra CA, Hay SI, Lucioparedes LS, Gikandi PW, Tatem AJ, Noor AM, Snow RW (2007). "Assembling a global database of malaria parasite prevalence for the Malaria Atlas Project". Malaria Journal6 (6): 17. doi:10.1186/1475-2875-6-17. PMC 1805762. PMID 17306022. 
99.    Hay SI, Okiro EA, Gething PW, Patil AP, Tatem AJ, Guerra CA, Snow RW (2010). "Estimating the global clinical burden of Plasmodium falciparum malaria in 2007". In Mueller, Ivo. PLoS Medicine7 (6): e1000290. doi:10.1371/journal.pmed.1000290. PMC 2885984. PMID 20563310. 
100.    Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IR, Johnston GL, Tatem AJ, Hay SI (2011). "A new world malaria map: Plasmodium falciparum endemicity in 2010". Malaria Journal10 (1): 378. doi:10.1186/1475-2875-10-378. PMC 3274487. PMID 22185615. 
101.    Feachem RG, Phillips AA, Hwang J, Cotter C, Wielgosz B, Greenwood BM, Sabot O, Rodriguez MH, Abeyasinghe RR, Ghebreyesus TA, Snow RW (2010). "Shrinking the malaria map: progress and prospects". Lancet376 (9752): 1566–78. doi:10.1016/S0140-6736(10)61270-6. PMC 3044848. PMID 21035842. 
102.    Greenwood B, Mutabingwa T (2002). "Malaria in 2002". Nature415 (6872): 670–2. doi:10.1038/415670a. PMID 11832954.
103.    Jamieson A, Toovey S, Maurel M (2006). Malaria: A Traveller's Guide. Struik. p. 30. ISBN 978-1-77007-353-1.
104.    Abeku TA (2007). "Response to malaria epidemics in Africa". Emerging Infectious Diseases14 (5): 681–6. doi:10.3201/eid1305.061333. PMC 2738452. PMID 17553244. 
105.    Cui L, Yan G, Sattabongkot J, Cao Y, Chen B, Chen X, Fan Q, Fang Q, Jongwutiwes S, Parker D, Sirichaisinthop J, Kyaw MP, Su XZ, Yang H, Yang Z, Wang B, Xu J, Zheng B, Zhong D, Zhou G (2012). "Malaria in the Greater Mekong Subregion: Heterogeneity and complexity". Acta Tropica121 (3): 227–39. doi:10.1016/j.actatropica.2011.02.016. PMC 3132579. PMID 21382335. 
106.    Machault V, Vignolles C, Borchi F, Vounatsou P, Pages F, Briolant S, Lacaux JP, Rogier C (2011). "The use of remotely sensed environmental data in the study of malaria" (PDF). Geospatial Health5 (2): 151–68. PMID 21590665.
107.    Harper K, Armelagos G (2011). "The changing disease-scape in the third epidemiological transition". International Journal of Environmental Research and Public Health7 (2): 675–97. doi:10.3390/ijerph7020675. PMC 2872288. PMID 20616997. 
108.    Prugnolle F, Durand P, Ollomo B, Duval L, Ariey F, Arnathau C, Gonzalez JP, Leroy E, Renaud F (2011). "A fresh look at the origin of Plasmodium falciparum, the most malignant malaria agent". In Manchester, Marianne. PLoS Pathogens7 (2): e1001283. doi:10.1371/journal.ppat.1001283. PMC 3044689. PMID 21383971. 
109.    Cox F (2002). "History of human parasitology". Clinical Microbiology Reviews15 (4): 595–612. doi:10.1128/CMR.15.4.595-612.2002. PMC 126866. PMID 12364371. 
110.    "DNA clues to malaria in ancient Rome". BBC News. February 20, 2001., in reference to Sallares R, Gomzi S (2001). "Biomolecular archaeology of malaria". Ancient Biomolecules3 (3): 195–213. OCLC 538284457.
111.    Sallares R (2002). Malaria and Rome: A History of Malaria in Ancient Italy. Oxford University Press. doi:10.1093/acprof:oso/9780199248506.001.0001. ISBN 978-0-19-924850-6.
112.    Hays JN (2005). Epidemics and Pandemics: Their Impacts on Human History. Santa Barbara, California: ABC-CLIO. p. 11. ISBN 978-1-85109-658-9.
113.    Reiter P (2000). "From Shakespeare to Defoe: Malaria in England in the Little Ice Age". Emerging Infectious Diseases6 (1): 1–11. doi:10.3201/eid0601.000101. PMC 2627969. PMID 10653562. 
114.    Lindemann M (1999). Medicine and Society in Early Modern Europe. Cambridge University Press. p. 62. ISBN 978-0-521-42354-0.
115.    Gratz NG, World Health Organization (2006). The Vector- and Rodent-borne Diseases of Europe and North America: Their Distribution and Public Health Burden. Cambridge University Press. p. 33. ISBN 978-0-521-85447-4.
116.    Webb Jr JLA (2009). Humanity's Burden: A Global History of Malaria. Cambridge University Press. ISBN 978-0-521-67012-8.
117.    "The Nobel Prize in Physiology or Medicine 1907: Alphonse Laveran". The Nobel Foundation. Retrieved 2012-05-14.
118.    Tan SY, Sung H (2008). "Carlos Juan Finlay (1833–1915): Of mosquitoes and yellow fever" (PDF). Singapore Medical Journal49 (5): 370–1. PMID 18465043.
119.    Chernin E (1983). "Josiah Clark Nott, insects, and yellow fever". Bulletin of the New York Academy of Medicine59 (9): 790–802. PMC 1911699. PMID 6140039.
120.    Chernin E (1977). "Patrick Manson (1844–1922) and the transmission of filariasis". American Journal of Tropical Medicine and Hygiene26 (5 Pt 2 Suppl): 1065–70. PMID 20786.
121.    "The Nobel Prize in Physiology or Medicine 1902: Ronald Ross". The Nobel Foundation. Retrieved 2012-05-14.
122.    "Ross and the Discovery that Mosquitoes Transmit Malaria Parasites". CDC Malaria website. Archived from the original on 2007-06-02. Retrieved 2012-06-14.
123.    Simmons JS (1979). Malaria in Panama. Ayer Publishing. ISBN 978-0-405-10628-6.
124.    Kaufman TS, Rúveda EA (2005). "The quest for quinine: Those who won the battles and those who won the war". Angewandte Chemie (International Edition in English)44 (6): 854–85. doi:10.1002/anie.200400663. PMID 15669029.
125.    Pelletier PJ, Caventou JB (1820). "Des recherches chimiques sur les Quinquinas" [Chemical research on quinquinas]. Annales de Chimie et de Physique (in French) 15: 337–65.
126.    Kyle R, Shampe M (1974). "Discoverers of quinine". Journal of the American Medical Association229 (4): 462. doi:10.1001/jama.229.4.462. PMID 4600403.
127.    Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U (2011). "Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria". Malaria Journal10 (1): 144. doi:10.1186/1475-2875-10-144. PMC 3121651. PMID 21609473. 
128.    Hsu E (2006). "Reflections on the 'discovery' of the antimalarial qinghao". British Journal of Clinical Pharmacology61 (3): 666–70. doi:10.1111/j.1365-2125.2006.02673.x. PMC 1885105. PMID 16722826. 
129.    Vogel V (2013). "Malaria as a Lifesaving Therapy". Science342 (6159): 684–687. doi:10.1126/science.342.6159.684.
130.    "Eradication of Malaria in the United States (1947–1951)". US Centers for Disease Control and Prevention. February 8, 2010. Retrieved 2012-05-02.
131.    Killeen G, Fillinger U, Kiche I, Gouagna L, Knols B (2002). "Eradication of Anopheles gambiae from Brazil: Lessons for malaria control in Africa?". Lancet Infectious Diseases2 (10): 618–27. doi:10.1016/S1473-3099(02)00397-3. PMID 12383612.
132.    Vanderberg JP (2009). "Reflections on early malaria vaccine studies, the first successful human malaria vaccination, and beyond". Vaccine27 (1): 2–9. doi:10.1016/j.vaccine.2008.10.028. PMC 2637529. PMID 18973784. 
133.    Gollin D, Zimmermann C (August 2007) (PDF). Malaria: Disease Impacts and Long-Run Income Differences (Report). Institute for the Study of Labor.
134.    Worrall E, Basu S, Hanson K (2005). "Is malaria a disease of poverty? A review of the literature". Tropical Health and Medicine10 (10): 1047–59. doi:10.1111/j.1365-3156.2005.01476.x. PMID 16185240. 
135.    Humphreys M (2001). Malaria: Poverty, Race, and Public Health in the United States. Johns Hopkins University Press. p. 256. ISBN 0-8018-6637-5.
136.    Sachs J, Malaney P (2002). "The economic and social burden of malaria". Nature415 (6872): 680–5. doi:10.1038/415680a. PMID 11832956.
137.    Greenwood BM, Bojang K, Whitty CJ, Targett GA (2005). "Malaria". Lancet365 (9469): 1487–98. doi:10.1016/S0140-6736(05)66420-3. PMID 15850634.
138.    Roll Back Malaria WHO partnership (2003). "Economic costs of malaria" (PDF). WHO.
139.    Ricci F (2012). "Social implications of malaria and their relationships with poverty". Mediterranean Journal of Hematology and Infectious Diseases4 (1): e2012048. doi:10.4084/MJHID.2012.048. PMC 3435125. PMID 22973492. 
140.    Lon CT, Tsuyuoka R, Phanouvong S, Nivanna N, Socheat D, Sokhan C, Blum N, Christophel EM, Smine A (2006). "Counterfeit and substandard antimalarial drugs in Cambodia". Transactions of the Royal Society of Tropical Medicine and Hygiene100 (11): 1019–24. doi:10.1016/j.trstmh.2006.01.003. PMID 16765399.
141.    Newton PN, Fernández FM, Plançon A, Mildenhall DC, Green MD, Ziyong L, Christophel EM, Phanouvong S, Howells S, McIntosh E, Laurin P, Blum N, Hampton CY, Faure K, Nyadong L, Soong CW, Santoso B, Zhiguang W, Newton J, Palmer K (2008). "A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia". PLoS Medicine5 (2): e32. doi:10.1371/journal.pmed.0050032. PMC 2235893. PMID 18271620.
142.    Newton PN Green MD, Fernández FM, Day NPJ, White NJ (2006). "Counterfeit anti-infective drugs". Lancet Infectious Diseases6 (9): 602–13. doi:10.1016/S1473-3099(06)70581-3. PMID 16931411. 
143.    Parry J (2005). "WHO combats counterfeit malaria drugs in Asia". British Medical Journal330 (7499): 1044. doi:10.1136/bmj.330.7499.1044-d. PMC 557259. PMID 15879383. 
144.    Gautam CS, Utreja A, Singal GL (2009). "Spurious and counterfeit drugs: A growing industry in the developing world". Postgraduate Medical Journal85 (1003): 251–6. doi:10.1136/pgmj.2008.073213. PMID 19520877.
145.    Caudron J-M, Ford N, Henkens M, Macé, Kidle-Monroe R, Pinel J (2008). "Substandard medicines in resource-poor settings: A problem that can no longer be ignored". Tropical Medicine & International Health13 (8): 1062–72. doi:10.1111/j.1365-3156.2008.02106.x. PMID 18631318. 
146.    Russell PF (January 6, 2009). "Communicable diseases. Malaria". Medical Department of the United States Army in World War II. U.S. Army Medical Department. Office of Medical History. Retrieved 2012-09-24.
147.    Melville CH (1910). "The prevention of malaria in war". In Ross R. The Prevention of Malaria. New York, New York: E.P. Dutton. p. 577.
148.    Bray RS (2004). Armies of Pestilence: The Effects of Pandemics on History. James Clarke. p. 102. ISBN 978-0-227-17240-7.
149.    Byrne JP (2008). Encyclopedia of Pestilence, Pandemics, and Plagues: A-M. ABC-CLIO. p. 383. ISBN 978-0-313-34102-1.
150.    Kakkilaya BS (April 14, 2006). "History of Malaria During Wars". Malariasite.com. Retrieved 2012-05-03.
151.    "History | CDC Malaria". Cdc.gov. February 8, 2010. Retrieved 2012-05-15.
152.    Strom S (April 1, 2011). "Mission Accomplished, Nonprofits Go Out of Business". The New York Times. nytimes.com. OCLC 292231852. Retrieved 2012-05-09.
153.    "Fighting AIDS, Tuberculosis and Malaria". The Global Fund. Retrieved 2012-05-09.
154.    Schoofs M (July 17, 2008). "Clinton foundation sets up malaria-drug price plan". Wall Street Journal. Retrieved 2012-05-14.
155.    "Executive summary and key points". World Malaria Report 2013. World Health Organization. Retrieved 13 February 2014.
156.    "World Malaria Report 2013". World Health Organization. Retrieved 13 February 2014.
157.    Meade MS, Emch M. (2010). Medical Geography (3rd ed.). Guilford Press. pp. 120–3. ISBN 978-1-60623-016-9.
158.    Williams LL (1963). "Malaria eradication in the United States". American Journal of Public Health and the Nation's Health53 (1): 17–21. doi:10.2105/AJPH.53.1.17. PMC 1253858. PMID 14000898. 
159.    Breeveld FJV, Vreden SGS, Grobusch MP (2012). "History of malaria research and its contribution to the malaria control success in Suriname: A review". Malaria Journal11: 95. doi:10.1186/1475-2875-11-95. PMC 3337231. PMID 22458802. 
160.    Yangzom T, Gueye CS, Namgay R, Galappaththy GN, Thimasarn K, Gosling R, Murugasampillay S, Dev V (2012). "Malaria control in Bhutan: Case study of a country embarking on elimination". Malaria Journal11: 9. doi:10.1186/1475-2875-11-9. PMC 3278342. PMID 22230355. 
161.    Hill AVS (2011). "Vaccines against malaria". Philosophical Transactions of the Royal Society B366 (1579): 2806–14. doi:10.1098/rstb.2011.0091. PMC 3146776. PMID 21893544. 
162.    Geels MJ, Imoukhuede EB, Imbault N, van Schooten H, McWade T, Troye-Blomberg M, Dobbelaer R, Craig AG, Leroy O (2011). "European Vaccine Initiative: Lessons from developing malaria vaccines" (PDF). Expert Review of Vaccines10 (12): 1697–708. doi:10.1586/erv.11.158. PMID 22085173.
163.    Crompton PD, Pierce SK, Miller LH (2010). "Advances and challenges in malaria vaccine development". Journal of Clinical Investigation120 (12): 4168–78. doi:10.1172/JCI44423. PMC 2994342. PMID 21123952. 
164.    Graves P, Gelband H (2006). "Vaccines for preventing malaria (blood-stage)". In Graves PM. Cochrane Database of Systematic Reviews (4): CD006199. doi:10.1002/14651858.CD006199. PMID 17054281. 
165.    Graves P, Gelband H (2006). "Vaccines for preventing malaria (SPf66)". In Graves PM. Cochrane Database of Systematic Reviews (2): CD005966. doi:10.1002/14651858.CD005966. PMID 16625647.
166.    Hoffman SL, Billingsley PF, James E, Richman A, Loyevsky M, Li T, Chakravarty S, Gunasekera A, Chattopadhyay R, Li M, Stafford R, Ahumada A, Epstein JE, Sedegah M, Reyes S, Richie TL, Lyke KE, Edelman R, Laurens MB, Plowe CV, Sim BK (2010). "Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria". Human Vaccines6 (1): 97–106. doi:10.4161/hv.6.1.10396. PMID 19946222. 
167.    Malaria Vaccine Advisory Committee (2006) (PDF). Malaria Vaccine Technology Roadmap (Report). PATH Malaria Vaccine Initiative (MVI). p. 2.
168.    Kalanon M, McFadden GI (2010). "Malaria, Plasmodium falciparum and its apicoplast". Biochemical Society Transactions38 (3): 775–82. doi:10.1042/BST0380775. PMID 20491664.
169.    Müller IB, Hyde JE, Wrenger C (2010). "Vitamin B metabolism in Plasmodium falciparum as a source of drug targets". Trends in Parasitology26 (1): 35–43. doi:10.1016/j.pt.2009.10.006. PMID 19939733.
170.    Du Q, Wang H, Xie J (2011). "Thiamin (vitamin B1) biosynthesis and regulation: A rich source of antimicrobial drug targets?". International Journal of Biological Sciences7 (1): 41–52. doi:10.7150/ijbs.7.41. PMC 3020362. PMID 21234302. 
171.    Biot C, Castro W, Botté CY, Navarro M (2012). "The therapeutic potential of metal-based antimalarial agents: Implications for the mechanism of action". Dalton Transactions41 (21): 6335–49. doi:10.1039/C2DT12247B. PMID 22362072.
172.    Roux C, Biot C (2012). "Ferrocene-based antimalarials". Future Medicinal Chemistry4 (6): 783–97. doi:10.4155/fmc.12.26. PMID 22530641.
173.    Aultman KS, Gottlieb M, Giovanni MY, Fauci AS (2002). "Anopheles gambiae genome: completing the malaria triad". Science298 (5591): 13. doi:10.1126/science.298.5591.13. PMID 12364752.
174.    Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M (2002). "Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite". Nature417 (6887): 452–5. doi:10.1038/417452a. PMID 12024215.
175.    "New hope in search for malaria vaccine". Africa Leader. Retrieved 23 May 2014.
176.    Rich SM, Ayala FJ. (2006). "Evolutionary origins of human malaria parasites". In Dronamraju KR, Arese P. Malaria: Genetic and Evolutionary Aspects. New York, New York: Springer. pp. 125–46. ISBN 978-0-387-28294-7.
177.    Baird JK. (2009). "Malaria zoonoses". Travel Medicine and Infectious Disease7 (5): 269–77. doi:10.1016/j.tmaid.2009.06.004. PMID 19747661.
178.    Ameri M (2010). "Laboratory diagnosis of malaria in nonhuman primates". Veterinary Clinical Pathology39 (1): 5–19. doi:10.1111/j.1939-165X.2010.00217.x. PMID 20456124.
179.    Mlambo G, Kumar N. (2008). "Transgenic rodent Plasmodium berghei parasites as tools for assessment of functional immunogenicity and optimization of human malaria vaccines". Eukaryotic Cell7 (11): 1875–9. doi:10.1128/EC.00242-08. PMC 2583535. PMID 18806208. 
180.    Lapointe DA, Atkinson CT, Samuel MD (2012). "Ecology and conservation biology of avian malaria". Annals of the New York Academy of Sciences1249: 211–26. doi:10.1111/j.1749-6632.2011.06431.x. PMID 22320256.

