Biomedical subjects
Publications and source records attributed to E L Kaplan.
Rheumatic fever and rheumatic heart disease continue to be a problem for medical and public health communities--the fact that penicillin has failed to eradicate this disease process is irrefutable proof of the need for more laboratory, epidemiological, and clinical research.
In the developing countries of the world, rheumatic fever and rheumatic heart disease remain significant medical and public health problems
Serotypes of group A streptococci are still a major cause of pharyngitis and some post-infectious sequelae such as rheumatic fever. As part of the worldwide effort to clarify the epidemiological pattern of group A streptococci in different countries, the present study was conducted to assess the prevalence of Streptococcus pyogenes serotypes in Iran. A total of 1588 throat swabs were taken from healthy school children in the city of Gorgan during February and March 1999. Of those isolates, 175 resulted positive for group A streptococci. The distribution pattern was similar for girls and boys, with 10.8% and 11.2%, respectively. Urban school children showed a higher rate of colonization compared to those in rural areas. Serotyping was performed on 65 of the positive isolates using standard techniques, and only 21 (32%) were M-type isolates. Their profiles fell into four types with M1 predominating, which could reflect the presence of rheumatic fever in the region. However, when isolates were challenged for T-antigen types, nearly all were positive (94%). The pattern of T types was diverse (18 types), with the most common T types being T1 (26%), TB3264 (15%), TB\1-19 & B\25\1-19 (9.2%) and T2 & 2\28 (7.7%). When isolates were tested for opacity factor, only 23 (35%) were positive while 34 (52%) responded to the serum opacity reaction test. Although the number of isolates in this study was not sufficient to make any epidemiological conclusions, the scarcity of serotyping studies in Iran could render these data useful for future attempts to develop a streptococcal vaccine.
Since the mid-1980s, there has been a resurgence of severe forms of invasive group A streptococcal (GAS) disease in many Western countries. In Hong Kong, a similar increase has also been observed in recent years. One hundred seven GAS isolates collected from 1995 to 1998 from individuals with necrotizing fasciitis, toxic shock syndrome, meningitis, or other type of bacteremic sepsis (invasive group, n = 24) as well as from individuals with minor skin and throat infections (noninvasive group, n = 83) were characterized through serologic and/or emm sequence typing. Thirty-two M protein gene sequence types were identified. Types M1, M4, and M12 were the most prevalent in both the invasive group and the noninvasive group; together they accounted for 70.8 and 37.3% of the isolates, respectively. No clear pattern of skin and throat infection M types was observed. Type M1 was overrepresented in the invasive and pharyngeal isolates. The same pulsed-field gel electrophoresis pattern was shared by most invasive and all pharyngeal M1 isolates. Overall, resistance to erythromycin (32%) and tetracycline (53%) was high, but M1 isolates were significantly less likely to have resistance to either antimicrobial agent than non-M1 isolates. One novel emm sequence type, stHK, was identified in an isolate from a patient with necrotizing fasciitis. Minor emm gene sequence alterations were noted for 31 isolates, and for 13 of these isolates, deletion, insertion, or point mutations were seen in the hypervariable 50 N-terminal residues.
Invasive group A streptococcal (GAS) infections have been of increasing concern worldwide during the past 15 years. Spread of group A streptococci to contacts with resulting invasive infection has been reported in families, in residential nursing homes, and even from patients to health care workers. We report an instance of temporally related life-threatening group A streptococcal infection in a husband and 2 weeks later in his wife. This example further emphasizes the need for careful observation among family members and other close contacts of patients with invasive group A streptococcal infection. Although at present there are no universal recommendations for monitoring or for antibiotic prophylaxis of close contacts of persons with invasive GAS infection, when added to existing literature, this report suggests additional consideration is required.
