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Tropical Sprue

Tropical sprue is a malabsorption disease of as of yet unknown etiology. It is characterized by gastrointestinal symptoms and megaloblastic anemia.


Presentation

Patients suffering from acute, symptomatic TS usually present gastrointestinal symptoms. Diarrhea is most frequently observed and is associated with malaise and fever. Subsequently, diarrhea partially subsides, but nausea, anorexia, abdominal pain and fatigue are experienced. Steatorrhea may be an important indication of TS [6].

Chronic TS results in nutrient deficiencies. Deficits concerning vitamin B12, folate and liposoluble vitamins are most commonly detected. Interestingly, vitamin B12 deficiencies are more pronounced in TS cases originating from the Caribbean. Patients that presumably contracted the disease in Asia more frequently present folate deficits. Nutrient deficiencies are often associated with weight loss, edema and stomatitis. Dehydration and general pallor may also be observed. Generally, patients do not associate their symptoms with previous travels to tropical climates since years may have passed.

Weight Loss
  • The respective roles of reduced dietary intake and malabsorption in the pathogenesis of weight loss in persons with chronic tropical sprue have been evaluated .[ncbi.nlm.nih.gov]
  • All patients presented with diarrhea, weight loss, anorexia and had megaloblastic anemia. In all patients, a distal duodenal biopsy showed partial villous atrophy.[ncbi.nlm.nih.gov]
  • However, in this era of globalization and worldwide travel, it is important for all clinicians to be aware of the possibility of TS in patients presenting with nonspecific, persistent gastrointestinal complaints like diarrhea and weight loss.[ncbi.nlm.nih.gov]
  • In each of these patients, diagnosis was delayed because of the failure to consider tropical sprue in the differential diagnosis of diarrhea and weight loss.[ncbi.nlm.nih.gov]
  • CASE REPORT: The authors report two cases of American residents living in Thailand and Vietnam who had been suffering from chronic diarrhea, weight loss, being easily fatigued and nutritional deficiency and who dramatically responded after treatment for[ncbi.nlm.nih.gov]
Anemia
  • All patients presented with diarrhea, weight loss, anorexia and had megaloblastic anemia. In all patients, a distal duodenal biopsy showed partial villous atrophy.[ncbi.nlm.nih.gov]
  • Malabsorption of folate and vitamin B 12 deficiency result in megaloblastic anemia.[merck.com]
  • Thus, anemia may be developed and intestinal damage is further aggravated.[symptoma.com]
  • […] intestinal absorption of nutrients results in malnutrition and anemia due to folate deficiency Applies To Sprue: NOS tropical Tropical steatorrhea ICD-9-CM Volume 2 Index entries containing back-references to 579.1 :[icd9data.com]
  • Thirty-five subjects had a megaloblastic anemia; this was a secondary to a combined deficiency of folate and vitamin B12 in 25 and to deficiency of only one of these vitamins in the other ten.[ncbi.nlm.nih.gov]
Malnutrition
  • Other causes of malabsorption, and primary malnutrition, have been excluded. The severity of the clinical state and intestinal malabsorption distinguish these patients from those we have described with tropical enteropathy.[ncbi.nlm.nih.gov]
  • […] intestinal absorption of nutrients results in malnutrition and anemia due to folate deficiency Applies To Sprue: NOS tropical Tropical steatorrhea ICD-9-CM Volume 2 Index entries containing back-references to 579.1 :[icd9data.com]
  • In contrast to the situation in travelers, sprue among the indigenous population of the tropics remains largely unchanged: a chronic debilitating disorder that represents a significant contributory factor to the pathogenesis of morbidity and malnutrition[ncbi.nlm.nih.gov]
  • Symptoms of Tropical Sprue The symptoms of tropical sprue are: Chronic diarrhea Excess gas or flatulence Sore tongue Weight loss and malnutrition Chronic fatigue or weakness Steatorrhea or particularly foul-smelling feces Patients with tropical sprue[healthinplainenglish.com]
  • The failed intestinal absorption of nutrients from the small intestine results in malnutrition and anemia that is due to folic acid deficiency.[icd10data.com]
Fatigue
  • CASE REPORT: The authors report two cases of American residents living in Thailand and Vietnam who had been suffering from chronic diarrhea, weight loss, being easily fatigued and nutritional deficiency and who dramatically responded after treatment for[ncbi.nlm.nih.gov]
  • Its symptoms are diarrhea, anorexia, and fatigue. If the disease is prolonged, anemia caused by… The onset of the disease is insidious .[britannica.com]
  • Diarrhea may partially subside before nausea, abdominal pain, light-colored, greasy stools and generalized fatigue are experienced.[symptoma.com]
  • Symptoms of Tropical Sprue The symptoms of tropical sprue are: Chronic diarrhea Excess gas or flatulence Sore tongue Weight loss and malnutrition Chronic fatigue or weakness Steatorrhea or particularly foul-smelling feces Patients with tropical sprue[healthinplainenglish.com]
Malaise
  • The illness usually starts with an attack of acute diarrhoea, fever and malaise following which, after a variable period, the patient settles into the chronic phase of diarrhoea, steatorrhoea, weight loss, anorexia, malaise, and nutritional deficiencies[en.wikipedia.org]
  • Symptoms and Signs Patients commonly have acute diarrhea with fever and malaise. A chronic phase of milder diarrhea, nausea, anorexia, abdominal cramps, and fatigue follows. Steatorrhea (foul-smelling, pale, bulky, and greasy stools) is common.[merck.com]
