The debrisoquin hydroxylation phenotype does not predict the metabolism of phenytoin.

Phenytoin plasma elimination kinetics and accrual of phenytoin metabolites in urine were studied in seven rapid and five slow hydroxylators of debrisoquin. There was no interphenotypic difference in phenytoin clearance, plasma half-life, volume of distribution, maximum rate of metabolism (Vmax), or Michaelis-Menton constant (Km). The total recovery of metabolites as percentage of given dose and the metabolite profiles in urine were similar for the two debrisoquin hydroxylator phenotypes. Similarly, no differences were observed between the groups with respect to stereoselective production of either dihydrodiol or para-phenolic metabolites of phenytoin. The debrisoquin hydroxylation phenotype was also investigated in 74 epileptic patients treated with phenytoin. Vmax and Km were graphically estimated from plasma concentrations at varying phenytoin dosage regimens in 36 of the patients. There was no correlation between the debrisoquin hydroxylation index and Vmax or Km. We conclude that the debrisoquin hydroxylation phenotype has no predictive value in guiding phenytoin dosage.

Absolute configuration of (+)-5-(o-hydroxyphenyl)-5-phenylhydantoin, the major metabolite of 5,5-diphenylhydantoin in the dog.

5-(3-Hydroxyphenyl)-5-phenylhydantoin (m-HPPH) has been resolved by crystallization of the brucine salts. The (+) enantiomer has been converted to (-)-5-cyclohexyl-5-phenylhydantoin, a compound previously demonstrated to have the R configuration. The R configuration can accordingly be assigned to (+)-m-HPPH, the principal metabolite of 5,5-diphenylhydantoin (phenytoin) in the dog.

Advances in the control of perioperative sepsis in total joint replacement.

Postoperative infection remains one of the most devastating complications of total joint arthroplasty. An improved understanding of the pathogenesis of prosthetic joint infection has led to a reduction in its incidence. Measures to prevent infection should begin in the planning stage of joint replacement and continue from the time of surgery for the duration of the implant.

Schistosomiasis.

Schistosomiasis is a curable parasitic infection that, if left untreated, can persist for 30 years even though the parasite cannot reproduce in its human host. Tissue pathology, particularly of the GI and GU tracts, is associated with the granulomatous immune response to parasite eggs. Schistosomiasis is not endemic to the United States because the specific snail intermediate hosts required for transmission are absent. Physicians in North America will see acute and chronic forms of schistosomiasis in travelers and former residents of endemic areas. Therapy with praziquantel is indicated for all species of schistosomes and all clinical manifestations of schistosomiasis.

Gastrointestinal infections in the immunocompromised host.

Gastrointestinal disease is a significant cause of morbidity and mortality in the immunocompromised patient. This article focuses on the infectious gastrointestinal complications associated with the treatment of malignant disease and with solid organ transplantation but not HIV. Gastrointestinal defenses and the various mechanisms by which they are impaired are reviewed. The major pathogens and malignancies of this patient population and an approach to their diagnosis, treatment, and prevention are discussed.

The American Society of Tropical Medicine and Hygiene initiative to stimulate educational programs to enhance medical expertise in tropical diseases.

More than a decade ago, at a time when current and emerging tropical diseases posed growing threats to the United States, expert panels convened by the Institute of Medicine of the U.S. National Academy of Sciences concluded that medical expertise within the United States competent to address diseases of the tropics had declined. Recognizing a national need to encourage and enhance such, The American Society of Tropical Medicine and Hygiene developed a program to stimulate new postgraduate medical education in diseases of the tropics. The Society formally requested academic institutions within the United States and Canada to propose new postgraduate programs. To assure the quality of these new curricular offerings, the Society developed an outline of key areas of competency and agreed to offer an examination that would grant physicians a Certificate of Knowledge in Clinical Tropical Medicine and Travelers Health. The certifying examination was to be an integral component of a program to stimulate academic institutions to provide instructional programs in tropical diseases and to encourage physicians to become trained, evaluated, and recognized for their knowledge of clinical tropical diseases and travelers' health. The Society's initiative to stimulate educational programs in tropical medicine is reviewed.

Large epidemics of hemorrhagic fevers in Mexico 1545-1815.