Cancer
From Wikipedia, the free encyclopedia
For other uses, see Cancer (disambiguation).
Cancer
Classification and external resources

A coronal CT scan showing a malignant mesothelioma
Legend: → tumor ←, ✱ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver.

ICD-10
C00—C97

ICD-9
140—239

DiseasesDB
28843

MedlinePlus
001289

MeSH
D009369

Cancer i/ˈkænsər/, known medically as malignantneoplasia, is a broad group of diseases involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, which may invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream. Not all tumors are cancerous; benign tumors do not invade neighboring tissues and do not spread throughout the body. There are over 200 different known cancers that affect humans.[1]
The causes of cancer are diverse, complex, and only partially understood. Many things are known to increase the risk of cancer, including tobacco use, dietary factors, certain infections, exposure to radiation, lack of physical activity, obesity, and environmental pollutants.[2] These factors can directly damage genes or combine with existing genetic faults within cells to cause cancerous mutations.[3] Approximately 5–10% of cancers can be traced directly to inherited genetic defects.[4] Many cancers could be prevented by not smoking, eating more vegetables, fruits and whole grains, eating less meat and refined carbohydrates, maintaining a healthy weight, exercising, minimizing sunlight exposure, and being vaccinated against some infectious diseases.[2][5]
Cancer can be detected in a number of ways, including the presence of certain signs and symptoms, screening tests, or medical imaging. Once a possible cancer is detected it is diagnosed by microscopic examination of a tissue sample. Cancer is usually treated with chemotherapy, radiation therapy, surgery, or a combination of these treatments. The chances of surviving the disease vary greatly by the type and location of the cancer and the extent of disease at the start of treatment. While cancer can affect people of all ages, and a few types of cancer are more common in children, the risk of developing cancer generally increases with age. In 2007, cancer caused about 13% of all human deaths worldwide (7.9 million). Rates are rising as more people live to an old age and as mass lifestyle changes occur in the developing world.[6]
Contents
•    1 Definitions
•    2 Signs and symptoms
o    2.1 Local effects
o    2.2 Systemic symptoms
o    2.3 Metastasis
•    3 Causes
o    3.1 Chemicals
o    3.2 Diet and exercise
o    3.3 Infection
o    3.4 Radiation
o    3.5 Heredity
o    3.6 Physical agents
o    3.7 Hormones
o    3.8 Other
•    4 Pathophysiology
o    4.1 Genetic alterations
o    4.2 Epigenetic alterations
o    4.3 Metastasis
•    5 Diagnosis
o    5.1 Classification
o    5.2 Pathology
•    6 Prevention
o    6.1 Dietary
o    6.2 Medication
o    6.3 Vaccination
•    7 Screening
o    7.1 Recommendations
o    7.2 Genetic testing
•    8 Management
o    8.1 Chemotherapy
o    8.2 Radiation
o    8.3 Surgery
o    8.4 Palliative care
o    8.5 Alternative medicine
•    9 Prognosis
•    10 Epidemiology
•    11 History
•    12 Society and culture
•    13 Research
•    14 Pregnancy
•    15 Other animals
•    16 Notes
•    17 Further reading
•    18 External links
Definitions
There is no one definition that describes all cancers. They are a large family of diseases which form a subset of neoplasms, which show features suggestive of malignancy. A neoplasm or tumor is a group of cells that have undergone unregulated growth, and will often form a mass or lump, but may be distributed diffusely.[7][8]
Six characteristics of malignancies have been proposed:
•    self-sufficiency in growth signalling
•    insensitivity to anti-growth signals
•    evasion of apoptosis
•    enabling of a limitless replicative potential
•    induction and sustainment of angiogenesis
•    activation of metastasis and invasion of tissue.[9]
The progression from normal cells to cells that can form a discernible mass to outright cancer involves multiple steps known as malignant progression.[9][10]
Signs and symptoms
Main article: Cancer signs and symptoms


Symptoms of cancer metastasis depend on the location of the tumor.
When cancer begins, it invariably produces no symptoms. Signs and symptoms only appear as the mass continues to grow or ulcerates. The findings that result depend on the type and location of the cancer. Few symptoms are specific, with many of them also frequently occurring in individuals who have other conditions. Cancer is the new "great imitator". Thus it is not uncommon for people diagnosed with cancer to have been treated for other diseases to which it was assumed their symptoms were due.[11]
Local effects
Local symptoms may occur due to the mass of the tumor or its ulceration. For example, mass effects from lung cancer can cause blockage of the bronchus resulting in cough or pneumonia; esophageal cancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and colorectal cancer may lead to narrowing or blockages in the bowel, resulting in changes in bowel habits. Masses in breasts or testicles may be easily felt. Ulceration can cause bleeding which, if it occurs in the lung, will lead to coughing up blood, in the bowels to anemia or rectal bleeding, in the bladder to blood in the urine, and in the uterus to vaginal bleeding. Although localized pain may occur in advanced cancer, the initial swelling is usually painless. Some cancers can cause buildup of fluid within the chest or abdomen.[11]
Systemic symptoms
General symptoms occur due to distant effects of the cancer that are not related to direct or metastatic spread. These may include: unintentional weight loss, fever, being excessively tired, and changes to the skin.[12]Hodgkin disease, leukemias, and cancers of the liver or kidney can cause a persistent fever of unknown origin.[11]
Some cancers may cause specific groups of systemic symptoms, termed paraneoplastic phenomena. Examples include the appearance of myasthenia gravis in thymoma and clubbing in lung cancer.[11]
Metastasis
Main article: Metastasis
Metastasis is the spread of cancer to other locations in the body. The symptoms of metastatic cancers depend on the location of the tumor, and can include enlarged lymph nodes (which can be felt or sometimes seen under the skin and are typically hard), enlarged liver or enlarged spleen, which can be felt in the abdomen, pain or fracture of affected bones, and neurological symptoms.[11]
Causes
Cancers are primarily an environmental disease with 90–95% of cases attributed to environmental factors and 5–10% due to genetics.[2]Environmental, as used by cancer researchers, means any cause that is not inherited genetically, such as lifestyle, economic and behavioral factors, and not merely pollution.[13] Common environmental factors that contribute to cancer death include tobacco (25–30%), diet and obesity (30–35%), infections (15–20%), radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.[2]
It is nearly impossible to prove what caused a cancer in any individual, because most cancers have multiple possible causes. For example, if a person who uses tobacco heavily develops lung cancer, then it was probably caused by the tobacco use, but since everyone has a small chance of developing lung cancer as a result of air pollution or radiation, then there is a small chance that the cancer developed because of air pollution or radiation.
Chemicals
Further information: Alcohol and cancer and Smoking and cancer


