Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms.

Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their efficacy in preventing soman-induced convulsions in rats pretreated with the oxime HI-6 to increase survival time, along with various doses of the test compounds (IM) either in the absence or presence of atropine sulfate (16 mg/kg, IM) 30 minutes prior to a soman challenge dose (180 micrograms/kg, SC; equivalent to 1.6 x LD50) that produced 100% convulsions. Without atropine sulfate, only tertiary anticholinergics (scopolamine, trihexyphenidyl, biperiden, benactyzine, benztropine, azaprophen and aprophen), caramiphen, carbetapentane and MK-801 were effective anticonvulsants. In the presence of atropine sulfate, the benzodiazepines (diazepam, midazolam, clonazepam, loprazolam and alprazolam), mecamylamine, flunarizine, diphenylhydantoin, clonidine, CGS 19755 and Organon 6370 studied were effective. We have examined the possibility that diazepam may exert some of its anticonvulsant effects through cholinergic mechanisms and found that a reduced release of ACh into synapses after diazepam and atropine treatment may account for diazepam's anticonvulsant activity against soman. We also found that at anticonvulsant doses biperiden and trihexyphenidyl each significantly reversed the effects of soman on striatal levels of DOPAC and HVA, the metabolites of dopamine, and have concluded that in addition to actions on muscarinic receptors, the anticonvulsant effects of these anticholinergics in soman poisoning may be partially related to their actions on the striatal dopaminergic system. These findings allow us to postulate that central muscarinic cholinergic mechanisms are primarily involved in eliciting the convulsions following exposure to soman and that subsequent recruitment of other excitatory neurotransmitter systems and loss of inhibitory control may be responsible for sustaining the convulsions and for producing the subsequent brain damage. Future studies to confirm these neuropharmacological mechanisms are proposed.     

Cholescintigraphy in the detection of cholelithiasis: a review of 23 cases and a case report demonstrating the sequential evolution of the appearance of the gallbladder defect

Cholescintigraphy of cholelithiasis has been reported as a defect or photon deficient area in the gallbladder. We present the case of a patient with gallstones whose cholescintigraphic study showed a sequential evaluation of the scan appearance from a defect, to a septation, a hole, and finally a filled-in appearance. Cholescintigrams and histopathologic findings after cholecystectomy of another 22 patients with cholelithiasis were also retrospectively reviewed. The results of the study concluded that: cholelithiasis is rarely demonstrated by cholescintigraphy and nonvisualization of the gallbladder may be due to acute or chronic cholecystitis associated with cholelithiasis.     

Calculation of Hydrolytic Rate Constants of Poly(ortho ester)s from Molecular Weights Determined by Gel Permeation Chromatography

Purpose. To obtained rate constants from weight-averaged (M_w) or z-averaged (M_z) molecular weights for polymers of Schule-Flory distribution and undergoing random scission. These constants were compared with those obtained by parallel ¹HNMR studies. Methods. The hydrolysis of two poly(ortho ester)s were followed by ¹HNMR and gel permeation chromatography (GPC). Results. Equations to convert number-averaged (M_n), M_w and M_z into fraction of backbone remaining (f_c) were derived. First-order hydrolytic rate constants of two poly(ortho ester)s; DETOSU-HD and DETOSU-CDM were calculated using these relationships. The rate constants calculated from ¹HNMR, M_z and M_w were 0.215, 0.218 and 0.182 hr^–1, respectively, for DETOSU-CDM and 0.152, 0.086 and 0.038 hr^–l for DETOSU-HD. The large discrepancy in the rates determined by ¹HNMR and GPC in the latter case was attributed to that the detector response (refractive index) of the monomers was lower than that of the high molecular weight polymer. The difference is small in the case of DETOSU-CDM, and the rates calculated from GPC data were comparable or nearly identical to that obtained from ¹HNMR data. Conclusions. Although GPC can yield rapid and valuable kinetic data for the degradation of biodegradable polymers, the system, however, must be carefully calibrated to account for the variations in Mark-Houwink coefficients and in the response of the mass detector between the high and low MW polymers.     

The HK/MBD Questionnaire: Replication and Validation of Distinct Factors in a Nonclinical Sample

Although Tarter et al.'s (1977) HK/MBD questionnaire has been found useful in subtyping populations of clinical alcoholics, its potential utility in nonclinical populations has yet to be determined. The current study examined the family history, personality, and substance use/abuse correlates of Tarter et al.'s HK/MBD questionnaire and factor analytically derived subscales (Alterman and McLellan, 1986) in a nonclinical sample of 580 young, adult males. In addition, a factor analysis of the HK/MBD questionnaire was undertaken to assess the extent to which the factor structure determined on a clinical alcoholic sample replicates in a nonclinical sample. Results indicated that each of the HK/MBD subscales showed relatively unique patterns of correlations with the various personality measures employed suggesting that they are measuring separate constructs. Perhaps of greatest importance, the HK/MBD items that appear to be of greatest relevance for understanding substance use/abuse are those related to antisocial behavior. Finally, the factor structure of the HK/MBD questionnaire in the nonclinical sample was found to be quite similar to the structure obtained in a clinical sample. These results demonstrate the multidimensional structure of the HK/MBD questionnaire and the utility of using the more homogeneous subscales in research with both clinical and nonclinical samples.     