In 1545, twenty-four years after the Spanish conquest of the Aztec empire, an epidemic of a malignant form of a hemorrhagic fever appeared in the highlands of Mexico. The illness was characterized by high fever, headache, and bleeding from the nose, ears, and mouth, accompanied by jaundice, severe abdominal and thoracic pain as well as acute neurological manifestations. The disease was highly lethal and lasted three to four days. It attacked primarily the native population, leaving the Spaniards almost unaffected. The hemorrhagic fevers remained in the area for three centuries and the etiologic agent is still unknown. In this report we describe, and now that more information is available, analyze four epidemics that occurred in Mexico during the colonial period with a focus on the epidemic of 1576 which killed 45% of the entire population of Mexico. It is important to retrieve such diseases and the epidemics they caused from their purely historical context and consider the reality that if they were to reemerge, they are potentially dangerous.

Differential perpetuation of malaria species among Amazonian Yanomami Amerindians.

To determine whether malaria perpetuates within isolated Amerindian villages in the Venezuelan Amazon, we surveyed malaria infection and disease among 1,311 Yanomami in three communities during a 16-month period. Plasmodium vivax was generally present in each of these small, isolated villages; asymptomatic infection was frequent, and clinical disease was most evident among children less than five years of age (odds ratio [OR] = 6.3, 95% confidence interval [CI] = 1.4-29.2) and among persons experiencing parasitemias > or = 1,000 parasites/mm3 of blood (OR = 45.0, 95% CI = 5.5-370.7). Plasmodium falciparum, in contrast, was less prevalent, except during an abrupt outbreak in which 72 infections resulted in symptoms in all age groups and at all levels of parasitemia, and occasionally were life-threatening. The observed endemic pattern of P. vivax infection may derive from the capacity of this pathogen to relapse, while the epidemic pattern of P. falciparum infection may reflect occasional introductions of strains carried by immigrants or residents of distant villages and the subsequent disappearance of this non-relapsing pathogen.

An outbreak of Chagas' disease in southwestern Bahia, Brazil.

An outbreak of 20 cases of acute Chagas' disease followed the movement of Triatoma infestans into the county of Riacho de Santana, Bahia, Brazil. The outbreak was unusual in that the majority of cases occurred in adults. Vector control measures were implemented. Three years after the outbreak, a rural community was examined to determine the extent of human infection and disease due to Trypanosoma cruzi. Ninety of 440 residents (20.5%) had serologic evidence of infection, but rates of electrocardiographic (EKG) abnormalities were low. Comparison of age-specific rates of seropositivity and EKG abnormalities with rates from areas with endemic Chagas' disease supported the hypothesis of a recent epidemic. Control measures appear to have interrupted transmission in the region.

A three-year follow-up study of infection with Trypanosoma cruzi and electrocardiographic abnormalities in a rural community in northeast Brazil.

The relationship between parasitemia, seroreactivity to Trypanosoma cruzi, and electrocardiographic abnormalities was studied in 115 individuals from a rural community in northeast Brazil where Chagas' disease is endemic. Vector control measures were introduced, and after 3 years 106 of the original participants were located and re-examined. Serum antibodies to T. cruzi were measured by complement fixation and indirect fluorescent antibody tests and parasitemia by xenodiagnosis and blood cultures. On both examinations more seropositive children than seropositive adults showed parasitemia, and parasitemia was more likely to persist over the 3-year period in younger individuals. Electrocardiographic (ECG) abnormalities were seen more frequently in seropositive individuals without parasitemia. However, ECG abnormalities, as expected, were more prevalent in older individuals and therefore no specific inverse relationship between ECG findings and parasitemia could be shown. The decreased prevalence of infection noted in younger individuals following the introduction of vector control measures indicates that this approach limited transmission.

Megaesophagus and seroreactivity to Trypanosoma cruzi in a rural community in northeast Brazil.

The relationship of symptoms and radiographic abnormalities suggestive of esophageal motility disorders with electrocardiographic (ECG) alterations and seroreactivity to Trypanosoma cruzi was studied in a defined population in a rural area endemic for Chagas' disease in Bahia, Brazil. Between January and June 1981, 680 individuals 5 years of age or older were examined with serologic tests, ECGs and questionnaires for esophageal motility disorder. Of these, 39.9% were seropositive for Chagas' disease. Symptoms of dysphagia occurred 2.5 times more frequently among seropositive individuals than among seronegative individuals. Radiographic esophageal abnormalities were 3.6 times more frequent among seropositive individuals than among seronegative individuals in the symptomatic group. Symptoms and radiographic abnormalities were more common in men than in women although this was not statistically significant. Among seropositive individuals the percentage with symptoms of dysphagia increased with age, with a peak prevalence rate of 23.9% in the 45- to 64-year-old age group. Also, in the seropositive group, 41.7% with X-ray abnormalities of the esophagus and 26.3% with symptoms of dysphagia presented an abnormal ECG.