The incidence of lung cancer is highly correlated with smoking.
Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with many forms of cancer,[14] and causes 90% of lung cancer.[15]
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen.[16] In Western Europe 10% of cancers in males and 3% of cancers in females are attributed to alcohol.[17]
Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.[18] Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[19] Tobacco is responsible for about one in three of all cancer deaths in the developed world,[14] and about one in five worldwide.[19]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 rates since the 1950s followed by decreases in lung cancer death rates in men since 1990.[20][21] However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.[22]
Cancer related to one's occupation is believed to represent between 2–20% of all cases.[23] Every year, at least 200,000 people die worldwide from cancer related to their workplace.[24] Most cancer deaths caused by occupational risk factors occur in the developed world.[24] 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.[25] 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.[24]
Diet and exercise
Diet, physical inactivity, and obesity are related to approximately 30–35% of cancer deaths.[2][26] In the United States excess body weight is associated with the development of many types of cancer and is a factor in 14–20% of all cancer deaths.[26] Physical inactivity is believed to contribute to cancer risk not only through its effect on body weight but also through negative effects on immune system and endocrine system.[26] More than half of the effect from diet is due to overnutrition rather than from eating too little healthy foods.
Diets that are low in vegetables, fruits and whole grains, and high in processed or red meats are linked with a number of cancers.[26] A high-salt diet is linked to gastric cancer, aflatoxin B1, a frequent food contaminate, with liver cancer, and Betel nut chewing with oral cancer.[27] This may partly explain differences in cancer incidence in different countries. For example, gastric cancer is more common in Japan due to its high-salt diet[28] and colon cancer is more common in the United States. Immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[29]
Infection
Main article: Infectious causes of cancer
Worldwide approximately 18% of cancer deaths are related to infectious diseases.[2] This proportion varies in different regions of the world from a high of 25% in Africa to less than 10% in the developed world.[2]Viruses are the usual infectious agents that cause cancer but bacteria and parasites may also have an effect.
A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.[30] Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[31]
Radiation
Main article: Radiation-induced cancer
Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and non-ionizingultraviolet radiation.[2] Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation.
Sources of ionizing radiation include medical imaging, and radon gas. Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear.[32] Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure.[32] Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.[32] Ionizing radiation is not a particularly strong mutagen.[32] Residential exposure to radon gas, for example, has similar cancer risks as passive smoking.[32] Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development.[32] Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.[32]
Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells randomly. If it happens to strike a chromosome, it can break the chromosome, result in an abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other types of chromosome abnormalities.[32] Major damage normally results in the cell dying, but smaller damage may leave a stable, partly functional cell that may be capable of proliferating and developing into cancer, especially if tumor suppressor genes were damaged by the radiation.[32] Three independent stages appear to be involved in the creation of cancer with ionizing radiation: morphological changes to the cell, acquiring cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptations that favor formation of a tumor.[32] Even if the radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly increase the likelihood of mutations.[32]
Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer.[32] It is also used in some kinds of medical imaging. It is estimated that 0.4% of cancers in 2007 in the United States are due to CTs performed in the past and that this may increase to as high as 1.5–2% with rates of CT usage during this same time period.[33]
Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.[34] Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.[34]
Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer.[35] However, studies have not found a consistent link between cell phone radiation and cancer risk.[36]
Heredity
Main article: Cancer syndrome
The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic mutation which has a large effect on cancer risk and these cause less than 3–10% of all cancer.[37] Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer,[37] and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer,[38] among others.
Physical agents
Some substances cause cancer primarily through their physical, rather than chemical, effects on cells.[39] A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers which are a major cause of mesothelioma, which is a cancer of the serous membrane, usually the serous membrane surrounding the lungs.[39] Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers such as wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects.[39] Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite).[39] Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer.[39]
Physical trauma resulting in cancer is relatively rare.[40] Claims that breaking bones resulted in bone cancer, for example, have never been proven.[40] Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer.[40] One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present.[40] Frequently drinking scalding hot tea may produce esophageal cancer.[40] Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma, rather than the cancer being caused directly by the trauma.[40] However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation. There is no evidence that inflammation itself causes cancer,[40] yet inflammation can contribute to proliferation, survival and migration of cancer cells by influencing the microenvironment around tumors.[41]
Hormones
Some hormones play a role in the development of cancer by promoting cell proliferation.[42]Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.[43]
Hormones are important agents in sex-related cancers such as cancer of the breast, endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer.[42] For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain why these women have higher risk of breast cancer, even in the absence of a breast-cancer gene.[42] Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry, and have a correspondingly much higher level of prostate cancer.[42] Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.[42]
Other factors are also relevant: obese people have higher levels of some hormones associated with cancer and a higher rate of those cancers.[42] Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones.[42] On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer.[42]Osteosarcoma may be promoted by growth hormones.[42] Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers.[42]
Other
Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHCincompatibility.[44] In humans and other vertebrates, the immune system uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumor cell engraftment by eliminating implanted cells. In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed.[44] The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.[45] Job stress does not appear to be a significant factor at least in lung, colorectal, breast and prostate cancers.[46]
Pathophysiology
Main article: Carcinogenesis


Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.
Genetic alterations
Cancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.[47]
The affected genes are divided into two broad categories. Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.[48]
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.
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-ablfusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region 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 resulting in the expression of viral oncogenes in the affected cell and its descendants.
Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.[49]
The errors which cause cancer are self-amplifying and compounding, for example:
•    A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
•    A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
•    A further mutation may cause loss of a tumor suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.
•    A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells.
The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution drives progression towards more invasive stages.[50]
Characteristic abilities developed by cancers are divided into a number of categories. Six categories were originally proposed, in a 2000 article called The Hallmarks of Cancer by Douglas Hanahan and Robert Weinberg: evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, and metastasis. Based on further work, the same authors added two more categories in 2011: reprogramming of energy metabolism and evasion of immune destruction.[9][10]
Epigenetic alterations


The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.[51]
Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification[52] and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).[53] Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations, and can be considered to be epimutations (equivalent to mutations).
Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger and Diederich[54] listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers.
While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[55][56][57][58]
Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation rates increase substantially in cells defective in DNA mismatch repair[59][60] or in homologous recombinational repair (HRR).[61] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[62]
Higher levels of DNA damage not only cause increased mutation (right side of figure), but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[63][64]
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[65] Germ line DNA repair mutations are noted in a box on the left side of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[66]
In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level from the top. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can “target” protein-coding genes and reduce their expression.
Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about 3 or 4 may be “driver” mutations, and the remaining ones may be “passenger” mutations.[67]
As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes which regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation in oncogenes and tumor suppressor genes as well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair genes, in particular, likely cause an increased frequency of mutations, some of which then occur in oncogenes and tumor suppressor genes.
Metastasis
Main article: Metastasis
Metastasis is the spread of cancer to other locations in the body. The new tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize.[68] Most cancer deaths are due to cancer that has spread from its primary site to other organs (metastasized).[69]
Metastasis is very common in the late stages of cancer, and it can occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body, extravasation into the new tissue, proliferation, and angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain, and the bones.[68]
Diagnosis


