Metabolic fate of valproic acid in the rhesus monkey. Formation of a toxic metabolite, 2-n-propyl-4-pentenoic acid

The metabolic fate of an iv bolus dose (13.5 mg kg-1) of valproic acid (VPA) was studied in adult male rhesus monkeys. Renal excretion proved to be the major route of elimination of the drug and a total of 17 metabolites, accounting collectively for some 82% of the administered dose, were identified in urine by GC-MS techniques. Many of these metabolites were present largely in the form of glucuronide conjugates, as was VPA itself. The principal pathways of VPA biotransformation were, in order of decreasing quantitative importance, ester glucuronide formation, omega-oxidation, beta-oxidation and (omega-1)-hydroxylation. In addition, three mono-unsaturated metabolites, identified as (E)-delta 2-, (E)-delta 3-, and delta 4-VPA, were detected in both plasma and urine. Quantitative analysis of these unsaturated VPA metabolites indicated that the delta 4 olefin, which is known to be a potent hepatotoxic agent, was the predominant isomer of the group.     

John B. Murphy: unique among American surgeons.

John B. Murphy (1857-1916), one of the most outstanding and controversial surgeons of his age, was a product of the strong clinical programs that developed in Chicago in the late 19th century. Heavily influenced by Christian Fenger, surgeon and surgical pathologist, he went to Europe for training under Theodore Billroth and others. He applied results of his dog lab experiments to human problems while maintaining a large private practice. He is best known for his teaching clinics, for his groundbreaking work with a button for intestinal anastomosis, and for encouraging early operation in appendicitis. Though often in trouble with his fellow surgeons who accused him of stealing patients, especially in the Haymarket affair and when Theodore Roosevelt was shot, he nevertheless made many contributions to the care of surgical patients and development of academic surgery.     

Auditory brainstem activity and development evoked by apical versus basal cochlear implant electrode stimulation in children.

OBJECTIVE: The role of apical versus basal cochlear implant electrode stimulation on central auditory development was examined. We hypothesized that, in children with early onset deafness, auditory development evoked by basal electrode stimulation would differ from that evoked more apically. METHODS: Responses of the auditory nerve and brainstem, evoked by an apical and a basal implant electrode, were measured over the first year of cochlear implant use in 50 children with early onset severe to profound deafness who used hearing aids prior to implantation. RESULTS: Responses at initial stimulation were of larger amplitude and shorter latency when evoked by the apical electrode. No significant effects of residual hearing or age were found on initial response amplitudes or latencies. With implant use, responses evoked by both electrodes showed decreases in wave and interwave latencies reflecting decreased neural conduction time through the brainstem. Apical versus basal differences persisted with implant experience with one exception; eIII-eV interlatency differences decreased with implant use. CONCLUSIONS: Acute stimulation shows prolongation of basally versus apically evoked auditory nerve and brainstem responses in children with severe to profound deafness. Interwave latencies reflecting neural conduction along the caudal and rostral portions of the brainstem decreased over the first year of implant use. Differences in neural conduction times evoked by apical versus basal electrode stimulation persisted in the caudal but not rostral brainstem. SIGNIFICANCE: Activity-dependent changes of the auditory brainstem occur in response to both apical and basal cochlear implant electrode stimulation.     

Effects of diabetes on the vascular system: current research evidence and best practice recommendations.

Diabetes mellitus has been referred to as a vascular disease because of its effect on the vascular endothelial wall. In recent years, research has identified specific effects of hyperglycemia and insulin resistance on the vasculature of the diabetic patient. Atherosclerosis is known to develop earlier in the diabetic patient and is more aggressive due to the metabolic effects of hyperglycemia and insulin resistance. The results of many large, randomized, prospective trials have provided practice changes in the management of the patient with diabetes. Trials such as the Framingham Study identified risk factors associated with atherosclerosis. Additional studies, such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, provided information about risk factors for diabetes and contributed to treatment recommendations for the person with type 1 or type 2 diabetes. Results of these and many other trials continue to change the recommendations for the person with diabetes to reduce mortality and prevent coronary heart disease, blindness, renal failure, and amputation. This paper will identify the effects of diabetes on the vascular system and outline best practice recommendations on the basis of clinical trials.