Bubonic leishmaniasis: a common manifestation of Leishmania (Viannia) braziliensis infection in Ceara, Brazil.

Enlarged regional lymph nodes have been reported to accompany the cutaneous lesions of Leishmania (Viannia) braziliensis (= L. braziliensis). A survey in Ceara State, Brazil indicated that 77% of persons (456 of 595) with parasitologically confirmed cutaneous leishmaniasis reported lymphadenopathy in addition to skin lesions. A group of 169 persons with recently diagnosed leishmaniasis and lymph nodes measuring > or = 2 cm in diameter (mean = 3.6 cm, maximum = 10.5 cm) underwent detailed clinical examination. Lymphadenopathy preceded the skin lesions in more than two-thirds of these, on the average by two weeks. Cultures of lymph node aspirates yielded Leishmania more frequently (86%) than cultures of aspirates of skin (53%) or biopsies of skin (74%). Parasites were isolated from the peripheral blood of one patient. Persons with lymphadenopathy gave a history of fever and had enlarged livers or spleens more often than a comparison group of 50 persons with cutaneous lesions but no lymphadenopathy. Persons with lymphadenopathy had more intense leishmanin skin reactions and lymphocyte proliferation following stimulation with specific antigens, whereas persons without lymphadenopathy had a higher frequency of previous infection. Isolates of parasites from both groups were identified as L. braziliensis. These data demonstrate the early spread of L. braziliensis beyond the skin and suggest differences in host immunity between persons with and without lymphadenopathy. Leishmaniasis braziliensis should be considered in cases of unexplained lymphadenopathy in endemic areas.

Salmonella prosthetic valve endocarditis.

Four cases of Salmonella prosthetic valve endocarditis have been reported previously in the English medical literature (Fraser et al. 1967; Yamamoto et al., 1974; Shanson et al., 1977; Bassa et al., 1989). This report describes a fifth case in a 62-year-old woman who developed tricuspid valve endocarditis after an episode of Salmonella gastroenteritis, and reviews prior cases of Salmonella prosthetic valve endocarditis.

Hypolipidemic activity of antiepileptic 5-phenylhydantoins in mice.

Administration (20 mg/kg i.p.) of antiepileptic 5-phenylhydantoins phenytoin, ethotoin, mephenytoin, and selected metabolites to mice over a period of 16 days produced lower serum concentrations of cholesterol and triglycerides with most of the compounds studied. Several compounds were more effective hypolipidemic agents than clofibrate at 150 mg/kg per day. Several N-alkylated derivatives of the most active compound, 5-ethyl-5-phenylhydantoin, a metabolite of mephenytoin, displayed activities equal to those of the underivatized compound. These in vivo studies suggest that antiepileptic phenylhydantoins, when used in chronic therapy in man, could possibly act as hypolipidemic agents.

A three year follow-up of chemotherapy with oxamniquine in a Brazilian community with endemic schistosomiasis mansoni.

Oral oxamniquine was tested as a control strategy for endemic schistosomiasis in a rural area of Bahia, Brazil. Adults were treated with a single dose (12.5 to 15 mg per kg) and children (less than 12 years old) with a total of 20 mg per kg in two doses. The 191 (infected) persons treated represented 69% of the infected population in the study area. Follow-up stool examinations (Kato-Katz method) at one, 3, 6, 13, 25 and 33 months showed the cure rate declining from 80% at three months to 46% at 33 months. Over one half of those not cured showed a decrease in egg counts throughout the follow-up which, after 33 months, remained 66% below the pre-treatment levels. Stool examinations conducted on all study area residents during three years before chemotherapy showed the prevalence and intensity of Schistosoma mansoni infection to be high and stable. 33 months after the chemotherapy the prevalence was 41% and for infected individuals the geometric mean egg count was 121 epg, a decline of respectively 35% and 40% from pre-treatment levels for each index. Chemotherapy of infected persons with oxamniquine protected the community as a whole from high worm burdens for almost three years, although at this point the prevalence began to rise towards pretreatment levels.

The burden of Leishmania chagasi infection during an urban outbreak of visceral leishmaniasis in Brazil.