Chest x-ray showing lung cancer in the left lung.
Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these lead to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.
Most people are distressed to learn that they have cancer. They may become extremely anxious and depressed. The risk of suicide in people with cancer is approximately double the normal risk.[70]
Classification
Further information: List of cancer types and List of oncology-related terms
Cancers are classified by the type of cell that the tumor cells resemble and is therefore presumed to be the origin of the tumor. These types include:
•    Carcinoma: Cancers derived from epithelial cells. This group includes many of the most common cancers, particularly in the aged, and include nearly all those developing in the breast, prostate, lung, pancreas, and colon.
•    Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), each of which develop from cells originating in mesenchymal cells outside the bone marrow.
•    Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively. Leukemia is the most common type of cancer in children accounting for about 30%.[71]
•    Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma and dysgerminoma, respectively).
•    Blastoma: Cancers derived from immature "precursor" cells or embryonic tissue. Blastomas are more common in children than in older adults.
Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, cancers of the liver parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a malignancy arising from primitive liver precursor cells is called a hepatoblastoma, and a cancer arising from fat cells is called a liposarcoma. For some common cancers, the English organ name is used. For example, the most common type of breast cancer is called ductal carcinoma of the breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.
Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly, some types of cancer use the -noma suffix, examples including melanoma and seminoma.
Some types of cancer are named for the size and shape of the cells under a microscope, such as giant cell carcinoma, spindle cell carcinoma, and small-cell carcinoma.
Pathology
The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade, genetic abnormalities, and other features of the tumor. Together, this information is useful to evaluate the prognosis of the 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 the molecular changes (such as mutations, fusion genes, and numerical chromosome changes) that has happened in the cancer cells, and may thus also indicate the future behavior of the cancer (prognosis) and best treatment.
•   
An invasive ductal carcinoma of the breast (pale area at the center) surrounded by spikes of whitish scar tissue and yellow fatty tissue.
•   
An invasive colorectal carcinoma (top center) in a colectomy specimen.
•   
A squamous-cell carcinoma (the whitish tumor) near the bronchi in a lung specimen.
•   
A large invasive ductal carcinoma in a mastectomy specimen.
Prevention
Cancer prevention is defined as active measures to decrease the risk of cancer.[72] The vast majority of cancer cases are due to environmental risk factors, and many, but not all, of these environmental factors are controllable lifestyle choices. Thus, cancer is considered a largely preventable disease.[73] Greater than 30% of cancer deaths could be prevented by avoiding risk factors including: tobacco, overweight / obesity, an insufficient diet, physical inactivity, alcohol, sexually transmitted infections, and air pollution.[74] Not all environmental causes are controllable, such as naturally occurring background radiation, and other cases of cancer are caused through hereditary genetic disorders, and thus it is not possible to prevent all cases of cancer.
Dietary
Main article: Diet and cancer
While many dietary recommendations have been proposed to reduce the risk of cancer, the evidence to support them is not definitive.[5][75] The primary dietary factors that increase risk are obesity and alcohol consumption; with a diet low in fruits and vegetables and high in red meat being implicated but not confirmed.[76][77] Consumption of coffee is associated with a reduced risk of liver cancer.[78] Studies have linked consumption of red or processed meat to an increased risk of breast cancer, colon cancer, and pancreatic cancer, a phenomenon which could be due to the presence of carcinogens in meats cooked at high temperatures.[79][80] Dietary recommendations for cancer prevention typically include an emphasis on vegetables, fruit, whole grains, and fish, and an avoidance of processed and red meat (beef, pork, lamb), animal fats, and refined carbohydrates.[5][75]
Medication
The concept that medications can be used to prevent cancer is attractive, and evidence supports their use in a few defined circumstances.[81] In the general population, NSAIDs reduce the risk of colorectal cancer however due to the cardiovascular and gastrointestinal side effects they cause overall harm when used for prevention.[82]Aspirin has been found to reduce the risk of death from cancer by about 7%.[83]COX-2 inhibitor may decrease the rate of polyp formation in people with familial adenomatous polyposis however are associated with the same adverse effects as NSAIDs.[84] Daily use of tamoxifen or raloxifene has been demonstrated to reduce the risk of developing breast cancer in high-risk women.[85] The benefit verses harm for 5-alpha-reductase inhibitor such as finasteride is not clear.[86]
Vitamins have not been found to be effective at preventing cancer,[87] although low blood levels of vitamin D are correlated with increased cancer risk.[88][89] Whether this relationship is causal and vitamin D supplementation is protective is not determined.[90]Beta-Carotene supplementation has been found to increase lung cancer rates in those who are high risk.[91]Folic acid supplementation has not been found effective in preventing colon cancer and may increase colon polyps.[92]
Vaccination
Vaccines have been developed that prevent infection by some carcinogenic viruses.[93]Human papillomavirus vaccine (Gardasil and Cervarix) decreases the risk of developing cervical cancer.[93] The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of liver cancer.[93] The administration of human papillomavirus and hepatitis B vaccinations is recommended when resources allow.[94]
Screening
Main article: Cancer screening
Unlike diagnosis efforts prompted by symptoms and medical signs, cancer screening involves efforts to detect cancer after it has formed, but before any noticeable symptoms appear.[95] This may involve physical examination, blood or urine tests, or medical imaging.[95]
Cancer screening is currently not possible for many types of cancers, and even when tests are available, they may not be recommended for everyone. Universal screening or mass screening involves screening everyone.[96]Selective screening identifies people who are known to be at higher risk of developing cancer, such as people with a family history of cancer.[96] Several factors are considered to determine whether the benefits of screening outweigh the risks and the costs of screening.[95] These factors include:
•    Possible harms from the screening test: for example, X-ray images involve exposure to potentially harmful ionizing radiation.
•    The likelihood of the test correctly identifying cancer.
•    The likelihood of cancer being present: Screening is not normally useful for rare cancers.
•    Possible harms from follow-up procedures.
•    Whether suitable treatment is available.
•    Whether early detection improves treatment outcomes.
•    Whether the cancer will ever need treatment.
•    Whether the test is acceptable to the people: If a screening test is too burdensome (for example, being extremely painful), then people will refuse to participate.[96]
•    Cost of the test.
Recommendations
The U.S. Preventive Services Task Force (USPSTF) strongly recommends cervical cancer screening in women who are sexually active and have a cervix at least until the age of 65.[97] They recommend that Americans be screened for colorectal cancer via fecal occult blood testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.[98] There is insufficient evidence to recommend for or against screening for skin cancer,[99]oral cancer,[100]lung cancer,[101] or prostate cancer in men under 75.[102] Routine screening is not recommended for bladder cancer,[103]testicular cancer,[104]ovarian cancer,[105]pancreatic cancer,[106] or prostate cancer.[107]
The USPSTF recommends mammography for breast cancer screening every two years for those 50–74 years old; however, they do not recommend either breast self-examination or clinical breast examination.[108] A 2011 Cochrane review came to slightly different conclusions with respect to breast cancer screening stating that routine mammography may do more harm than good.[109]
Japan screens for gastric cancer using photofluorography due to the high incidence there.[6]
Genetic testing
See also: Cancer syndrome
Gene    Cancer types
BRCA1, BRCA2
Breast, ovarian, pancreatic
HNPCC, MLH1, MSH2, MSH6, PMS1, PMS2
Colon, uterine, small bowel, stomach, urinary tract
Genetic testing for individuals at high-risk of certain cancers is recommended.[94][110] Carriers of these mutations may then undergo enhanced surveillance, chemoprevention, or preventative surgery to reduce their subsequent risk.[110]
Management
Main article: Management of cancer
Many treatment options for cancer exist with the primary ones including surgery, chemotherapy, radiation therapy, and palliative care. Which treatments are used depends upon the type, location and grade of the cancer as well as the person's health and wishes.
Chemotherapy
Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs (chemotherapeutic agents) as part of a standardized regimen. The term encompasses any of a large variety of different anticancer drugs, which are divided into broad categories such as alkylating agents and antimetabolites.[111] Traditional chemotherapeutic agents act by killing cells that divide rapidly, one of the main properties of most cancer cells.
Targeted therapy is a form of chemotherapy which target specific molecular differences between cancer and normal cells. The first targeted therapies to be developed blocked the estrogen receptor molecule, inhibiting the growth of breast cancer. Another common example is the class of Bcr-Abl inhibitors, which are used to treat chronic myelogenous leukemia (CML).[112] Currently, there are targeted therapies for breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.[113]
The efficacy of chemotherapy depends on the type of cancer and the stage. In combination with surgery, chemotherapy has proven useful in a number of different cancer types including: breast cancer, colorectal cancer, pancreatic cancer, osteogenic sarcoma, testicular cancer, ovarian cancer, and certain lung cancers.[114] The overall effectiveness ranges from being curative for some cancers, such as some leukemias,[115][116] to being ineffective, such as in some brain tumors,[117] to being needless in others, like most non-melanoma skin cancers.[118] The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Even when it is impossible for chemotherapy to provide a permanent cure, chemotherapy may be useful to reduce symptoms like pain or to reduce the size of an inoperable tumor in the hope that surgery will be possible in the future.
Radiation
Radiation therapy involves the use of ionizing radiation in an attempt to either cure or improve the symptoms of cancer. It works by damaging the DNA of cancerous tissue leading to cellular death. To spare normal tissues (such as skin or organs which radiation must pass through to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding, healthy tissue. As with chemotherapy, different cancers respond differently to radiation therapy.[119][120][121]
Radiation therapy is used in about half of all cases and the radiation can be from either internal sources in the form of brachytherapy or external sources. Radiation is typically used in addition to surgery and or chemotherapy but for certain types of cancer, such as early head and neck cancer, may be used alone. For painful bone metastasis, it has been found to be effective in about 70% of people.[122]
Surgery
Surgery is the primary method of treatment of most isolated solid cancers and may play a role in palliation and prolongation of survival. It is typically an important part of making the definitive diagnosis and staging the tumor as biopsies are usually required. In localized cancer surgery typically attempts to remove the entire mass along with, in certain cases, the lymph nodes in the area. For some types of cancer this is all that is needed to eliminate the cancer.[114]
Palliative care
Palliative care refers to treatment which attempts to make the person feel better and may or may not be combined with an attempt to treat the cancer. Palliative care includes action to reduce the physical, emotional, spiritual, and psycho-social distress experienced by people with cancer. Unlike treatment that is aimed at directly killing cancer cells, the primary goal of palliative care is to improve the person's quality of life.
People at all stages of cancer treatment should have some kind of palliative care to provide comfort. In some cases, medical specialtyprofessional organizations recommend that people and physicians respond to cancer only with palliative care and not with cure-directed therapy.[123] This includes:[124]
1.    people with low performance status, corresponding with limited ability to care for themselves[123]
2.    people who received no benefit from prior evidence-based treatments[123]
3.    people who are not eligible to participate in any appropriate clinical trial[123]
4.    people for whom the physician sees no strong evidence that treatment would be effective[123]
Palliative care is often confused with hospice and therefore only involved when people approach end of life. Like hospice care, palliative care attempts to help the person cope with the immediate needs and to increase the person's comfort. Unlike hospice care, palliative care does not require people to stop treatment aimed at prolonging their lives or curing the cancer.
Multiple national medical guidelines recommend early palliative care for people whose cancer has produced distressing symptoms (pain, shortness of breath, fatigue, nausea) or who need help coping with their illness. In people who have metastatic disease when first diagnosed, oncologists should consider a palliative care consult immediately. Additionally, an oncologist should consider a palliative care consult in any person they feel has less than 12 months of life even if continuing aggressive treatment.[125][126][127]
Alternative medicine
Complementary and alternative cancer treatments are a diverse group of health care systems, practices, and products that are not part of conventional medicine.[128] "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine.[129] Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments have been investigated and shown to be ineffective but still continue to be marketed and promoted.[130]
Prognosis
See also: List of cancer mortality rates and Cancer survivor
Cancer has a reputation as a deadly disease. Taken as a whole, about half of people receiving treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) die from cancer or its treatment.[6] Survival is worse in the developing world.[6] However, the survival rates vary dramatically by type of cancer, with the range running from basically all people surviving to almost no one surviving.
Those who survive cancer are at increased risk of developing a second primary cancer at about twice the rate of those never diagnosed with cancer.[131] The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, partly due to the treatment for the first cancer, and potentially related to better compliance with screening.[131]
Predicting either short-term or long-term survival is difficult and depends on many factors. The most important factors are the particular kind of cancer and the patient's age and overall health. People who are frail with many other health problems have lower survival rates than otherwise healthy people. A centenarian is unlikely to survive for five years even if the treatment is successful. People who report a higher quality of life tend to survive longer.[132] People with lower quality of life may be affected by major depressive disorder and other complications from cancer treatment and/or disease progression that both impairs their quality of life and reduces their quantity of life. Additionally, patients with worse prognoses may be depressed or report a lower quality of life directly because they correctly perceive that their condition is likely to be fatal.
Epidemiology
Main article: Epidemiology of cancer
See also: List of countries by cancer rate


Death rate from malignant cancer per 100,000 inhabitants in 2004.[133]
  no data
  ≤ 55
  55–80
  80–105
  105–130
  130–155
  155–180      180–205
  205–230
  230–255
  255–280
  280–305
  ≥ 305
In 2008, approximately 12.7 million cancers were diagnosed (excluding non-melanoma skin cancers and other non-invasive cancers),[6] and in 2010 nearly 7.98 million people died.[134] Cancers as a group account for approximately 13% of all deaths each year with the most common being: lung cancer (1.4 million deaths), stomach cancer (740,000 deaths), liver cancer (700,000 deaths), colorectal cancer (610,000 deaths), and breast cancer (460,000 deaths).[135] This makes invasive cancer the leading cause of death in the developed world and the second leading cause of death in the developing world.[6] Over half of cases occur in the developing world.[6]
Deaths from cancer were 5.8 million in 1990[134] and rates have been increasing primarily due to an aging population and lifestyle changes in the developing world.[6] The most significant risk factor for developing cancer is old age.[136] Although it is possible for cancer to strike at any age, most people who are diagnosed with invasive cancer are over the age of 65.[136] According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer."[137] Some of the association between aging and cancer is attributed to immunosenescence,[138] errors accumulated in DNA over a lifetime,[139] and age-related changes in the endocrine system.[140] The effect of aging on cancer is complicated with a number of factors such as DNA damage and inflammation promoting it and a number of factors such as vascular aging and endocrine changes inhibiting it.[141]
Some slow-growing cancers are particularly common. Autopsy studies in Europe and Asia have shown that up to 36% of people have undiagnosed and apparently harmless thyroid cancer at the time of their deaths, and that 80% of men develop prostate cancer by age 80.[142][143] As these cancers did not cause the person's death, identifying them would have represented overdiagnosis rather than useful medical care.
The three most common childhood cancers are leukemia (34%), brain tumors (23%), and lymphomas (12%).[144] In the United States cancer affects about 1 in 285 children.[145] Rates of childhood cancer have increased by 0.6% per year between 1975 to 2002 in the United States[146] and by 1.1% per year between 1978 and 1997 in Europe.[144] Death from childhood cancer have decreased by half since 1975 in the United States.[145]
History
Main article: History of cancer