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BACKGROUND: Despite the past 15 years of heightened awareness of the disease-causing potential of group A streptococci, the possible epidemiological influence of rapid changes in prevalent serotypes has not been fully appreciated. METHODS: We analysed throat cultures collected as part of routine medical care in a semi-closed community of nearly 500 children and adults between January, 1999, and April, 2000. beta-haemolytic streptococci from all positive cultures were characterised by serological grouping, T-agglutination pattern, and serotyping for M protein or opacity factor. FINDINGS: We saw an increase in the number of symptomatic individuals with pharyngitis beginning in mid-1999. Between July 1 and Dec 31, 1999, 111 (29%) of 378 throat cultures yielded group A streptococci, 102 (92%) of which were serotype M1. Between Jan 1 and Mar 31, 2000, 126 (45%) of 277 throat cultures yielded group A streptococci. Unexpectedly, 106 (84%) of these throat isolates were serotype M6, and only 16 (13%) were M1. 20 (28%) of the 71 individuals with M1 infection subsequently acquired infection with M6. INTERPRETATION: This rapid and almost complete shift in predominance of group A streptococcal serotype in this community draws attention to the dynamic epidemiology of these organisms. This change has important implications for further understanding the epidemiology of group A streptococcal infections, and for the development and use of a vaccine.
We compared recommended doses of 2 oral macrolide antibiotics (10 days of clarithromycin, 5 days of azithromycin) for eradicating group A streptococci from the throats of individuals aged > or = 12 years with symptomatic pharyngitis and a positive throat culture. Patients received either clarithromycin (250 mg b.i.d. for 10 days [n=260]) or azythromycin (500 mg on day 1, followed by 250 mg q.d. for 4 days [n=265]). Follow-up throat cultures were obtained both at 13--19 days and at 28--38 days. We evaluated 392 patients (median age, 26 years; clarithromycin, 194 patients; azyithromycin, 198 patients). Ten days of clarithromycin therapy was more effective than 5 days of azithromycin therapy in eradicating the organism (91% [176/194] vs. 82% [162/198]; P=.012). More than 97% of all streptococcal isolates were macrolide-sensitive. Whether these bacteriologic eradication rates were the result of the 2 macrolides compared or were due to differences in duration of therapy could not be determined, but the statistically significant difference in eradication of group A streptococci does raise additional questions about shortened courses of macrolide therapy for this common infection.
Rapid antigen detection tests (ADTs) are promoted for identification of group A streptococci (GAS) in the upper respiratory tract. Although debate persists about their sensitivity, most investigators consider ADTs to be highly specific. Nevertheless, reports continue to describe false-positive ADT results (positive ADT result, negative culture result). This study examined culture results from 522 adult patients with acute pharyngitis and a positive ADT result; unexpectedly, 15% had throat culture results negative for GAS. Normal bacterial flora from 30% of these "negative" culture results produced a positive ADT result. An ADT-reactive organism belonging to the Streptococcus milleri group was isolated from 1 culture; it carried group A carbohydrate antigen. Although S. milleri previously has been associated with false-positive ADT reactions, the frequency of this phenomenon is unknown. The present, large study suggests that false-positive ADT reactions may be more common than previously reported, an observation that must be precisely explained and epidemiologically and clinically defined.
