No excess of DR*3/4 in Ashkenazi Jewish or Hispanic IDDM patients

The gene frequencies, haplotype relative risks, and zygotic assortments of HLA-DR in three ethnically defined samples of insulin-dependent diabetes mellitus (IDDM) patients were determined in a prospective family study. Although DR3 and DR4 were positively associated with IDDM in the probands of 123 northern European, 94 Ashkenazi Jewish, and 49 New York Hispanic families, significant excess of DR*3/4 heterozygotes was observed only among the probands from families of northern European ancestry. There was also a significant decrease in the frequency of Bw62,DR4 haplotypes derived by northern European patients from their mothers compared with their fathers. This difference, together with data reported in the literature, suggests that the expressivity of the susceptible genotype(s) in IDDM patients may be modified by protective maternal effects associated with Bw62,DR4 and probably other DR4 haplotypes. Samples of IDDM patients from populations with high frequencies of these modifiers should have different DR-gene frequencies contributed by fathers and mothers, capable of accounting for the observed Hardy-Weinberg disequilibrium. We postulate that, because the mechanism of action of these modifiers is distinct from that of the susceptibility gene, the difference must be considered in devising strategies for elucidation of the mode of inheritance of the disease and for understanding the molecular nature of the susceptibility.     

Calcium paradox in skeletal muscles: physiologic and microscopic observations

Immersion of rat hemidiaphragms in Ca2+-free Krebs solution (KS) containing Ca2+ chelator in vitro leads to separation of basal lamina from the plasma membrane, as well as transient contracture and rapid loss of twitch response [calcium paradox (CP) phase 1]. Subsequent immersion in regular KS results in necrosis of muscle fibers accompanied by slowly increasing contracture (CP phase 2). This contracture could be prevented or reduced by using either Ca2+-free KS or calcium channel blockers, but not by dantrolene sodium, implying that after drastic reduction of extracellular and sarcolemmal Ca2+ during CP phase 1, the sarcolemma has lost its ability to control normal Ca2+ fluxes. Contracture did not develop at 21 degrees C. CP is a convenient model to study calcium-induced muscle cell death and the role of Ca2+ in maintaining sarcolemmal integrity.     

18 Graduate Medical Education and Knowledge Translation: One Problem-Specific Approach in Residency

Traditional graduate medical education approaches to improving clinical performance based upon the latest research have included Journal Club and didactic lectures. Unfortunately, these educational interventions have rarely been demonstrated to change practice behavior or improve patient-important outcomes. Using a structured approach to identifying a gap between best-evidence knowledge and clinical practice, an illustrative one-year residency-wide translational research project was developed in a four year emergency medicine training program. Step one (assigned to the second year residents): identify and quantitatively justify a Knowledge Translation (KT) deficit within our institution. They identified steroids in adult bacterial meningitis as an unequivocal therapeutic option. Based upon a structured one-year chart review, they next demonstrated that only 7% of meningitis patients received pre-antimicrobial steroids. The next step (assigned to the first year residents): identify and quantify the physician "leaks" within the pipeline of information from publication to bedside utilization via an online survey. The third year residents hypothesized plugs for these information leaks, including examples of other specialties or institutions which have successfully navigated this specific clinical scenario. Finally, at an end-of-year Journal Club, the fourth year residents formulated a protocol for the appropriate use of steroids in suspected adult meningitis and brought together individuals from within the institution contributing to the best-practice leak. Knowledge Translation involves multiple stages beyond simple evidence awareness and usually involves continuation beyond the emergency department. The Washington University KT project offers a structured, multidisciplinary example of moving beyond contemplation to implementation of an unequivocal therapy.     

The prediction of outcome in schizophrenia. IV: Eleven-year follow-up of the Washington IPSS cohort

Two- and five-year follow-up observations of the International Pilot Study of Schizophrenia's Washington cohort provided data bearing on several controversial issues regarding the course of schizophrenia. Forty schizophrenic patients have now been observed 11 years after their index admission. Social, occupational, hospital utilization, and symptom areas of functioning continue to be only modestly correlated with one another and do not become increasingly uniform over time. Initial prognostic variables continue to be more predictive of long-term outcome than are cross-sectional symptom manifestations. Restricted affect at the initial evaluation had been a predictor of 5-year outcome, but it was not a significant predictor of outcome at 11 years. While serious long-term consequences of illness are observed, the follow-up data suggest that the illness tends to reach a plateau of psychopathology early in the course, with as many patients tending to improve in the long-term as those who tend to show further deterioration.     

Temporal lobe epilepsy caused by domoic acid intoxication: Evidence for glutamate receptor–mediated excitotoxicity in humans

We describe the development of temporal lobe epilepsy in an 84-year-old man who had suffered domoic acid intoxication. Following intoxication he had nausea, vomiting, confusion, and coma. Generalized convulsions and complex partial status epilepticus progressively developed. After 3 weeks he improved and was seizure free with severe residual memory deficit. Electroencephalograms initially showed periodic epileptiform discharges, later evolving to epileptic abnormalities over frontotemporal regions with diffuse slow waves. Eight months after the intoxication the electroencephalogram was normal. One year after the acute episode, complex partial seizures developed. Electroencephalograms showed epileptic discharges independently over both temporal lobes, with left-sided predominance. Magnetic resonance imaging revealed a hyperintense T2-weighted signal and atrophy of both hippocampi; a positron emission tomographic scan showed bitemporal decreased glucose metabolism. Pneumonia developed and the patient died 31/4 years after the intoxication. Autopsy disclosed severe bilateral hippocampal sclerosis. The seizures following acute domoic acid intoxication, the postmortem pathology, and the fact that temprol lobe epilepsy developed 1 year after intoxication indicate that the human hippcampus is also vulnerable to kainate receptor excitotoxicity, and provide strong evidence supporting the role of excitotoxic injury in epileptogenesis. This report provides a unique human parallel to, and validates the animal model of, Kainate-induced epilepsy as an important tool for studying temporal lobe epilepsy.     

Neonatal Graves'' disease.

A newborn boy was noted by his mother to have a prominent left eye at birth, but an eye examination was delayed until age 7 months, at which time his ophthalmologist diagnosed exophthalmos. Computed tomography was interpreted as showing mild, diffuse, optic nerve thickening bilaterally suggestive of optic nerve gliomas. Subsequent examination in our clinic revealed pseudoproptosis secondary to retraction of the left upper eyelid. Magnetic resonance imaging demonstrated normal orbital structures. The mother was noted to be clinically hyperthyroid, and abnormal thyroid function tests confirmed the diagnosis. Although the infant was euthyroid, neonatal Graves' ophthalmopathy was diagnosed. He was managed by close observation while his mother was treated for her hyperthyroidism.