Engraving with two views of a Dutch woman who had a tumor removed from her neck in 1689.
Cancer has existed for all of human history.[147] The earliest written record regarding cancer is from circa 1600 BC in the Egyptian Edwin Smith Papyrus and describes cancer of the breast.[147]Hippocrates (ca. 460 BC – ca. 370 BC) described several kinds of cancer, referring to them with the Greek word καρκίνοςkarkinos (crab or crayfish).[147] This name comes from the appearance of the cut surface of a solid malignant tumor, with "the veins stretched on all sides as the animal the crab has its feet, whence it derives its name".[148]Galen stated that "cancer of the breast is so called because of the fancied resemblance to a crab given by the lateral prolongations of the tumor and the adjacent distended veins".[149]:738Celsus (ca. 25 BC – 50 AD) translated karkinos into the Latincancer, also meaning crab and recommended surgery as treatment.[147]Galen (2nd century AD) disagreed with the use of surgery and recommended purgatives instead.[147] These recommendations largely stood for 1000 years.[147]
In the 15th, 16th and 17th centuries, it became acceptable for doctors to dissect bodies to discover the cause of death.[150] 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.[151]
The physician John Hill described tobacco snuff as the cause of nose cancer in 1761.[150] This was followed by the report in 1775 by British surgeon Percivall Pott that cancer of the scrotum was a common disease among chimney sweeps.[152] 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.[153]
Society and culture
Though many diseases (such as heart failure) may have a worse prognosis than most cases of cancer, cancer is the subject of widespread fear and taboos. The euphemism "after a long illness" is still commonly used (2012), reflecting an apparent stigma.[154] This deep belief that cancer is necessarily a difficult and usually deadly disease is reflected in the systems chosen by society to compile cancer statistics: the most common form of cancer—non-melanoma skin cancers, accounting for about one-third of all cancer cases worldwide, but very few deaths[155][156]—are excluded from cancer statistics specifically because they are easily treated and almost always cured, often in a single, short, outpatient procedure.[157]
Cancer is regarded as a disease that must be "fought" to end the "civil insurrection"; a War on Cancer has been declared. Military metaphors are particularly common in descriptions of cancer's human effects, and they emphasize both the parlous state of the affected individual's health and the need for the individual to take immediate, decisive actions himself, rather than to delay, to ignore, or to rely entirely on others caring for him. The military metaphors also help rationalize radical, destructive treatments.[158][159]
In the 1970s, a relatively popular alternative cancer treatment was a specialized form of talk therapy, based on the idea that cancer was caused by a bad attitude.[160] People with a "cancer personality"—depressed, repressed, self-loathing, and afraid to express their emotions—were believed to have manifested cancer through subconscious desire. Some psychotherapists said that treatment to change the patient's outlook on life would cure the cancer.[160] Among other effects, this belief allows society to blame the victim for having caused the cancer (by "wanting" it) or having prevented its cure (by not becoming a sufficiently happy, fearless, and loving person).[161] It also increases patients' anxiety, as they incorrectly believe that natural emotions of sadness, anger or fear shorten their lives.[161] The idea was excoriated by the notoriously outspoken Susan Sontag, who published Illness as Metaphor while recovering from treatment for breast cancer in 1978.[160] Although the original idea is now generally regarded as nonsense, the idea partly persists in a reduced form with a widespread, but incorrect, belief that deliberately cultivating a habit of positive thinking will increase survival.[161] This notion is particularly strong in breast cancer culture.[161]
One idea about why people with cancer are blamed or stigmatized, called the just-world hypothesis, is that blaming cancer on the patient's actions or attitudes allows the blamers to regain a sense of control. This is based upon the blamers' belief that the world is fundamentally just, and so any dangerous illness, like cancer, must be a type of punishment for bad choices, because in a just world, bad things would not happen to good people.[162]
In 2007, the overall costs of cancer in the U.S. — including treatment and indirect mortality expenses (such as lost productivity in the workplace) — was estimated to be $226.8 billion. In 2009, 32% of Hispanics and 10% of children 17 years old or younger lacked health insurance; "uninsured patients and those from ethnic minorities are substantially more likely to be diagnosed with cancer at a later stage, when treatment can be more extensive and more costly."[163]
Research
Main article: Cancer research
Because cancer is a class of diseases,[164][165] 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.[166]Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but this has not been the case in practice.[167] It is more likely that angiogenesis inhibitors and other cancer therapeutics will be used in combination to reduce cancer morbidity and mortality.[168]
Experimental cancer treatments are treatments that are being studied to see whether they work. Typically, these are studied in clinical trials to compare the proposed treatment to the best existing treatment. They may be entirely new treatments, or they may be treatments that have been used successfully in one type of cancer, and are now being tested to see whether they are effective in another type.[169] More and more, such treatments are being developed alongside companion diagnostic tests to target the right drugs to the right patients, based on their individual biology.[170]
Cancer research is the intense scientific effort to understand disease processes and discover possible therapies.
Research about cancer causes focuses on the following issues:
•    Agents (e.g. viruses) and events (e.g. mutations) which cause or facilitate genetic changes in cells destined to become cancer.
•    The precise nature of the genetic damage, and the genes which are affected by it.
•    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 which lead to further progression of the cancer.
The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new treatments for cancer since U.S. President Nixon declared the "War on Cancer" in 1971. Since then, the U.S. has spent over $200 billion on cancer research, including resources from the public and private sectors and foundations.[171] During that time, the country has seen a five percent decrease in the cancer death rate (adjusting for size and age of the population) between 1950 and 2005.[172]
Hypercompetition for the financial resources that are required to conduct science appears to suppress the creativity, cooperation, risk-taking, and original thinking required to make fundamental discoveries, unduly favoring low-risk research into small incremental advancements over innovative research that might discover radically new and dramatically improved therapy. Other consequences of the highly pressured competition for research resources appear to be a substantial number of research publications whose results cannot be replicated, and perverse incentives in research funding that encourage grantee institutions to grow without making sufficient investments in their own faculty and facilities.[173][174][175][176]
Pregnancy
Because cancer is largely a disease of older adults, it is not common in pregnant women. Cancer affects approximately 1 in 1,000 pregnant women.[177] The most common cancers found during pregnancy are the same as the most common cancers found in non-pregnant women during childbearing ages: breast cancer, cervical cancer, leukemia, lymphoma, melanoma, ovarian cancer, and colorectal cancer.[177]
Diagnosing a new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed to be a normal discomfort associated with pregnancy.[177] As a result, cancer is typically discovered at a somewhat later stage than average in many pregnant or recently pregnant women. Some imaging procedures, such as MRIs (magnetic resonance imaging), CT scans, ultrasounds, and mammograms with fetal shielding are considered safe during pregnancy; some others, such as PET scans are not.[177]
Treatment is generally the same as for non-pregnant women.[177] However, radiation and radioactive drugs are normally avoided during pregnancy, especially if the fetal dose might exceed 100 cGy. In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed late in the pregnancy. Early deliveries to speed the start of treatment are not uncommon. Surgery is generally safe, but pelvic surgeries during the first trimester may cause miscarriage. Some treatments, especially certain chemotherapy drugs given during the first trimester, increase the risk of birth defects and pregnancy loss (spontaneous abortions and stillbirths).[177]
Elective abortions are not required and, for the most common forms and stages of cancer, do not improve the likelihood of the mother surviving or being cured.[177] In a few instances, such as advanced uterine cancer, the pregnancy cannot be continued, and in others, such as an acute leukemia discovered early in pregnancy, the pregnant woman may choose to have abortion so that she can begin aggressive chemotherapy without worrying about birth defects.[177]
Some treatments may interfere with the mother's ability to give birth vaginally or to breastfeed her baby.[177] Cervical cancer may require birth by Caesarean section. Radiation to the breast reduces the ability of that breast to produce milk and increases the risk of mastitis. Also, when chemotherapy is being given after birth, many of the drugs pass through breast milk to the baby, which could harm the baby.[177]
Other animals
In non-humans, a few types of transmissible cancer have been described, wherein the cancer spreads between animals by transmission of the tumor cells themselves. This phenomenon is seen in dogs with Sticker's sarcoma, also known as canine transmissible venereal tumor,[178] as well as devil facial tumor disease in Tasmanian devils.
Notes
1.    ^"How many different types of cancer are there? : Cancer Research UK : CancerHelp UK". Retrieved 11 May 2012.
2.    ^ abcdefgh Anand P, Kunnumakkara AB, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (September 2008). "Cancer is a preventable disease that requires major lifestyle changes". Pharm. Res.25 (9): 2097–116. doi:10.1007/s11095-008-9661-9. PMC 2515569. PMID 18626751.
3.    ^ Kinzler, Kenneth W.; Vogelstein, Bert (2002). "Introduction". The genetic basis of human cancer (2nd, illustrated, revised ed.). New York: McGraw-Hill, Medical Pub. Division. p. 5. ISBN 978-0-07-137050-9.
4.    ^"Heredity and Cancer". American Cancer Society. Retrieved July 22, 2013.
5.    ^ abc Kushi LH, Doyle C, McCullough M, et al. (2012). "American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity". CA Cancer J Clin62 (1): 30–67. doi:10.3322/caac.20140. PMID 22237782.
6.    ^ abcdefgh Jemal A, Bray, F, Center, MM, Ferlay, J, Ward, E, Forman, D (February 2011). "Global cancer statistics". CA: a cancer journal for clinicians61 (2): 69–90. doi:10.3322/caac.20107. PMID 21296855.