HYPOTHESIS: Nesidioblastosis is an important cause of adult hyperinsulinemic hypoglycemia, and control of this disorder can often be obtained with a 70% distal pancreatectomy. DESIGN: The records of all adult patients operated on for hypoglycemia between 1974 and 1999 were reviewed retrospectively. Patients with the pathologic diagnosis of nesidioblastosis were contacted for follow-up (1.5-21 years) and are presented. Patients' results were compared with those of 36 other individuals with this disorder who were previously reported in the literature. SETTING: The University of Chicago Medical Center (Chicago, Ill), a tertiary care facility. PATIENTS: A consecutive sample of all patients operated on for hypoglycemia. INTERVENTIONS: Seventy percent distal pancreatectomy for all patients with nesidioblastosis, and maintenance therapy with verapamil hydrochloride for 2 patients. MAIN OUTCOME MEASURES: Achievement of normoglycemia with and without medication, development of insulin-dependent diabetes mellitus, pancreatic exocrine insufficiency, and need for reoperation. RESULTS: Of 32 adult patients who underwent surgical exploration for hyperinsulinemic hypoglycemia at our institution, 27 (84%) were found to have 1 or more insulinomas, and 5 (16%) were diagnosed with nesidioblastosis. Each patient with nesidioblastosis underwent a 70% distal pancreatectomy. Follow-up duration for the 5 patients ranged from 1.5 to 21 years, with 3 patients (60%) asymptomatic and taking no medications, and 2 patients (40%) experiencing some recurrences of hypoglycemia. The 2 patients with recurrences are now successfully treated with a calcium channel blocker, an approach, to our knowledge, never before reported for adult-onset nesidioblastosis. CONCLUSIONS: Nesidioblastosis is an uncommon but clinically important cause of hypoglycemia in the adult population, and must always be considered in a patient with a presumptive preoperative diagnosis of insulinoma. This study indicates that a 70% distal pancreatectomy is often successful in controlling hypoglycemia, and rarely results in diabetes mellitus. However, the optimal treatment of this disorder remains to be determined.
OBJECTIVE: To evaluate the efficacy of oral penicillin V and intramuscular benzathine penicillin G (BPG) in eradicating group A streptococci from the upper respiratory tract. METHODOLOGY: Two randomized, single-blind, multicenter antibiotic efficacy trials in children using recommended doses of either oral penicillin V or intramuscular BPG for treatment of acute-onset pharyngitis associated with isolation of group A streptococci were conducted. Throat examinations and cultures were obtained at enrollment and on days 5 to 8, 10 to 14, and 29 to 31. RESULTS: Thirty-five percent of 284 evaluable patients treated with oral penicillin V and 37% of BPG-treated patients were microbiologic treatment failures at either 10 to 14 or 29 to 31 days. CONCLUSIONS: Although these findings do not provide sufficient evidence to change current treatment recommendations or public health policy, important questions are raised about currently recommended penicillin doses, about the role of the carrier state, and possibly about adequate bioavailability of intramuscular BPG. These findings require confirmation.
BACKGROUND: Although pheochromocytomas are believed to account for fewer than 0.3% of all cases of hypertension, aggressive diagnostic and surgical intervention is recommended whenever a pheochromocytoma is suspected because uncontrolled catecholamine release from the tumors can lead to catastrophic consequences. Many biochemical diagnostic and imaging localization tests exist for detecting pheochromocytomas. We sought to evaluate the sensitivity of these tests used over a 35-year period at a single institution. METHODS: Thirty-five patients with complete medical records who had pathologically confirmed pheochromocytomas between 1962 and 1997 at the University of Chicago Hospitals were identified. Sensitivity and 95% confidence intervals were calculated for 12 laboratory diagnostic tests and 5 imaging studies. RESULTS: The most sensitive laboratory diagnostic tests in our study were plasma total catecholamines (95%) and urine total metanephrines (100%). Testing for urine vanillylmandelic acid, while less expensive and easier to perform than many other tests, had a slightly lower sensitivity (89%). The most sensitive imaging tests in the study were magnetic resonance imaging (100%) and iodine I-131 metaiodobenzylguanidine scintigraphy (100%). The more often used computed tomography had only 88% sensitivity. Localization was safely and successfully performed on two pregnant patients using magnetic resonance imaging and ultrasound. CONCLUSIONS: By properly choosing from the wide array of laboratory diagnostic and imaging tests, pheochromocytomas can be identified and localized with nearly 100% sensitivity. These tests should be performed in any patient for whom the diagnosis of pheochromocytoma is being considered.