First noted in the city of Teresina in 1981, the last decades have witnessed a remarkable increase in urban transmission of American visceral leishmaniasis (VL) in many Brazilian cities. Teresina, the site of this study, has faced two large outbreaks of VL. The first occurred from 1981-1985 when almost 1000 new cases were reported. The second started in the 1990s, and between 1993 and 1996 more than 1200 new cases were detected. This report describes the prevalence of infection with Leishmania chagasi in Teresina at the end of the second outbreak and gives estimates of the number of people who became infected during the epidemic. Between June 1995 and May 1996, 200 households were chosen at random from a list of addresses covering about 93% of Teresina's urban households. In each household, one person over the age of 1 year was screened for Leishmania antibodies and skin-tested. Nearly 50% of persons had a positive leishmanin reaction, but only 13.9% had detectable antibodies to L. chagasi. While prevalence estimates based on the leishmanin skin-test increased with age (P<0.001), those based on serological tests showed a lesser, and non significant, variation with age (P=0.31). Using a geometric growth equation, and assuming that the annual distribution of clinical cases may serve as an approximation to what would have been the distribution of infections by year, we estimated that over 320000 persons were infected during the epidemic. Little is known about the epidemiology of VL in urban areas, where social networks, population density, and relationships of housing with the natural environment are more varied and complex than in the rural scene. In those areas, control interventions have failed to eliminate transmission of the parasite and prevent new epidemics. Further epidemiological studies of VL in urban areas might be needed to inform control actions.

Hypolipidemic activity of phthalimide derivatives V: Reduced and hydrolytic products of simple cyclic imides.

A series of cyclic imides and related compounds have previously been shown to possess hypolipidemic activity at the low dose level of 20 mg/kg/d. Hydrolytic and reduced products of the cyclic imides were synthesized and examined to discern if possible metabolic products were the active chemical species of these hypolipidemic agents. Phthalimide proved to be the most active cyclic imide tested. Unfortunately, the new products did not, in general, improve hypolipidemic activity in rodents. The exceptions were piperidine which demonstrated improved hypotriglyceridemic activity, and 3,4,5,6-dibenzohomopiperidin-2-one, which demonstrated improved hypocholesterolemic activity compared to phthalimide.

Leishmanial infections: a consideration in travellers returning from abroad.

Seven cases of leishmaniasis, including a fatal case of visceral leishmaniasis and 6 cases of dermal leishmaniasis, were seen in Boston over a four-year period. Diagnosis was made by isolation of organisms in culture or by identification of organisms in stained preparations of tissue. Proper management of patients with leishmanial infections requires an appreciation of the geographical strain differences of each species.

Hypolipidemic activity of 3- and 4-phenyl-piperidine-2,6-diones and selected N-substituted derivatives.

Three- and 4-phenyl-piperidine-2,6-dione derivatives were investigated for hypolipidemic activity at 20 mg/kg/day intraperitoneally in rodents. The 3-phenyl compound afforded the best activity and effectiveness in both normal and hyperlipidemia-induced mice. The agent lowered lipids by blocking the de novo hepatic synthesis of cholesterol and triglycerides, specifically at the sites of ATP-dependent citrate lyase, acetyl CoA synthetase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. The agent caused a more rapid clearance of cholesterol by the fecal route. Cholesterol levels of the chylomicrons, very low density lipoprotein and low density lipoprotein (LDL) were reduced, whereas high density lipoprotein cholesterol was significantly elevated after drug administration. Triglyceride content was lowered in the chylomicron and LDL fractions. These modulations of lipid content of serum lipoproteins by the drug suggest a favorable situation for treatment of hyperlipidemic states.

Experimental Chagas' disease in dogs. A pathologic and ECG study of the chronic indeterminate phase of the infection.

Pathology of the chronic latent phase of Chagas' disease is poorly understood. In our experiment, nine dogs were inoculated with Trypanosoma cruzi and acute disease developed within 15 to 25 days, followed by a chronic asymptomatic period that varied from eight months to three years, at which time the animals were killed. Although ECG changes were minimal, all animals showed a mild focal chronic myocarditis, with a few microscopic foci of fibrosis. Focal or diffuse fibrosis, scleroatrophy, and fatty replacement were present in various parts of the conducting system, especially in the atrioventricular node, the distal portion of His' main bundle, and the initial portion of the right bundle. These lesions were considered to be sequelae from inflammation and necrosis during the acute phase of the infection. In addition to characterizing the lesions of the chronic indeterminate phase of Chagas' disease in the canine model, the present findings suggest that the lesions may be responsible for ECG changes that may appear in subjects with otherwise asymptomatic T cruzi infection.