7.    ^"Cancer Glossary". cancer.org. American Cancer Society. Retrieved September 11, 2013.
8.    ^"What is cancer?". cancer.gov. National Cancer Institute. Retrieved September 11, 2013.
9.    ^ abcHanahan, Douglas; Weinberg, Robert A. (January 7, 2000). "The hallmarks of cancer". Cell100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931.
10.    ^ ab Hanahan, Douglas; Weinberg, Robert A. (2011). "Hallmarks of Cancer: The Next Generation". Cell144 (5): 646–74. doi:10.1016/j.cell.2011.02.013. PMID 21376230.
11.    ^ abcde Holland Chp. 1
12.    ^ O'Dell, edited by Michael D. Stubblefield, Michael W. (2009). Cancer rehabilitation principles and practice. New York: Demos Medical. p. 983. ISBN 978-1-933864-33-4.
13.    ^ Kravchenko J, Akushevich I, Manton, KG (2009). Cancer mortality and morbidity patterns in the U. S. population: an interdisciplinary approach. Berlin: Springer. ISBN 0-387-78192-7. "The term environment refers not only to air, water, and soil but also to substances and conditions at home and at the workplace, including diet, smoking, alcohol, drugs, exposure to chemicals, sunlight, ionizing radiation, electromagnetic fields, infectious agents, etc. Lifestyle, economic and behavioral factors are all aspects of our environment."
14.    ^ ab Sasco AJ, Secretan MB, Straif K (August 2004). "Tobacco smoking and cancer: a brief review of recent epidemiological evidence". Lung Cancer. 45 Suppl 2: S3–9. doi:10.1016/j.lungcan.2004.07.998. PMID 15552776.
15.    ^ Biesalski HK, Bueno de Mesquita B, Chesson A, Chytil F, Grimble R, Hermus RJ, Köhrle J, Lotan R, Norpoth K, Pastorino U, Thurnham D (1998). "European Consensus Statement on Lung Cancer: risk factors and prevention. Lung Cancer Panel". CA Cancer J Clin48 (3): 167–76; discussion 164–6. doi:10.3322/canjclin.48.3.167. PMID 9594919.
16.    ^ Seitz HK, Pöschl G, Simanowski UA (1998). "Alcohol and cancer". Recent Dev Alcohol. Recent Developments in Alcoholism 14: 67–95. doi:10.1007/0-306-47148-5_4. ISBN 0-306-45747-4. PMID 9751943.
17.    ^ Schütze M, Boeing H, Pischon T, Rehm J, Kehoe T, Gmel G, Olsen A, Tjønneland AM, Dahm CC, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Benetou V, Zylis D, Kaaks R, Rohrmann S, Palli D, Berrino F, Tumino R, Vineis P, Rodríguez L, Agudo A, Sánchez MJ, Dorronsoro M, Chirlaque MD, Barricarte A, Peeters PH, van Gils CH, Khaw KT, Wareham N, Allen NE, Key TJ, Boffetta P, Slimani N, Jenab M, Romaguera D, Wark PA, Riboli E, Bergmann MM (2011). "Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study". BMJ342: d1584. doi:10.1136/bmj.d1584. PMC 3072472. PMID 21474525.
18.    ^ Kuper H, Boffetta P, Adami HO (September 2002). "Tobacco use and cancer causation: association by tumour type". Journal of Internal Medicine252 (3): 206–24. doi:10.1046/j.1365-2796.2002.01022.x. PMID 12270001.
19.    ^ ab Kuper H, Adami HO, Boffetta P (June 2002). "Tobacco use, cancer causation and public health impact". Journal of Internal Medicine251 (6): 455–66. doi:10.1046/j.1365-2796.2002.00993.x. PMID 12028500.
20.    ^ Thun MJ, Jemal A (October 2006). "How much of the decrease in cancer death rates in the United States is attributable to reductions in tobacco smoking?". Tob Control15 (5): 345–7. doi:10.1136/tc.2006.017749. PMC 2563648. PMID 16998161.
21.    ^ Dubey S, Powell CA (May 2008). "Update in lung cancer 2007". Am. J. Respir. Crit. Care Med.177 (9): 941–6. doi:10.1164/rccm.200801-107UP. PMC 2720127. PMID 18434333.
22.    ^ Proctor RN (May 2004). "The global smoking epidemic: a history and status report". Clin Lung Cancer5 (6): 371–6. doi:10.3816/CLC.2004.n.016. PMID 15217537.
23.    ^ Irigaray P, Newby JA, Clapp R, Hardell L, Howard V, Montagnier L, Epstein S, Belpomme D (December 2007). "Lifestyle-related factors and environmental agents causing cancer: an overview". Biomed. Pharmacother.61 (10): 640–58. doi:10.1016/j.biopha.2007.10.006. PMID 18055160.
24.    ^ abc"WHO calls for prevention of cancer through healthy workplaces" (Press release). World Health Organization. 27 April 2007. Retrieved 13 October 2007.
25.    ^"National Institute for Occupational Safety and Health- Occupational Cancer". United States National Institute for Occupational Safety and Health. Retrieved 13 October 2007.
26.    ^ abcd Kushi LH, Byers T, Doyle C, Bandera EV, McCullough M, McTiernan A, Gansler T, Andrews KS, Thun MJ (2006). "American Cancer Society Guidelines on Nutrition and Physical Activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity". CA Cancer J Clin56 (5): 254–81; quiz 313–4. doi:10.3322/canjclin.56.5.254. PMID 17005596.
27.    ^ Park S, Bae J, Nam BH, Yoo KY (2008). "Aetiology of cancer in Asia" (PDF). Asian Pac. J. Cancer Prev.9 (3): 371–80. PMID 18990005.
28.    ^ Brenner H, Rothenbacher D, Arndt V (2009). "Epidemiology of stomach cancer". Methods Mol. Biol. Methods in Molecular Biology 472: 467–77. doi:10.1007/978-1-60327-492-0_23. ISBN 978-1-60327-491-3. PMID 19107449.
29.    ^ Buell P, Dunn JE (May 1965). "Cancer mortality among Japanese Issei and Nisei of California". Cancer18 (5): 656–64. doi:10.1002/1097-0142(196505)18:5<656::AID-CNCR2820180515>3.0.CO;2-3. PMID 14278899.
30.    ^ Pagano JS, Blaser M, Buendia MA, Damania B, Khalili K, Raab-Traub N, Roizman B (December 2004). "Infectious agents and cancer: criteria for a causal relation". Semin. Cancer Biol.14 (6): 453–71. doi:10.1016/j.semcancer.2004.06.009. PMID 15489139.
31.    ^ Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME (May 2010). "Chronic bacterial and parasitic infections and cancer: a review" (PDF). J Infect Dev Ctries4 (5): 267–81. doi:10.3855/jidc.819. PMID 20539059.
32.    ^ abcdefghijkl Little JB (2000). "Chapter 14: Ionizing Radiation". In Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, Gansler TS, Holland JF, Frei E III. Cancer medicine (6th ed.). Hamilton, Ont: B.C. Decker. ISBN 1-55009-113-1.
33.    ^ Brenner DJ, Hall EJ (November 2007). "Computed tomography—an increasing source of radiation exposure". N. Engl. J. Med.357 (22): 2277–84. doi:10.1056/NEJMra072149. PMID 18046031.
34.    ^ ab Cleaver JE, Mitchell DL (2000). "15. Ultraviolet Radiation Carcinogenesis". In Bast RC, Kufe DW, Pollock RE, et al. Holland-Frei Cancer Medicine (5th ed.). Hamilton, Ontario: B.C. Decker. ISBN 1-55009-113-1. Retrieved 31 January 2011.
35.    ^"IARC classifies radiofrequency electromagnetic fields as possibly carcinogenic to humans". World Health Organization.
36.    ^"Cell Phones and Cancer Risk - National Cancer Institute". Cancer.gov. 2013-05-08. Retrieved 2013-12-15.
37.    ^ ab Roukos DH (April 2009). "Genome-wide association studies: how predictable is a person's cancer risk?". Expert Rev Anticancer Ther9 (4): 389–92. doi:10.1586/era.09.12. PMID 19374592.
38.    ^ Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (March 2010). "Colorectal cancer". Lancet375 (9719): 1030–47. doi:10.1016/S0140-6736(10)60353-4. PMID 20304247.
39.    ^ abcde Maltoni CFM, Holland JF (2000). "Chapter 16: Physical Carcinogens". In Bast RC, Kufe DW, Pollock RE, et al. Holland-Frei Cancer Medicine (5th ed.). Hamilton, Ontario: B.C. Decker. ISBN 1-55009-113-1. Retrieved 31 January 2011.
40.    ^ abcdefg Gaeta, John F (2000). "Chapter 17: Trauma and Inflammation". In Bast RC, Kufe DW, Pollock RE, et al. Holland-Frei Cancer Medicine (5th ed.). Hamilton, Ontario: B.C. Decker. ISBN 1-55009-113-1. Retrieved 27 January 2011.
41.    ^ Hendrik Ungefroren; Susanne Sebens; Daniel Seidl; Hendrik Lehnert; Ralf Haas (2011). "Interaction of tumor cells with the microenvironment". Cell Communication and Signaling9 (18). doi:10.1186/1478-811X-9-18.
42.    ^ abcdefghij Henderson BE, Bernstein L, Ross RK (2000). "Chapter 13: Hormones and the Etiology of Cancer". In Bast RC, Kufe DW, Pollock RE, et al. Holland-Frei Cancer Medicine (5th ed.). Hamilton, Ontario: B.C. Decker. ISBN 1-55009-113-1. Retrieved 27 January 2011.
43.    ^ Rowlands MA, Mari-Anne; , Gunnell D, Harris R, Vatten LJ, Holly JM, Martin RM (May 15, 2009). "Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis". Int J Cancer.124 (10): 2416–29. doi:10.1002/ijc.24202. PMC 2743036. PMID 19142965.
44.    ^ ab Tolar J, Neglia JP (June 2003). "Transplacental and other routes of cancer transmission between individuals". J. Pediatr. Hematol. Oncol.25 (6): 430–4. doi:10.1097/00043426-200306000-00002. PMID 12794519.
45.    ^ Dingli D, Nowak MA (September 2006). "Cancer biology: infectious tumour cells". Nature443 (7107): 35–6. Bibcode:2006Natur.443...35D. doi:10.1038/443035a. PMC 2711443. PMID 16957717.
46.    ^ Heikkilä, K; Nyberg, ST; Theorell, T; Fransson, EI; Alfredsson, L; Bjorner, JB; Bonenfant, S; Borritz, M; Bouillon, K; Burr, H; Dragano, N; Geuskens, GA; Goldberg, M; Hamer, M; Hooftman, WE; Houtman, IL; Joensuu, M; Knutsson, A; Koskenvuo, M; Koskinen, A; Kouvonen, A; Madsen, IE; Magnusson Hanson, LL; Marmot, MG; Nielsen, ML; Nordin, M; Oksanen, T; Pentti, J; Salo, P; Rugulies, R; Steptoe, A; Suominen, S; Vahtera, J; Virtanen, M; Väänänen, A; Westerholm, P; Westerlund, H; Zins, M; Ferrie, JE; Singh-Manoux, A; Batty, GD; Kivimäki, M; IPD-Work, Consortium (Feb 7, 2013). "Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women". BMJ (Clinical research ed.)346: f165. doi:10.1136/bmj.f165. PMC 3567204. PMID 23393080.
47.    ^ Croce CM (January 2008). "Oncogenes and cancer". N. Engl. J. Med.358 (5): 502–11. doi:10.1056/NEJMra072367. PMID 18234754.
48.    ^ Knudson AG (November 2001). "Two genetic hits (more or less) to cancer". Nature Reviews Cancer1 (2): 157–62. doi:10.1038/35101031. PMID 11905807.
49.    ^ Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E (September 2004). "Hypoxia and defective apoptosis drive genomic instability and tumorigenesis". Genes & Development18 (17): 2095–107. doi:10.1101/gad.1204904. PMC 515288. PMID 15314031.
50.    ^ Merlo LM, Pepper JW, Reid BJ, Maley CC (December 2006). "Cancer as an evolutionary and ecological process". Nature Reviews Cancer6 (12): 924–35. doi:10.1038/nrc2013. PMID 17109012.
51.    ^ Baylin SB, Ohm JE (February 2006). "Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?". Nature Reviews Cancer6 (2): 107–16. doi:10.1038/nrc1799. PMID 16491070.
52.    ^ Kanwal, R; Gupta, S (2012). "Epigenetic modifications in cancer". Clinical Genetics81 (4): 303–11. doi:10.1111/j.1399-0004.2011.01809.x. PMC 3590802. PMID 22082348.
53.    ^ Baldassarre, G; Battista, S; Belletti, B; Thakur, S; Pentimalli, F; Trapasso, F; Fedele, M; Pierantoni, G; Croce, CM; Fusco, A (2003). "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma". Molecular and Cellular Biology23 (7): 2225–38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC 150734. PMID 12640109./
54.    ^ Schnekenburger, M; Diederich, M (2012). "Epigenetics Offer New Horizons for Colorectal Cancer Prevention". Current Colorectal Cancer Reports8 (1): 66–81. doi:10.1007/s11888-011-0116-z. PMC 3277709. PMID 22389639.
55.    ^ Jacinto FV, Esteller M (July 2007). "Mutator pathways unleashed by epigenetic silencing in human cancer". Mutagenesis22 (4): 247–53. doi:10.1093/mutage/gem009. PMID 17412712.
56.    ^ Lahtz C, Pfeifer GP (February 2011). "Epigenetic changes of DNA repair genes in cancer". J Mol Cell Biol3 (1): 51–8. doi:10.1093/jmcb/mjq053. PMC 3030973. PMID 21278452.
57.    ^ Bernstein C, Nfonsam V, Prasad AR, Bernstein H (March 2013). "Epigenetic field defects in progression to cancer". World J Gastrointest Oncol5 (3): 43–9. doi:10.4251/wjgo.v5.i3.43. PMC 3648662. PMID 23671730.