The optimization of a series of anilide derivatives of (R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC(50) = 35 +/- 1.4 microM). It was found that small electron-withdrawing groups on the ortho position of the anilide, i.e., chloro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailability of the compounds in this series is optimal (as measured by AUC) when the anilide is substituted at the 4-position with an electron-withdrawing group (i.e., carboxyl, carboxyamide, and sulfoxyamide). N-(2-Chloro-4-isobutylsulfamoylphenyl)-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inhibits PDHK in the primary enzymatic assay with an IC(50) of 13 +/- 1.5 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 micromol/kg, and increases the ex vivo activity of PDH in muscle, kidney, liver, and heart tissues. However, in contrast to sodium dichloroacetate (DCA), these PDHK inhibitors did not lower blood glucose levels. Nevertheless, they are effective at increasing the utilization and disposal of lactate and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.
N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
BACKGROUND: The sequelae during the first two decades after acute hepatitis C virus (HCV) infection have been well studied, but the outcome thereafter is unknown. OBJECTIVE: To conduct an extended study of the natural history of HCV infection by using archived serum specimens originally collected between 1948 and 1954. DESIGN: Retrospective cohort study. SETTING: A university, a Veterans Affairs medical center, and a medical follow-up agency that had access to the serum specimens and accompanying demographic and medical records. PARTICIPANTS: 8568 military recruits who were evaluated for group A streptococcal infection and acute rheumatic fever between 1948 and 1954. Blood samples were taken from the recruits and, after testing, were stored frozen for almost 45 years. MEASUREMENTS: The presence of antibodies to HCV was determined by enzyme-linked immunoassay, supplementary recombinant immunoblot assay, and polymerase chain reaction for HCV RNA. Morbidity and mortality were also assessed. RESULTS: Of 8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay and recombinant immunoblot assay. The rate was 1.8% among the African-American persons and 0.1% among the white persons in the total sample (relative risk, 25.9 [95% CI, 8.4 to 80.0]). During the 45-year follow-up, liver disease occurred in 2 of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the 17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%) had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to 2.6]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years after the original phlebotomy, 5 (29%) died of non-liver-related disease a median of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes. One hundred nineteen HCV-negative persons (1.4%) died of liver disease. CONCLUSIONS: The rate of HCV infection from 1948 to 1954 among a sample of military recruits parallels that among present-day military recruits and volunteer blood donors. During 45 years of follow-up, HCV-positive persons had low liver-related morbidity and mortality rates. This suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought.
Elevated levels of B lymphocytes with a unique surface alloantigen have been reported to be characteristic of patients with acute rheumatic fever or rheumatic heart disease. Mouse monoclonal antibodies (mAbs) to this alloantigen have been proposed as being useful in identifying individuals at risk for the development of these sequelae of group A streptococcal infection. However, previous studies have suggested that the discriminating ability of the mAbs was highest when the mAbs were made by using lymphocytes from the same ethnic population. To confirm and extend this observation, additional mouse mAbs were developed and their properties defined. These three mAbs-PG-12A, PG-13A, and PG-20A-reacted with B cells from more than 90% of North Indian patients with acute rheumatic fever or rheumatic heart disease. Each of these three new mAbs identified the highest levels of reactive B cells in patients with active acute rheumatic fever. Lower levels of positive reacting lymphocytes were found in individuals with quiescent chronic rheumatic heart disease, and markedly reduced percentages of reactive cells were observed in normal control subjects. The proportion of reactive lymphocytes in individual patients varied according to which of the three was tested, suggesting the possibility of a spectrum of "rheumatic" epitopes in susceptible individuals. The data further suggested that enhanced discriminatory ability for identifying "at-risk" susceptible patients could be obtained by testing with a combination of mAbs. If reduction in the incidence of acute rheumatic fever can be facilitated by early identification of susceptible individuals, accurate and sensitive detection of a marker antigen would result in more cost-effective public health measures. Additional population studies are required to more precisely define and confirm these detection techniques.
This study examines the management of patients diagnosed with pheochromocytoma at a major academic teaching hospital. The findings indicate that most patients can be safely managed as outpatients preoperatively, resulting in significantly shorter hospitalizations and no adverse sequelae.