  • Signs & Symptoms of Tropical Sprue The initial symptoms of Tropical Sprue comprise of acute diarrhea , malaise and fever and after sometime, patient will have a chronic stage of diarrhea, steatorrhea, anorexia, weight loss, malaise with nutritional deficiencies[epainassist.com]
  • Tropical Sprue Symptoms The condition normally begins with a bout of acute diarrhea, malaise and fever. This is followed by chronic diarrhea, malaise, anorexia, steatorrhoea, weight loss and various other nutritional deficiencies.[healthtipsandguides.net]
  • Diarrhea is most frequently observed and is associated with malaise and fever. Subsequently, diarrhea partially subsides, but nausea, anorexia, abdominal pain and fatigue are experienced. Steatorrhea may be an important indication of TS.[symptoma.com]
Diarrhea
  • All patients presented with diarrhea, weight loss, anorexia and had megaloblastic anemia. In all patients, a distal duodenal biopsy showed partial villous atrophy.[ncbi.nlm.nih.gov]
  • Diarrhea is most frequently observed and is associated with malaise and fever. Subsequently, diarrhea partially subsides, but nausea, anorexia, abdominal pain and fatigue are experienced. Steatorrhea may be an important indication of TS.[symptoma.com]
  • Therefore, if the usual causes of persistent diarrhea are ruled out, keeping a high index of suspicion for TS in patients who have a travel history to one of the endemic regions is important.[ncbi.nlm.nih.gov]
  • Accordingly, once these more common etiologies have been ruled out, TS must be considered in patients presenting with diarrhea after travel to endemic regions.[ncbi.nlm.nih.gov]
  • Symptoms and Signs Patients commonly have acute diarrhea with fever and malaise. A chronic phase of milder diarrhea, nausea, anorexia, abdominal cramps, and fatigue follows. Steatorrhea (foul-smelling, pale, bulky, and greasy stools) is common.[merck.com]
Chronic Diarrhea
  • Abstract A diagnosis of tropical sprue, an infrequent affliction of inhabitants and travelers in tropical regions, should be considered in patients with a compatible history, malabsorption, and chronic diarrhea.[ncbi.nlm.nih.gov]
  • CASE REPORT: The authors report two cases of American residents living in Thailand and Vietnam who had been suffering from chronic diarrhea, weight loss, being easily fatigued and nutritional deficiency and who dramatically responded after treatment for[ncbi.nlm.nih.gov]
  • Background Tropical sprue (TS) is a syndrome characterized by acute or chronic diarrhea, weight loss, and malabsorption of nutrients. It occurs in residents of or visitors to the tropics and subtropics.[emedicine.com]
Abdominal Cramps
  • A chronic phase of milder diarrhea, nausea, anorexia, abdominal cramps, and fatigue follows. Steatorrhea (foul-smelling, pale, bulky, and greasy stools) is common.[merck.com]
  • Risk factors are: Living in the tropics Long periods of travel to tropical destinations Symptoms Symptoms include: Abdominal cramps Diarrhea, worse on a high-fat diet Excess gas (flatus) Fatigue Fever Leg swelling Weight loss Symptoms may not appear for[ufhealth.org]
Abdominal Pain
  • Diarrhea may partially subside before nausea, abdominal pain, light-colored, greasy stools and generalized fatigue are experienced.[symptoma.com]
  • Vitamin D and calcium - may cause abdominal pain, bone pain, weakness, tingling. Vitamin K - risk of prolonged INR and haemorrhage. Steatorrhoea. Abdominal pain - may be mild and does not usually dominate the clinical picture.[patient.info]
  • During the initial phase: Acute diarrhea (gets worse on consuming oily-foods) Fever Weakness, fatigue Cramps in the abdomen causing severe abdominal pain Excess accumulation of gas, indigestion Nausea, vomiting, and dehydration Infants with Tropical Sprue[dovemed.com]
Intestinal Disease
  • INTRODUCTION: Two decades ago tropical sprue, Immunoproliferative Small Intestinal Disease (IPSID) and infections were common causes of malabsorption in India.[ncbi.nlm.nih.gov]
  • Abstract Aside from infectious intestinal diseases with known etiology, there is a group of gastrointestinal disorders mainly affecting the small intestine of individuals predominantly living in and less often visiting or returning from the Third World[ncbi.nlm.nih.gov]
  • IPSID, immunoproliferative small intestinal disease enteropathy malabsorption parasites sprue tropical Statistics from Altmetric.com Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the[doi.org]
  • Immunoproliferative small intestinal disease: portrait of a potentially preventable cancer from the Third World. Am J Med 1990 89 483–490. [ PubMed ] 60.[ncbi.nlm.nih.gov]
  • Baker S: Idiopathic small intestinal disease in the tropics . Crit Rev Trop Med 1982, 1 :197–254. Google Scholar 25.[link.springer.com]
Sore Mouth
  • TS is also known by several other names, including: Tropical Enteropathy Postinfective Tropical Malabsorption Idiopathic Tropical Malabsorption Syndrome Aphthae Tropical Cochin China Diarrhea Ceylon Sore Mouth Tropical Sprue Incidence The exact prevalence[hxbenefit.com]
  • Ceylon sore mouth. White flux. Diarrhea alba. Cochin China diarrhea. Psilosis. Aphthae tropical. Sp : Esprue tropical. Fr :Sprue (stéatorrhée) tropique. Ger : Tropische Sprue.[isradiology.org]
Purpura
  • Nonerosive upper gastrointestinal diseases include the following: Cutaneous burns [8] Whipple disease Connective tissue disorders Acquired immunodeficiency syndrome (AIDS) [2] Enteropathy, such as angioedema (idiopathic or hereditary) and Henoch-Schönlein purpura[emedicine.medscape.com]
Hyperpigmentation
  • Features suggestive of nutrient deficiencies like knuckle hyperpigmentation ( P 0.0001) and stomatitis ( P 0.001) were more common in patients with tropical sprue.[irjournal.org]

