Encomium: Theodore puck,a life in biophysics applied to medicine

The dopamine hypothesis of schizophrenia proposed that dopaminergic pathways are involved in the etiology of the disease. In particular, interest among psychiatrists has focused on the D₂ receptor because of its affinity to antipsychotic drugs. Recently a new dopamine receptor gene has been cloned, and named the dopamine D₃ receptor. The D₃ receptor is a potential site for antipsychotic drug action and may be involved in the pathophysiology of schizophrenia. We have carried out a linkage study between the susceptibility gene for schizophrenia and polymorphism of the dopamine D₃ receptor gene in two Japanese pedigrees. The LOD scores were negative for, all genetic models and for all affective status at a recombination fraction θ = 0. Linkage of DRD₃ has been excluded for the model 1 (dominant model) and the model13 (recessive model). The LOD score was - 3.43 at θ = 0 for model 1 (dominant model) and broad definition of affected status. These results were consistent with previous studies. © 1994 Wiley-Liss, Inc.     

Reduced oxidative function in gingival crevicular neutrophils in periodontal disease.

Measurable amounts of viable and functional polymorphonuclear neutrophils (PMNs) are recovered from pooled washings of the gingival crevice of healthy individuals. In the present study, we have assessed the ability of the PMNs removed from single healthy or diseased pocket sites to mount an oxidative burst when challenged with phorbol myristate acetate (PMA) and compared these activities with each other and with those obtained with autologous peripheral-blood PMNs. The oxidative burst after PMA stimulation was evaluated by using methods developed for the flow cytometer. The results showed that the PMNs collected from untreated disease sites were minimally responsive to PMA when compared with peripheral-blood PMNs collected at the same time from the same individual. Thus, whereas the peripheral-blood PMNs exhibited significantly lower resting oxidative product formation and a 500% increase when stimulated with PMA, all gingival-crevicular PMNs exhibited significantly higher resting formation of oxidized products but only a 150% increase after PMA stimulation. PMNs obtained from a consistently healthy site had significantly higher resting production of oxidized products and were able to mount the greatest absolute increase in oxidized products after PMA stimulation when compared with PMNs collected from diseases sites. Mechanical debridement of these diseased sites, which both reduced the bacterial numbers and restored clinical health, resulted in the recovery of gingival-crevicular PMNs that exhibited an oxidative burst more typical of that observed in PMNs obtained from healthy gingival sites and from the peripheral blood. This suggested that the PMNs collected from the diseased sites either had been exhausted by the large numbers of bacteria present in these sites or had been specifically inhibited by these bacteria.     

Factors predicting cases with unexpected clinical findings at necropsy.

AIMS/BACKGROUND: A major medical role for postmortem examinations is the detection of clinically unexpected disease processes contributing to death. The aim of the present study was to determine whether simple clinical parameters can predict the presence of important unanticipated findings at necropsy. METHODS: Prospective audit of adult necropsies carried out in a single year to assess the extent of unexpected findings at necropsy, to compare these cases with non-necropsied deaths to confirm they are a similar population and to seek features that predict which cases have unexpected necropsy findings. RESULTS: No correlation was found between age, sex, duration of in-hospital treatment, surgical intervention, clinical specialty, or necropsy request rates and incidence of unexpected findings in 187 adult necropsies. CONCLUSIONS: No parameters have been identified for patient selection to permit an increase in the yield of clinically unexpected findings. Until there is clear evidence that the current practice of patient selection is anything more than random, an increase in postmortem examination rates, as proposed by the Joint Working Party of the Royal College of Pathologists, the Royal College of Physicians of London and the Royal College of Surgeons of England in their report The Autospy and Audit, will increase the workload without necessarily producing a commensurate gain in knowledge.     

Alterations of the myocardial skeletal framework in acute myocardial infarction with and without ventricular rupture. A preliminary report

Thinning and dilatation (expansion) of the infarct region and complete rupture of the ventricular wall are significant complications of acute transmural myocardial infarction associated with increased morbidity and mortality. The pathogenesis of these related events is unknown. Recent studies of myocardial connective tissue have delineated an extensive array of intercellular and pericellular structures which serve as a skeletal framework and which may modulate contractile activity. We have employed a modified silver impregnation method to visualize the connective tissue components by light microscopy. To explore whether the skeletal framework is altered in acute myocardial infarction with and without ventricular rupture, we studied 9 human hearts at autopsy, and 4 canine infarcts of known duration. The human infarctions included 4 nonruptured cases with infarcts 1-5 days old, and 5 ruptured cases with infarcts 3-10 days old. Sections from normal, lateral, and central infarct or ventricular rupture sites were stained with silver. The normal tissue from each heart served as a control. Silver staining was moderately decreased in the lateral infarct zones, and markedly decreased in the central non-ruptured infarct zones. In the 5 ventricular rupture cases, the rupture site had no silver staining. A similar pattern was observed in the 4 canine infarcts. Thus, we conclude that the skeletal framework is markedly altered in the central zone of acute myocardial infarction. The acute changes of silver stained connective tissue may contribute significantly to the development of infarct expansion or ventricular wall rupture.     

Chemiluminescent response to pathogenic organisms: normal human polymorphonuclear leukocytes

Chemiluminescence (CL) is a sensitive indicator of phagocytosis and intracellular killing; however, little is known of the normal CL response by human polymorphonuclear leukocytes to different pathogenic microorganisms. We investigated the luminol-enhanced CL response of normal polymorphonuclear leukocytes to a number of common bacterial pathogens and two yeasts. We analyzed the CL response to viable and heat-killed microorganisms at 25 and 37 degrees C. The CL response to all microorganisms was greater and more rapid at 37 degrees C. Variable responses were observed with viable and heat-killed microorganisms; some were unaffected, whereas other demonstrated reduced CL. Each microorganism caused a reproducible response pattern, which could be placed into two general categories. In the first category were those which caused a rapid exponential rise and decay in CL: Enterobacter cloacae, Salmonella typhimurium, Shigella flexneri, Staphylococcus aureus, Candida albicans, and zymosan. In the second category were those which rose slowly over a longer time course to a poorly defined peak: Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, and Streptococcus pyogenes. The CL response also reflected serum opsonic activity. The effect of inactivated complement, factor B, and removal of specific antibody were investigated. Increasing the concentration of zymosan gave a proportional rise in peak CL; however, a strain of E. coli caused a variation in peak time rather than peak height. Different CL kinetics were shown for three strains of K. pneumoniae, possibly a result of each having different membrane or cell wall characteristics. This study defines the nature and factors affecting the normal CL response to a variety of common pathogenic microorganisms.     

Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

BACKGROUND. Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS. In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS. Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS. Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.     

Influence of perinatal malnutrition on adult physiological and behavioral reactivity in rats

A series of experiments examined the behavioral and pituitary-adrenal response to novelty of perinatally malnourished rats tested as adults after nutritional rehabilitation begun at weaning. Neither the behavioral measures of ambulation, rearing and defecation, nor the plasma corticosterone response to a brief exposure to an open field differentiated the previously malnourished subjects from controls. Similar to controls, previously malnourished subjects were also capable of displaying a graded corticoid elevation to environments increasingly different from the home cage. However, exploratory behavior, as measured by head-dip frequency and duration in the hole-board, was reduced in the previously malnourished rats. Although latency and amount of fluid consumed in a novel environment did not differ, previously malnourished rats were unable to use the cues associated with a consummatory behavior to modulate the pituitary-adrenal response to novelty. Thus, perinatal malnutrition does not influence either the behavioral or physiological activational response to novel stimulation but appears to alter the ability of the animal to use a consummatory behavior to modulate this response.