58.    ^ Bernstein, Carol; r., Anil; Nfonsam, Valentine; Bernstei, Harris (2013). "DNA Damage, DNA Repair and Cancer". In Prof. Clark Chen (Ed.). New Research Directions in DNA Repair. InTech. doi:10.5772/53919. ISBN 978-953-51-1114-6.
59.    ^ Narayanan, L; Fritzell, JA; Baker, SM; Liskay, RM; Glazer, PM (1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proceedings of the National Academy of Sciences of the United States of America94 (7): 3122–7. doi:10.1073/pnas.94.7.3122. PMC 20332. PMID 9096356.
60.    ^ Hegan, DC; Narayanan, L; Jirik, FR; Edelmann, W; Liskay, RM; Glazer, PM (2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC 2612936. PMID 16728433.
61.    ^ Tutt, AN; Van Oostrom, CT; Ross, GM; Van Steeg, H; Ashworth, A (2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: Synergism with ionizing radiation". EMBO Reports3 (3): 255–60. doi:10.1093/embo-reports/kvf037. PMC 1084010. PMID 11850397.
62.    ^ German, J (1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". American Journal of Human Genetics21 (2): 196–227. PMC 1706430. PMID 5770175.
63.    ^ O'Hagan, HM; Mohammad, HP; Baylin, SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". In Lee, Jeannie T. PLoS genetics4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
64.    ^ Cuozzo, C; Porcellini, A; Angrisano, T; Morano, A; Lee, B; Di Pardo, A; Messina, S; Iuliano, R; Fusco, A; Santillo, MR; Muller, MT; Chiariotti, L; Gottesman, ME; Avvedimento, EV (2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS genetics3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
65.    ^ Malkin, D (2011). "Li-fraumeni syndrome". Genes & cancer2 (4): 475–84. doi:10.1177/1947601911413466. PMC 3135649. PMID 21779515.
66.    ^ Fearon, ER (1997). "Human cancer syndromes: Clues to the origin and nature of cancer". Science278 (5340): 1043–50. doi:10.1126/science.278.5340.1043. PMID 9353177.
67.    ^ Vogelstein, B; Papadopoulos, N; Velculescu, VE; Zhou, S; Diaz Jr, LA; Kinzler, KW (2013). "Cancer genome landscapes". Science339 (6127): 1546–58. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594.
68.    ^ ab"Metastatic Cancer: Questions and Answers". National Cancer Institute. Retrieved 2008-08-28.
69.    ^"What is Metastasized Cancer?". National Comprehensive Cancer Network. Retrieved 18 July 2013.
70.    ^ Anguiano L, Mayer DK, Piven ML, Rosenstein D (Jul–Aug 2012). "A literature review of suicide in cancer patients". Cancer Nursing35 (4): E14–26. doi:10.1097/NCC.0b013e31822fc76c. PMID 21946906.
71.    ^ Varricchio, Claudette G. (2004). A cancer source book for nurses. Boston: Jones and Bartlett Publishers. p. 229. ISBN 0-7637-3276-1.
72.    ^"Cancer prevention: 7 steps to reduce your risk". Mayo Clinic. 27 September 2008. Retrieved 30 January 2010.
73.    ^ Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M (2005). "Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors". Lancet366 (9499): 1784–93. doi:10.1016/S0140-6736(05)67725-2. PMID 16298215.
74.    ^"Cancer". World Health Organization. Retrieved 9 January 2011.
75.    ^ ab Wicki A, Hagmann, J (September 2011). "Diet and cancer". Swiss medical weekly141: w13250. doi:10.4414/smw.2011.13250. PMID 21904992.
76.    ^ Cappellani A, Di Vita M, Zanghi A, Cavallaro A, Piccolo G, Veroux M, Berretta M, Malaguarnera M, Canzonieri V, Lo Menzo E (2012). "Diet, obesity and breast cancer: an update". Front Biosci (Schol Ed)4: 90–108. PMID 22202045.
77.    ^ Key TJ (January 2011). "Fruit and vegetables and cancer risk". Br. J. Cancer104 (1): 6–11. doi:10.1038/sj.bjc.6606032. PMC 3039795. PMID 21119663.
78.    ^ Larsson SC, Wolk A (May 2007). "Coffee consumption and risk of liver cancer: a meta-analysis". Gastroenterology132 (5): 1740–5. doi:10.1053/j.gastro.2007.03.044. PMID 17484871.
79.    ^ Zheng W, Lee SA (2009). "Well-done meat intake, heterocyclic amine exposure, and cancer risk". Nutr Cancer61 (4): 437–46. doi:10.1080/01635580802710741. PMC 2769029. PMID 19838915.
80.    ^ Ferguson LR (February 2010). "Meat and cancer". Meat Sci.84 (2): 308–13. doi:10.1016/j.meatsci.2009.06.032. PMID 20374790.
81.    ^ Holland Chp.33
82.    ^ Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D (March 2007). "Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force". Annals of Internal Medicine146 (5): 376–89. doi:10.7326/0003-4819-146-5-200703060-00010. PMID 17339623.
83.    ^ Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (January 2011). "Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials". Lancet377 (9759): 31–41. doi:10.1016/S0140-6736(10)62110-1. PMID 21144578.
84.    ^ Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF, Maguire C, Hind D, Tappenden P (June 2010). "Chemoprevention of colorectal cancer: systematic review and economic evaluation". Health Technol Assess14 (32): 1–206. doi:10.3310/hta14320. PMID 20594533.
85.    ^ Thomsen A, Kolesar JM (December 2008). "Chemoprevention of breast cancer". Am J Health Syst Pharm65 (23): 2221–8. doi:10.2146/ajhp070663. PMID 19020189.
86.    ^ Wilt TJ, MacDonald R, Hagerty K, Schellhammer P, Kramer BS (2008). "Five-alpha-reductase Inhibitors for prostate cancer prevention". In Wilt, Timothy J. Cochrane Database Syst Rev (2): CD007091. doi:10.1002/14651858.CD007091. PMID 18425978.
87.    ^"Vitamins and minerals: not for cancer or cardiovascular prevention". Prescrire Int19 (108): 182. August 2010. PMID 20939459.
88.    ^ Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC (April 2006). "Prospective study of predictors of vitamin D status and cancer incidence and mortality in men". J. Natl. Cancer Inst.98 (7): 451–9. doi:10.1093/jnci/djj101. PMID 16595781.
89.    ^"Vitamin D Has Role in Colon Cancer Prevention". Archived from the original on 4 December 2006. Retrieved 27 July 2007.
90.    ^ Schwartz GG, Blot WJ (April 2006). "Vitamin D status and cancer incidence and mortality: something new under the sun". J. Natl. Cancer Inst.98 (7): 428–30. doi:10.1093/jnci/djj127. PMID 16595770.
91.    ^ Fritz H, Kennedy D, Fergusson D, Fernandes R, Doucette S, Cooley K, Seely A, Sagar S, Wong R, Seely D (2011). "Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis". In Minna, John D. PLoS ONE6 (6): e21107. Bibcode:2011PLoSO...6E1107F. doi:10.1371/journal.pone.0021107. PMC 3124481. PMID 21738614.
92.    ^ Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER (June 2007). "Folic acid for the prevention of colorectal adenomas: a randomized clinical trial". JAMA297 (21): 2351–9. doi:10.1001/jama.297.21.2351. PMID 17551129.
93.    ^ abc"Cancer Vaccine Fact Sheet". NCI. 8 June 2006. Retrieved 15 November 2008.
94.    ^ ab Lertkhachonsuk AA, Yip CH, Khuhaprema T, Chen DS, Plummer M, Jee SH, Toi M, Wilailak S (2013). "Cancer prevention in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013". Lancet Oncology14 (12): e497–507. doi:10.1016/S1470-2045(13)70350-4. PMID 24176569.
95.    ^ abc"What Is Cancer Screening?". National Cancer Institute.
96.    ^ abc Wilson JMG, Jungner G. (1968) Principles and practice of screening for disease. Geneva:World Health Organization. Public Health Papers, #34.
97.    ^"Screening for Cervical Cancer". U.S. Preventive Services Task Force. 2003.
98.    ^"Screening for Colorectal Cancer". U.S. Preventive Services Task Force. 2008.
99.    ^"Screening for Skin Cancer". U.S. Preventive Services Task Force. 2009.
100.    ^"Screening for Oral Cancer". U.S. Preventive Services Task Force. 2004.
101.    ^"Lung Cancer Screening". U.S. Preventive Services Task Force. 2004.
102.    ^"Screening for Prostate Cancer". U.S. Preventive Services Task Force. 2008.
103.    ^"Screening for Bladder Cancer". U.S. Preventive Services Task Force. 2004.
104.    ^"Screening for Testicular Cancer". U.S. Preventive Services Task Force. 2004.
105.    ^"Screening for Ovarian Cancer". U.S. Preventive Services Task Force. 2004.
106.    ^"Screening for Pancreatic Cancer". U.S. Preventive Services Task Force. 2004.
107.    ^ Chou, Roger; Croswell, Jennifer M.; Dana, Tracy; Bougatous, Christina; Blazina, Ian; Fu, Rongwei; Gleitsmann, Ken; Koenig, Helen C. et al. (7 October 2011). "Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force". United States Preventive Services Task Force. Retrieved 8 October 2011.
108.    ^"Screening for Breast Cancer". U.S. Preventive Services Task Force. 2009.
109.    ^ Gøtzsche PC, Nielsen M (2011). "Screening for breast cancer with mammography". In Gøtzsche, Peter C. Cochrane Database Syst Rev (1): CD001877. doi:10.1002/14651858.CD001877.pub4. PMID 21249649.
110.    ^ ab Gulati AP, Domchek, SM (Jan 2008). "The clinical management of BRCA1 and BRCA2 mutation carriers". Current oncology reports10 (1): 47–53. doi:10.1007/s11912-008-0008-9. PMID 18366960.
111.    ^ Lind M.J., M.J. (2008). "Principles of cytotoxic chemotherapy". Medicine36 (1): 19–23. doi:10.1016/j.mpmed.2007.10.003.
112.    ^ National Cancer Institute (Dec 2012). "Targeted Cancer Therapies". www.cancer.gov. Retrieved 9 March 2014.
113.    ^NCI: Targeted Therapy tutorials
114.    ^ ab Holland Chp. 40
115.    ^ Nastoupil, LJ; Rose, AC; Flowers, CR (May 2012). "Diffuse large B-cell lymphoma: current treatment approaches". Oncology (Williston Park, N.Y.)26 (5): 488–95. PMID 22730604.
116.    ^ Freedman, A (October 2012). "Follicular lymphoma: 2012 update on diagnosis and management". American journal of hematology87 (10): 988–95. doi:10.1002/ajh.23313. PMID 23001911.
117.    ^ Rampling, R; James, A; Papanastassiou, V (June 2004). "The present and future management of malignant brain tumours: surgery, radiotherapy, chemotherapy". Journal of neurology, neurosurgery, and psychiatry. 75 Suppl 2 (Suppl 2): ii24–30. doi:10.1136/jnnp.2004.040535. PMC 1765659. PMID 15146036.
118.    ^ Madan, V; Lear, JT; Szeimies, RM (February 20, 2010). "Non-melanoma skin cancer". Lancet375 (9715): 673–85. doi:10.1016/S0140-6736(09)61196-X. PMID 20171403.
119.    ^ CK Bomford, IH Kunkler, J Walter. Walter and Miller’s Textbook of Radiation therapy (6th Ed), p311
120.    ^ "Radiosensitivity" on GP notebook http://www.gpnotebook.co.uk/simplepage.cfm?ID=2060451853
121.    ^ "Radiation therapy- what GPs need to know" on patient.co.uk http://www.patient.co.uk/showdoc/40002299/
122.    ^ Holland Chp. 41
123.    ^ abcdeAmerican Society of Clinical Oncology. "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation (American Society of Clinical Oncology). Retrieved August 14, 2012
124.    ^
    The American Society of Clinical Oncology made this recommendation based on various cancers. See American Society of Clinical Oncology. "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation (American Society of Clinical Oncology). Retrieved August 14, 2012
    for lung cancer, see Azzoli, CG; Temin, S; Aliff, T; Baker, S; Brahmer, J; Johnson, DH; Laskin, JL; Masters, G; Milton, D; Nordquist, L; Pao, W; Pfister, DG; Piantadosi, S; Schiller, JH; Smith, R; Smith, TJ; Strawn, JR; Trent, D; Giaccone, G; American Society of Clinical Oncology (2011). "2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer". Journal of clinical oncology : official journal of the American Society of Clinical Oncology29 (28): 3825–31. doi:10.1200/JCO.2010.34.2774. PMC 3675703. PMID 21900105. and Ettinger, DS; Akerley, W; Bepler, G; Blum, MG; Chang, A; Cheney, RT; Chirieac, LR; d'Amico, TA; Demmy, TL; Ganti, AK; Govindan, R; Grannis Jr, FW; Jahan, T; Jahanzeb, M; Johnson, DH; Kessinger, A; Komaki, R; Kong, FM; Kris, MG; Krug, LM; Le, QT; Lennes, IT; Martins, R; O'Malley, J; Osarogiagbon, RU; Otterson, GA; Patel, JD; Pisters, KM; Reckamp, K; Riely, GJ (2010). "Non-small cell lung cancer". Journal of the National Comprehensive Cancer Network : JNCCN8 (7): 740–801. PMID 20679538.