Workup

TS may be diagnosed in people indigenous to endemic regions and those who traveled there. Because up to ten years may pass until manifestation of first symptoms, a thorough medical history has to be obtained. There are no pathognomonic symptoms of TS. While an acute diarrhea may be caused by TS, this is not sufficient to confirm this diagnosis. Therefor, chronic gastrointestinal problems need to be detected.

After clinical examination, blood samples need to be analyzed to check for megaloblastic anemia and nutritional deficiencies. The former corresponds to disturbances regarding formation and maturation of erythrocytes and is characterized by reduced hematocrit and hemoglobin values whereas erythrocytic cell volume and erythrocytic hemoglobin content are increased. Vitamin B12 and folate levels are usually decreased. Additionally, hypoalbuminemia may be detected.

In order to distinguish steatorrhea caused by malabsorption from chronic diarrhea, stool should be tested for its fat content. While excretion of more than 15 g stool fat per day is diagnostic for steatorrhea, less than 7 g stool fat per day rule out the latter. D-xylose absorption tests may be very helpful to confirm malabsorption. In more than 90% of TS patients, D-xylose absorption is altered. Radiographic imaging with contrast agents such as barium sulfate may reveal dilation of the small intestine, thickening of the intestinal folds and therefore segmentation of the contrast agent.