Improved Scoring System to Assess Adult Donors For Cadaver Renal Transplantation

We previously proposed a quantitative approach to assess donor organs for cadaver renal transplantation. To improve on our original scoring system, we studied 34 324 patients who received cadaver renal transplants from adult donors between 1994 and 1999 and were reported to the UNOS Scientific Renal Transplant Registry. A scoring system was developed from five donor variables (age, 0-25 points; history of hypertension, 0-4; creatinine clearance before procurement, 0-4; cause of death, 0-3; HLA mismatch, 0-3) that showed a significant correlation with renal function and long-term graft survival. Cadaver kidneys were stratified by cumulative donor score: grade A, 0-9 points; grade B, 10-19; grade C, 20-29; and grade D, 30-39. The influence of donor score on renal function and graft survival was most severe above 20 points, designated 'marginal' kidneys. In summary, a donor scoring system developed from a large population database was useful in predicting outcome after cadaver renal transplantation. The improved system provides a quantitative approach to evaluation of marginal kidneys and may improve allocation of these organs in cadaver renal transplantation.     

Event-related potentials elicited during a visual Go-Nogo task in adults with phenylketonuria.

OBJECTIVE: The aim of the present study was to examine the nature of previously reported deficits in sustained attention and response inhibition in adults with the developmental disorder, phenylketonuria (PKU). METHODS: This study used event-related potentials (ERPs) to examine the performance of PKU adults (n=9) and a matched control group (n=9) on a visual Go-Nogo task. RESULTS: Comparison of behavioural measures between the PKU and control groups failed to reach statistical significance, yet analysis of the ERPs showed statistically significant amplitude reductions in the P1 and N1 components elicited following presentation of stimuli, and a reduction in the amplitude of the N2 component elicited following presentation of Nogo stimuli. CONCLUSIONS: These results suggest that adults with PKU, despite being continuously treated from birth, manifest subtle impairments in distinct aspects of information processing including early sensory processing of visually presented information, as well as impairments in inhibitory functions. SIGNIFICANCE: The results contribute to an understanding of the neurophysiological mechanisms that are implicated in PKU and highlight the sensitivity of ERP techniques for the identification of the loci of information processing deficits in clinical groups.     

The High Mortality of Gastrointestinal Bleeding in HIV-Seropositive Patients: A Multivariate Analysis of Risk Factors and Warning Signs of Mortality in 50 Consecutive Patients

The patterns of which human immunodeficiency virus (HIV)-seropositive patients underwent endoscopy for gastrointestinal bleeding at a university hospital were analyzed in 50 consecutive patients admitted from July 1984 through December 1989, and criteria were developed as to which patients are most likely to benefit from endoscopy. Analyzed patient data included the medical records, follow-up until July 1990 obtained by telephone questionnaire in 46 patients, and autopsy findings in the 11 patients undergoing autopsy. Thirty-seven percent of the patients did not undergo endoscopic or radiographic examinations indicated to determine the cause of bleeding. The adequacy of the evaluation was not related to race, intravenous drug abuse, homosexuality, hemophilia, the diagnosis of known AIDS, or being a public patient. In 21 of the 28 cases in which the cause of bleeding was determined, the diagnosed lesions had a specific, effective therapy. The mortality from gastrointestinal bleeding was 39.0%, compared with 8.3% in 48 controls without known HIV infection (p less than 0.001 by Fisher's exact test, odds ratio = 7.0, odds ratio confidence interval = 5.0-9.7). Statistically significant independent predictors of mortality included leukocytosis, concurrent major diseases, intravenous drug abuse, transfusion of 5 or more units of packed erythrocytes, and the presence of a bloody nasogastric aspirate or hematemesis (Wilk's lambda statistic = 0.369, p less than 0.0001). In particular, 10 of 11 patients (89%) with two or more concurrent major diseases died, whereas only three of 24 patients (13%) with no concurrent diseases died during the hospitalization. We conclude a large percentage of HIV-seropositive patients did not undergo a diagnostic evaluation for gastrointestinal bleeding at a university hospital, and there was no discernible rational pattern as to which patients underwent endoscopy. Endoscopy is an important and indicated procedure in HIV-seropositive patients with no or one concomitant major illness. HIV-seropositive patients with gastrointestinal bleeding and two or more concomitant major illnesses have an exceedingly poor prognosis, and are less likely to benefit from invasive diagnostic tests and aggressive therapy.