Inhibition of GABA-gated chloride channel function by arachidonic acid

The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.     

Does the end-to-end venous anastomosis offer a functional advantage over the end-to-side venous anastomosis in high-output arteriovenous grafts?

This study explores the hemodynamics, mechanics, and biologic response of end-to-end versus end-to-side venous anastomoses in a canine arteriovenous graft model. Femoral polytetrafluoroethylene grafts were implanted bilaterally in a paired fashion (n = 22). Detailed local hemodynamic measurements were made by use of color Doppler ultrasound imaging at 1, 4, 8, and 12 weeks after implant. Measurements included volumetric flow rate and Doppler-derived spectral window (percent window) as a measure of turbulence. Amplitude and velocity of vessel wall movement were also measured. Volume of perivascular tissue vibration quantitated kinetic energy transfer through the vessel wall. Volumetric flow rate (end to end, 1013 +/- 70 ml/min; end to side, 1015 +/- 72 ml/min), percent window (end to end, 6.6% +/- 0.6%, end to side, 5.6% +/- 0.4%) and volume of perivascular tissue vibration (end to end, 19.6 +/- 1.2 ml, end to side, 16.3 +/- 1.8 ml) were statistically equivalent in the two graft types (end to end vs end to side p greater than 0.05). Both graft types developed venous intimal-medial thickening of a similar magnitude: end to end, 0.35 +/- 0.05 mm, end to side, 0.43 +/- 0.09 mm, normal vein 0.070 +/- 0.004 mm (analysis of variance [ANOVA] p less than 0.001, p less than 0.01 for end to end or end to side vs control, end to end vs end to side p greater than 0.05 by Student-Newman-Keuls test). The best correlations with venous intimal-medial thickening were obtained from inverse percent window (r = 0.84, p less than 0.001) and volume of perivascular tissue vibration (r = 0.68, p less than 0.001). In the end to end configuration the relative amplitude of venous wall movement decreased, and the relative velocity of wall motion increased over time. We conclude that in the circumstances of this high flow arteriovenous graft model the end-to-end venous anastomosis does not significantly differ from the end-to-side venous anastomosis in terms of flow stability, turbulence, or kinetic energy transfer. The magnitude of the hyperplastic response is statistically equivalent for the two anastomotic types, but the pattern is somewhat different, possibly providing evidence for differences in stress distribution. Differences in the relative amplitude and velocity of vessel wall movement suggest that anastomotic geometry may affect the way in which kinetic energy is dissipated at the graft/vessel interface.     

Lyme disease: ocular manifestations

We present three cases of Lyme disease, complicated by ocular manifestations. These included optic nerve abnormalities and corneal opacities.     

Keratoacanthoma-Like Squamous Cell Carcinoma Within the Fibroepithelial Polyp

Acrochordons (skin tags) are often considered clinically insignificant cutaneous redundancies that should be removed and destroyed with no histopathologic analysis performed. One rarely finds another neoplasm within an acrochordon. We describe a patient with an acrochordon that contained a squamous cell carcinoma that had features resembling a keratoacanthoma. This is the first time to our knowledge that an invasive squamous cell carcinoma has been described within an acrochordon.     

Documentation of students' clinical reasoning using a computer simulation

Computer simulations can provide both a clinical experience for teaching problem solving and a method of documenting a student's clinical reasoning style. The CAMPS simulation consists of approximately 500 items describing a patient's history, physical examination and laboratory results, and treatments. The student has full option to select any item in any order, producing a wide variation of performances. Since all of the students interact with the same clinical problems, the faculty member can make comparisons of that individual student with the class. From the record of the simulation encounter, the person responsible for student evaluations can prepare a narrative that lists the overall performance, the specific omissions and commissions, and comparisons with the class. Experience with a group of 111 students in a basic pediatric course showed that this method of documenting clinical inquiry detected a variety of levels of performances. Comparisons of the results of these tests with the faculty observations showed that 16% of these students who were judged to be very good or excellent in problem solving by the faculty performed at least 1 SD below the class average on the simulations. This project highlights the power of computer simulations to provide documentation of student performance with the additional benefit of a cost of less than $1 per student.     