So as to confirm TS, an endoscopic examination is required. Mucosal lesions are generally present but differ greatly in manifestation [7]. During the endoscopic examination, biopsies should be obtained for further analyses. Ongoing research focuses on non-invasive markers for small intestine integrity and function. In this line, Australian scientists proposed to utilize a 13 C-sucrose breath test to detect intestinal damage in children [8].

Macrocytic Anemia
  • Patients with tropical sprue typically present with macrocytic anemia due to malabsorption of folate and/or vitamin B(12).[ncbi.nlm.nih.gov]
  • Keywords Main Side Effect Main Drug Interaction Macrocytic Anemia Tropical Sprue Celiac Sprue These keywords were added by machine and not by the authors.[link.springer.com]
  • Past studies have indicated a megaloblastic macrocytic anemia, steatorrhea, impaired absorption of glucose, and abnormal x-ray patterns of the small bowel in untreated patients with tropical sprue.* The present study was initiated to evaluate the oral[jamanetwork.com]
  • Cf Celiac sprue. trop·i·cal sprue ( trop'ik-ăl sprū ) A disorder that occurs in warmer climates, often associated with enteric infection and nutritional deficiency, and frequently complicated by folate deficiency with macrocytic anemia.[medical-dictionary.thefreedictionary.com]
  • A macrocytic anemia is common with megaloblastic change in the bone marrow due to folate deficiency. Vitamin B12 deficiency takes longer to develop.[histopathology-india.net]
Macrocytosis
  • Neither patient was anemic, although one had hypersegmented polymorphonuclear leukocytes and both had macrocytosis and megaloblastic bone marrows.[ncbi.nlm.nih.gov]
  • Macrocytosis occurs early. Serum and erythrocyte levels of folate are low. Anaemia may also be hypochromic from defective absorption of iron. Jejunal biopsy shows shows partial villous atrophy which is not specific for tropical sprue.[histopathology-india.net]
  • Macrocytosis may be demonstrated in the gastric mucosa. Small bowel biopsy will disclose the morphologic changes previously discussed. Lactase deficiency is expected, but sucrase and maltase activity may be normal.[history.amedd.army.mil]
Megaloblastic Bone Marrow
  • Neither patient was anemic, although one had hypersegmented polymorphonuclear leukocytes and both had macrocytosis and megaloblastic bone marrows.[ncbi.nlm.nih.gov]
  • It is associated with a macrocytic anemia and megaloblastic bone marrow, and with histological and radiological changes in the small bowel. Its etiology remains unknown.[isradiology.org]

Treatment

If patients present with symptoms of acute diarrhea, TS is rarely diagnosed. Instead, symptomatic treatment will be realized in order to compensate for fluid loss, electrolyte imbalances and symptomatic anemia. Symptoms may be sufficiently severe to require urgent attention and hospitalization.

Only when blood screens reveal low levels of vitamin B12 and folate as well as megaloblastic anemia, malabsorption may be suspected. Deficient nutrients may not be limited to those characteristic for TS and should be replaced (e.g., 5 to 10 mg folate, per os, qd; 1 mg vitamin B12, i.m., qw). If fluid therapy is not sufficient to compensate for hemodynamic disturbances or if a severe case of anemia is registered, blood or blood product transfusions may be required. The anemia should improve considerably upon compensation for nutrient deficiencies [9].

Causative treatment is difficult due to the fact that the etiology of TS is not yet understood. It has been reported that antibiotics are effective in TS treatment. This could, however, not be confirmed in patients who contracted the disease in southern India. Tetracycline has been recommended for TS treatment. It should be administered in high doses for up to two months (250 mg, per os, qid) and in somewhat lower doses (250 mg, per os, bid) for another four months [10]. Tetracycline may be replaced with doxycycline. Antibiotic treatment may be extended to up to one year if the patient is improving but if the disease could not yet be cured after six months.

Relapses may occur. Therefore, any TS patient should be revised at least once a month. It should be verified if all nutrient deficiencies are indeed corrected, if water and electrolyte imbalances do not persist. If a patient does not respond at all after four weeks of treatment, differential diagnoses have to be considered.

Prognosis

Prognosis of TS is good if adequate treatment is provided. If left untreated, recurrences are frequent and mucosal damage may result in severe malabsorption, nutrient deficiencies and even malnutrition.