    for breast cancer, see Carlson, RW; Allred, DC; Anderson, BO; Burstein, HJ; Carter, WB; Edge, SB; Erban, JK; Farrar, WB; Goldstein, LJ; Gradishar, WJ; Hayes, DF; Hudis, CA; Jahanzeb, M; Kiel, K; Ljung, BM; Marcom, PK; Mayer, IA; McCormick, B; Nabell, LM; Pierce, LJ; Reed, EC; Smith, ML; Somlo, G; Theriault, RL; Topham, NS; Ward, JH; Winer, EP; Wolff, AC; NCCN Breast Cancer Clinical Practice Guidelines Panel (2009). "Breast cancer. Clinical practice guidelines in oncology". Journal of the National Comprehensive Cancer Network : JNCCN7 (2): 122–92. PMID 19200416.
    for colon cancer, see Engstrom, PF; Arnoletti, JP; Benson Ab, 3rd; Chen, YJ; Choti, MA; Cooper, HS; Covey, A; Dilawari, RA; Early, DS; Enzinger, PC; Fakih, MG; Fleshman Jr, J; Fuchs, C; Grem, JL; Kiel, K; Knol, JA; Leong, LA; Lin, E; Mulcahy, MF; Rao, S; Ryan, DP; Saltz, L; Shibata, D; Skibber, JM; Sofocleous, C; Thomas, J; Venook, AP; Willett, C; National Comprehensive Cancer Network (2009). "NCCN Clinical Practice Guidelines in Oncology: Colon cancer". Journal of the National Comprehensive Cancer Network : JNCCN7 (8): 778–831. PMID 19755046.
    for other general statements see Smith, Thomas J.; Hillner, Bruce E. (2011). "Bending the Cost Curve in Cancer Care". New England Journal of Medicine364 (21): 2060–5. doi:10.1056/NEJMsb1013826. PMID 21612477. and Peppercorn, J. M.; Smith, T. J.; Helft, P. R.; Debono, D. J.; Berry, S. R.; Wollins, D. S.; Hayes, D. M.; Von Roenn, J. H.; Schnipper, L. E.; American Society of Clinical Oncology (2011). "American Society of Clinical Oncology Statement: Toward Individualized Care for Patients with Advanced Cancer". Journal of Clinical Oncology29 (6): 755–60. doi:10.1200/JCO.2010.33.1744. PMID 21263086.
125.    ^"NCCN Guidelines".
126.    ^"Clinical Practice Guidelines for Quality Palliative Care". The National Consensus Project for Quality Palliative Care (NCP).
127.    ^ Levy MH, Back, A, Bazargan, S, Benedetti, C, Billings, JA, Block, S, Bruera, E, Carducci, MA, Dy, S, Eberle, C, Foley, KM, Harris, JD, Knight, SJ, Milch, R, Rhiner, M, Slatkin, NE, Spiegel, D, Sutton, L, Urba, S, Von Roenn, JH, Weinstein, SM, National Comprehensive Cancer Network (September 2006). "Palliative care. Clinical practice guidelines in oncology". Journal of the National Comprehensive Cancer Network: JNCCN4 (8): 776–818. PMID 16948956.
128.    ^ Cassileth BR, Deng G (2004). "Complementary and alternative therapies for cancer". Oncologist9 (1): 80–9. doi:10.1634/theoncologist.9-1-80. PMID 14755017.
129.    ^What Is CAM?National Center for Complementary and Alternative Medicine. retrieved 3 February 2008.
130.    ^ Vickers A (2004). "Alternative cancer cures: 'unproven' or 'disproven'?". CA Cancer J Clin54 (2): 110–8. doi:10.3322/canjclin.54.2.110. PMID 15061600.
131.    ^ ab Rheingold, Susan; Neugut, Alfred; Meadows, Anna (2003). "156: Secondary Cancers: Incidence, Risk Factors, and Management". In Frei, Emil; Kufe, Donald W.; Holland, James F. Holland-Frei Cancer Medicine (6th ed.). Hamilton, Ont: BC Decker. p. 2399. ISBN 1-55009-213-8. Retrieved 5 November 2009.
132.    ^ Montazeri A (December 2009). "Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008". Health Qual Life Outcomes7: 102. doi:10.1186/1477-7525-7-102. PMC 2805623. PMID 20030832.
133.    ^"WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved 11 November 2009.
134.    ^ ab Lozano, R (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
135.    ^WHO (October 2010). "Cancer". World Health Organization. Retrieved 5 January 2011.
136.    ^ ab Coleman, William B. and Rubinas, Tara C. (2009). "4". In Tsongalis, Gregory J. and Coleman, William L. Molecular Pathology: The Molecular Basis of Human Disease. Amsterdam: Elsevier Academic Press. p. 66. ISBN 0-12-374419-9.
137.    ^ Johnson, George (28 December 2010). "Unearthing Prehistoric Tumors, and Debate". The New York Times.
138.    ^ Pawelec G, Derhovanessian, E, Larbi, A (Aug 2010). "Immunosenescence and cancer". Critical reviews in oncology/hematology75 (2): 165–72. doi:10.1016/j.critrevonc.2010.06.012. PMID 20656212.
139.    ^ Alberts, B, Johnson A, Lewis J, et al. (2002). "The Preventable Causes of Cancer". Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-4072-9. "A certain irreducible background incidence of cancer is to be expected regardless of circumstances: mutations can never be absolutely avoided, because they are an inescapable consequence of fundamental limitations on the accuracy of DNA replication, as discussed in Chapter 5. If a human could live long enough, it is inevitable that at least one of his or her cells would eventually accumulate a set of mutations sufficient for cancer to develop."
140.    ^ Anisimov VN, Sikora, E, Pawelec, G (Aug 2009). "Relationships between cancer and aging: a multilevel approach". Biogerontology10 (4): 323–38. doi:10.1007/s10522-008-9209-8. PMID 19156531.
141.    ^ de Magalhaes JP (2013). "How ageing processes influence cancer". Nature Reviews Cancer13 (5): 357–65. doi:10.1038/nrc3497. PMID 23612461.
142.    ^ Fraumeni, Joseph F.; Schottenfeld, David; Marshall, James M. (2006). Cancer epidemiology and prevention. Oxford [Oxfordshire]: Oxford University Press. p. 977. ISBN 0-19-514961-0.
143.    ^ Bostwick, David G.; Eble, John N. (2007). Urological Surgical Pathology. St. Louis: Mosby. p. 468. ISBN 0-323-01970-6.
144.    ^ ab Kaatsch P, Sikora, E, Pawelec, G (June 2010). "Epidemiology of childhood cancer". Cancer treatment reviews36 (4): 277–85. doi:10.1016/j.ctrv.2010.02.003. PMID 20231056.
145.    ^ ab Ward, Elizabeth; DeSantis, Carol; Robbins, Anthony; Kohler, Betsy; Jemal, Ahmedin (January 2014). "Childhood and adolescent cancer statistics, 2014". CA: A Cancer Journal for Clinicians: n/a–n/a. doi:10.3322/caac.21219.
146.    ^ Ward EM, Thun, MJ, Hannan, LM, Jemal, A (Sep 2006). "Interpreting cancer trends". Annals of the New York Academy of Sciences1076: 29–53. Bibcode:2006NYASA1076...29W. doi:10.1196/annals.1371.048. PMID 17119192.
147.    ^ abcdef Hajdu SI, Thun, MJ, Hannan, LM, Jemal, A (March 2011). "A note from history: landmarks in history of cancer, part 1". Cancer117 (5): 1097–102. doi:10.1002/cncr.25553. PMID 20960499.
148.    ^ Paul of Aegina, 7th Century AD, quoted in Moss, Ralph W. (2004). "Galen on Cancer". CancerDecisions. Archived from the original on 16 July 2011. Referenced from Michael Shimkin, Contrary to Nature, Washington, D.C.: Superintendent of Document, DHEW Publication No. (NIH) 79-720, p. 35.
149.    ^ Majno, Guido; Joris, Isabelle (August 12, 2004). Cells, Tissues, and Disease : Principles of General Pathology: Principles of General Pathology. Oxford University Press. ISBN 978-0-19-974892-1. Retrieved September 11, 2013.
150.    ^ ab Hajdu SI, Thun, MJ, Hannan, LM, Jemal, A (June 2011). "A note from history: landmarks in history of cancer, part 2". Cancer117 (12): 2811–20. doi:10.1002/cncr.25825. PMID 21656759.
151.    ^ Yalom, Marilyn (1998). A history of the breast (1st Ballantine Books ed.). New York: Ballantine Books. ISBN 0-679-43459-3.
152.    ^ Hajdu SI, Thun, MJ, Hannan, LM, Jemal, A (July 2011). "A note from history: Landmarks in history of cancer, part 3". Cancer118 (4): 1155–68. doi:10.1002/cncr.26320. PMID 21751192.
153.    ^ Grange JM, Stanford JL, Stanford CA (2002). "Campbell De Morgan's 'Observations on cancer', and their relevance today". Journal of the Royal Society of Medicine95 (6): 296–9. doi:10.1258/jrsm.95.6.296. PMC 1279913. PMID 12042378.
154.    ^Ehrenreich, Barbara (November 2001). "Welcome to Cancerland". Harper's Magazine. ISSN 0017-789X.
155.    ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
156.    ^"Skin cancers". World Health Organization. Retrieved 19 January 2011.
157.    ^ McCulley, Michelle; Greenwell, Pamela (2007). Molecular therapeutics: 21st-century medicine. London: J. Wiley. p. 207. ISBN 0-470-01916-6.
158.    ^ Gwyn, Richard (1999). "10". In Cameron, Lynne; Low, Graham. Researching and applying metaphor. Cambridge, UK: Cambridge University Press. ISBN 0-521-64964-1.
159.    ^ Sulik, Gayle (2010). Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health. New York: Oxford University Press. pp. 78–89. ISBN 0-19-974045-3. OCLC 535493589.
160.    ^ abc Olson, James Stuart (2002). Bathsheba's Breast: Women, Cancer and History. Baltimore: The Johns Hopkins University Press. pp. 145–170. ISBN 0-8018-6936-6. OCLC 186453370.
161.    ^ abcd Ehrenreich, Barbara (2009). Bright-sided: How the Relentless Promotion of Positive Thinking Has Undermined America. New York: Metropolitan Books. pp. 15–44. ISBN 0-8050-8749-4.
162.    ^ Huff, Charlotte (24 September 2013). "A Sick Stigma: Why are cancer patients blamed for their illness?". Slate.
163.    ^"Cancer Facts and Figures 2012". Journalist's Resource.org.
164.    ^"What Is Cancer?". National Cancer Institute. Retrieved 17 August 2009.
165.    ^"Cancer Fact Sheet". Agency for Toxic Substances & Disease Registry. 30 August 2002. Retrieved 17 August 2009.
166.    ^ Wanjek, Christopher (16 September 2006). "Exciting New Cancer Treatments Emerge Amid Persistent Myths". Retrieved 17 August 2009.
167.    ^ Hayden EC, Thun, MJ, Hannan, LM, Jemal, A (April 2009). "Cutting off cancer's supply lines". Nature458 (7239): 686–687. doi:10.1038/458686b. PMID 19360048.
168.    ^ Bagri, A; Kouros-Mehr, Hosein; Leong, KG; Plowman, GD (Mar 2010). "Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale.". Trends in molecular medicine16 (3): 122–32. doi:10.1016/j.molmed.2010.01.004. PMID 20189876.
169.    ^ Sleigh SH, Barton CL (2010). "Repurposing Strategies for Therapeutics". Pharm Med24 (3): 151–159. doi:10.2165/11536770-000000000-00000.
170.    ^ Winther H, Jorgensen JT (2010). "Drug-Diagnostic Co-Development in Cancer". Pharm Med24 (6): 363–375. doi:10.2165/11586320-000000000-00000.
171.    ^ Sharon Begley (16 September 2008). "Rethinking the War on Cancer". Newsweek. Retrieved 8 September 2008.
172.    ^Kolata, Gina (23 April 2009). "Advances Elusive in the Drive to Cure Cancer". The New York Times. Retrieved 5 May 2009.
173.    ^ Bruce Albertsa, Marc W. Kirschnerb, Shirley Tilghmanc, and Harold Varmus, Rescuing US biomedical research from its systemic flaws, Proceedings of the National Academy of Sciences of the United States of America, vol. 111 no. 16, April 2014
174.    ^ Kolata, Gina (April 23, 2009). "Advances Elusive in the Drive to Cure Cancer". The New York Times. Retrieved 2009-12-29.
175.    ^ Kolata, Gina (June 27, 2009). "Grant System Leads Cancer Researchers to Play It Safe". The New York Times. Retrieved 2009-12-29.
176.    ^ Leaf, Clifton (2004-03-22). "Why We're Losing The War On Cancer". Fortune Magazine (CNN Money).
177.    ^ abcdefghij Connie Henke Yarbro, Debra Wujcik, Barbara Holmes Gobel, ed. (2011). Cancer nursing: principles and practice (7 ed.). Jones & Bartlett Publishers. pp. 901–905. ISBN 978-1-4496-1829-2.
178.    ^ Murgia C, Pritchard JK, Kim SY, Fassati A, Weiss RA (August 2006). "Clonal origin and evolution of a transmissible cancer". Cell126 (3): 477–87. doi:10.1016/j.cell.2006.05.051. PMC 2593932. PMID 16901782.
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