Steady state verapamil tissue distribution in the dog: differing tissue accumulation

Plasma, heart, and extracardiac tissue verapamil concentrations were measured after sustained intravenous infusions in 11 dogs to determine the differential tissue accumulation of verapamil. A steady state verapamil concentration of 327 +/- 50 ng/ml decreased the mean arterial blood pressure from 104 +/- 9 to 90 +/- 6 mm Hg (p = 0.08) and the P-R interval increased from 118 +/- 4 to 176 +/- 13 ms (p less than 0.001) with second-degree atrioventricular block developing in 6 animals. Verapamil accumulated in organs in the following order: Lung much greater than kidney greater than spleen greater than ventricular myocardium = liver greater than atrial myocardium greater than cerebral cortex greater than fat = skeletal muscle. Levels in the ventricular free wall were consistently greater than atrial levels, but no difference was observed between left versus right-sided cardiac chambers. In summary, affinity of different organs for verapamil is highly variable and organ-specific; furthermore, differential intracardiac chamber accumulation occurs.     

Dynamic pituitary and ovarian changes occurring during the anestrus to estrus transition in the golden hamster

Anestrous hamsters exhibit daily afternoon gonadotropin and progesterone surges, but little estrogen secretion. In the first experiment, short day anestrous females were transferred to long days to detect hormonal changes associated with recovery of cyclicity. Morning and afternoon blood samples were taken at increasing durations in long days. Females autopsied at their first vaginal estrus after transfer to long days differed from long day estrous controls only in their lower uterine weights. Some females at all durations exhibited signs of recovery, though they had not yet shown estrus. They did not display afternoon gonadotropin surges and had low circulating progesterone but high estradiol levels, stimulated uteri, and enhanced follicular development. Results of the second and third experiments provided evidence that the daily gonadotropin surges are not the cause per se of anestrus, and that changes in estrogen secretion are essential for the transition to and from anestrus. Phenobarbital blockade of the daily surges in anestrous females did not result in increased follicular growth and estrogen secretion. Furthermore, daily afternoon injections of gonadotropins it appears that the daily surges in anestrous hamsters simply reflect low estradiol levels. It is still not known what signal promotes rapid follicular maturation during the recovery from anestrus. Once initiated, however, this recovery appears to occur within a few days, with a rapid cascade of events. First, follicular development and estrogen secretion resume, and the daily LH surges cease. Then, progesterone levels decline, and an ovulatory surge of gonadotropins is triggered.     

Molecular and signaling mechanisms of atherosclerosis in insulin resistance.

Although the prevalence of cardiovascular complications is increased in insulin-resistant individuals, the underlying causes of this link have been elusive. Recent work suggests that several intracellular signal transduction pathways are inappropriately activated by hyperinsulinemia, hyperglycemia, increased free fatty acids, dyslipidemia, various inflammatory cytokines and adipokines--factors that are increased in insulin resistance. Once activated, substantial cross talk occurs between these pathways, especially a self-reinforcing cascade of vascular inflammation and cell dysfunction, greatly increasing the risk and severity of atherosclerosis in the insulin-resistant individual. We review several key cell-signalling pathways, describe how they are activated in they insulin-resistant state and the damage they induce, and discusses possible therapeutic approaches to limit vascular damage.     

Predictors of Partner Notification for C. trachomatis and N. gonorrhoeae: An Examination of Social Cognitive and Psychological Factors

Efforts to control chlamydial and gonococcal infections include notifying eligible sexual partners of possible infection, primarily by asking the diagnosed patient to notify their partners. This approach, known as patient referral, is widely used but poorly understood. The current study examined psychosocial and cognitive factors associated with patient referral among an urban, minority sample of 168 participants recently diagnosed with Chlamydia trachomatis or Neisseria gonorrhoeae. At a follow-up interview 1-month from diagnosis, participants were more likely to have notified all eligible partners if they had greater intention to notify at baseline (OR = 3.72; 95% CI = 1.34, 10.30) and if they had only one partner at baseline (OR = 4.08; 95% CI = 1.61, 10.31). There were also gender differences as well as differences based on type of partner (i.e., regular, casual, one-time). The implications of these findings for the design of programs to promote patient referral for sexually transmitted infections are discussed. Schwartz, Malka, Augenbraun, McCormack, and Wilson are with the State University of New York, Downstate Medical Center, Brooklyn, NY, USA; Rubin is with the New York City Department of Health, Bureau of STD Control, New York, NY, USA; Rubin, Hogben, and Liddon are with the Centers for Disease Control and Prevention, Atlanta, GA, USA; Schwartz is with the Department of Preventive Medicine and Community Health, SUNY Downstate Medical Center, Box 1240, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.