Etiology

The etiology of the disease is poorly understood. Endemic regions are India, Southeast Asia and the Caribbean. The fact that not only the indigenous population but also long-term visitors may contract TS led to the hypothesis of an infectious disease. To date, the most widely accepted hypothesis is that of enteropathogenic, toxin-producing coliform bacteria colonizing the small intestine, causing small intestine bacterial overgrowth and mediating mucosal damage. Such damage does not necessarily occur right after bacterial infection. Distinct genera of Enterobacteriaceae, mainly Enterobacter, Escherichia and Klebsiella have been associated with TS [1] [2] [3] [4].

In some cases, TS is detected in travelers that visited endemic regions months or even years before. It is surprising that the aforementioned are usually eliminated within days after infection but that they are able to persist for such a long time in the intestinal tract of TS patients. Thus, a variety of additional, as of yet unknown factors presumably affects symptom onset and disease progress. It has been speculated that other gastrointestinal infectious diseases may finally trigger TS. Further research has to be conducted to confirm this suspicion and to clarify the role of genetics, diet and environmental factors. Indeed, dietary fats and seasonal eating habits have been proposed to affect TS development.

Mucosal damage is associated with malabsorption of certain nutrients, particularly of vitamin B12  and folate, and these deficits cause megaloblastic anemia and other symptoms associated with nutrient deficiencies.

Epidemiology

As its name suggests, TS is endemic to tropical regions, even certain areas inside tropical regions of India, Southeast Asia and the Caribbean. It may be detected in patients that traveled to the aforementioned regions, especially if stays exceeded one month.

The overall incidence of the disease has been decreasing. It has been suggested that immediate use of antibiotics to treat cases of traveler's diarrhea may account for this trend. However, since the etiology of the disease is only poorly understood, no reliable conclusions can be drawn at this moment.

Absolute numbers concerning incidence and prevalence of TS are difficult to obtain. For Puerto Rico, a prevalence of up to 8% has been estimated.

No differences have been detected regarding males and females or people of different races. TS mainly affects adults, but can occasionally be observed in children.

Sex distribution
Age distribution

Pathophysiology

Enteropathogenic, coliform bacteria presumably trigger small intestine bacterial overgrowth and mucosal damage that finally cause the malabsorption syndrome TS. Possibly, an acute infection with the above mentioned bacteria provokes certain damage to the mucosal layer of jejunum and ileum. Subsequently, malabsorption of certain nutrients, particularly of vitamin B12 and folate, occur. Simultaneously, enteroglucagon levels increase and delay the intestinal transit. Small intestine bacterial overgrowth may result from delayed transit and an altered intestinal environment. Apparently, these processes not only depend on each other but also potentiate each other. In this context, folate deficiencies have been proposed to aggravate mucosal damage, which would re-initiate the vicious circle.

The physiological flora of the small intestine mainly consists in Streptococcus and Lactobacillus strains. Here, coliform bacteria are not part of the normal intestinal flora, but they are nevertheless commonly found. Coliforms are known to frequently trigger acute enteritis and subsequent diarrhea [5]. In this context, pathogenicity cannot be ascribed to certain species of coliform bacteria. It's rather the specific strain that may have adopted the facility to release exotoxins and to adhere to the intestinal mucosa by transformation, possibly also by transduction and conjugation. Enterotoxins released by coliform bacteria in the small intestine are grouped into highly antigenic, heat labile toxins and less antigenic, heat stable toxins.

As has been indicated above, TS mainly affects jejunum and ileum. Less frequently, pathological lesions are found in the duodenum and in the distal ileum in close proximity to the ileocecal valve. Stomach and colon are rarely affected.

Prevention

No direct evidence indicates that antibiotic prophylaxis can prevent tropical sprue.

Summary

Tropical sprues (TS) is a disease that may be diagnosed in people living in or traveling to certain parts of the Caribbean, India and Southeast Asia. It's etiology is poorly understood. The most widely accepted hypothesis is based on the assumption that patients become infected with enteropathogenic Enterobacteriaceae while staying in the above mentioned regions. A series of unknown factors may then trigger the disease in any moment and up to ten years after initial infection.

Pathohistologic examinations of tissue samples obtained from TS patients revealed severe mucosal damage in jejunum and ileum. Such damage is associated with malabsorption and thus results in nutrient deficiencies, particularly in vitamin B12 and folate deficits.

Acute TS is associated with diarrhea and fever. These symptoms subside and are often replaced with nausea, abdominal pain and fatigue. The latter corresponds to a symptomatic anemia that is caused by nutrient deficiencies.

TS may be suspected based on presentation, medical history and laboratory analysis of blood samples, but an endoscopic examination and biopsy analysis is necessary to confirm the diagnosis.

Treatment primarily consists in fluid therapy, correction of electrolyte imbalances and compensation for nutrient deficiencies. Prolonged antibiotic treatment is recommended for TS and usually shows good effects.

Patient Information

Tropical sprue (TS) is a rare disorder that may be diagnosed in people living in or traveling to certain parts of the Caribbean, India and Southeast Asia. It is not yet known how the disease is caused, but scientist suggest that TS may be initialized by an infection with certain bacteria such as enteropathogenic Escherichia coli strains. These bacteria may colonize the small intestine, adhere to the intestinal mucosa and release different toxins. This way, they are causing significant damage to the intestinal mucosa. Because one of the main functions of the small intestine is to absorb nutrients, it does not come as a surprise that nutrient deficiencies may result from lesions in jejunum and ileum. These nutrient deficits, however, affect different processes throughout the body, e.g. erythrocyte formation and maturation as well as enterocyte function. Thus, anemia may be developed and intestinal damage is further aggravated. To date, it is not understood why this chain of events is triggered in some patients while others are apparently able to eliminate the above mentioned bacteria within a few days.

Symptoms may manifest up to ten years after initial infection, i.e., after traveling to endemic regions. Acute diarrhea, malaise and fever are the earliest symptoms, but they are very unspecific. Diarrhea may partially subside before nausea, abdominal pain, light-colored, greasy stools and generalized fatigue are experienced. Patients presenting with such symptoms to their physician will receive fluid therapy and will be thoroughly examined in order to reveal the trigger of the symptoms. Therefore, blood samples will be analyzed. In case of TS, they may reveal nutrient deficiencies, particularly reduced vitamin B12 and folate levels, but also hemogram alterations due to the above mentioned anemia. In order to confirm diagnosis, however, an endoscopic examination has to be conducted, tissue samples have to be collected and analyzed microscopically.

If TS is confirmed, prolonged antibiotic treatment will be initiated. Any deficient nutrients will be replaced. Patients usually respond well but slow to such treatment, which is why it is generally administered for six months. During recovery, blood samples will be obtained regularly in order to detect possible relapses, nutrient deficiencies that remain without compensation and electrolyte imbalances.

References

Article

  1. Gray G. Tropical Sprue. In: Blaser M, Smith P, Ravdin J, eds. Infections of the Gastrointestinal Tract. New York: Raven Press; 1995:333.
  2. Klipstein, FA. Tropical Sprue. Gastroenterology. 1968; 54:275.
  3. Gorbach SL, Banwell JG, Jacobs B, et al. Tropical sprue and malnutrition in West Bengal. I. Intestinal microflora and absorption. Am J Clin Nutr. 1970; 23(12):1545-1558.
  4. Klipstein FA, Holdeman LV, Corcino JJ, Moore WE. Enterotoxigenic intestinal bacteria in tropical sprue. Ann Intern Med. 1973; 79(5):632-641.
  5. Cook GC. Aetiology and pathogenesis of postinfective tropical malabsorption (tropical sprue). Lancet. 1984; 1(8379):721-723.
  6. Green PH, Shane E, Rotterdam H, Forde KA, Grossbard L. Significance of unsuspected celiac disease detected at endoscopy. Gastrointest Endosc. 2000; 51(1):60-65.
  7. Klipstein FA, SJ B. Regarding the definition of tropical sprue. Gastroenterology. 1970; 58(5):717-721.
  8. Ritchie BK, Brewster DR, Davidson GP, et al. 13C-sucrose breath test: novel use of a noninvasive biomarker of environmental gut health. Pediatrics. 2009; 124(2):620-626.
  9. Nath SK. Tropical sprue. Curr Gastroenterol Rep. 2005; 7(5):343-349.
  10. Gilman A, ed. The Pharmacological Basis of Therapeutics. Vol 8. New York, NY: Pergamon Press Inc.; 1990.

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Last updated: 2018-06-22 10:40