Immunobiology of tumor necrosis factor receptor superfamily

The proteins of the tumor necrosis factor (TNF) receptor superfamily are a group of cell-surface receptors critically involved in the maintenance of homeostasis of the immune system. By interacting with their corresponding ligands, these receptors either induce cell death or promote cell survival of immune cells. The number of recognized members of the TNF receptor and ligand superfamily has expanded substantially in the last several years. More important, the biologic function of this group of proteins has been closely associated with the regulation of the immune response and the pathogenesis of autoimmune disease. Thus, the direct targeting of these receptors by either inducing apoptosis or blocking survival of autoimmune T and B cells may be an important therapeutic strategy in the treatment of autoimmune disease. This review summarizes the recent progress in immunobiology of the TNF receptor superfamily and focuses on our studies of three critical family members-FasL/Fas, TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL-Rs, and B lymphocyte stimulator(BLyS)/BLyS-Rs--to demonstrate the therapeutic potential of targeting these receptors for the treatment of autoimmune disease.     

The effects of calcium and magnesium on inhibitory junctional transmission in smooth muscle of guinea pig small intestine

Summary The membrane potential of smooth muscle cells in the circular layer of the guinea pig ileum was recorded using intracellular electrodes. Transmural stimulation, in the presence of atropine, caused a transient hyperpolarization, an inhibitory junction potential (IJP). IJP's are thought to result from the action of transmitter released from intramural inhibitory nerves. It has been reported that, in the guinea pig jejunum, the amplitude of the IJP resulting from field stimulation is not altered by changes in the calcium and magnesium ion concentration in the bathing solution. Experiments reported here have shown that the IJP amplitude decreased markedly on reducing the calcium ion concentration and or increasing the magnesium ion concentration. Indirect evidence is presented suggesting that the decrease in amplitude of the IJP is due to a decrease in the amount of transmitter released.     

Developmentally programmed expression of AID in chicken B cells

In mice, activation induced deaminase, AID, is expressed only in germinal center B cells. It is required for the initiation of somatic hypermutation and class switch recombination. In chickens and most mammals immunoglobulin gene rearrangement generates limited diversity and the primary immunoglobulin repertoire depends on subsequent somatic hypermutation or gene conversion. Immunoglobulin gene conversion in chickens starts in the embryonic bursa, before antigen exposure. The demonstrated requirement for AID for gene conversion in the bursal lymphoma cell line, DT40, implies developmental regulation of AID expression. To test this prediction, we examined the timing and location of AID mRNA expression. An abrupt increase in AID mRNA coincided with the onset of extensive Ig gene conversion in the bursa. Expression was also detected at earlier stages, implying either that expression of AID is not the only controlling factor for gene conversion, or that gene conversion can precede the formation of bursal follicles.     

Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: Evidence for impaired inhibitory control of the HPA axis in heavy drinkers.

Alcoholism and heavy drinking are associated with a number of physiological, behavioral, affective, and cognitive problems. One such problem involves dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, with alcoholics showing higher basal cortisol levels and reduced inhibitory feedback control. In addition, alcohol consumption is associated with decreased heart rate variability (HRV). In the present study we examined the relationships among alcohol consumption, cortisol excretion, and HRV in 542 apparently healthy men. Men in the top tertile of self-reported alcohol consumption had higher cortisol levels and lower HRV compared to men in the lower two tertiles of alcohol consumption. In addition, the inverse relationship between cortisol and HRV was greatly attenuated in the heavy drinking group even after accounting for a number of potential confounding factors. These results support prior research on the HPA axis dysregulation in alcoholics and suggest impaired inhibitory control of the HPA axis in heavy drinkers. The findings are consistent with the neurovisceral integration model, which links central and peripheral processes, and may provide a comprehensive framework for the future investigation of the complex mix of physiological, behavioral, affective, and cognitive factors which comprise the heavy drinking phenotype.     

Internal medicine and general surgery residents' attitudes about the ACGME duty hours regulations: a multicenter study.

PURPOSE: To assess internal medicine and general surgery residents' attitudes about the effects of the Accreditation Council for Graduate Medical Education duty hours regulations on medical errors, quality of patient care, and residency experiences. METHOD: In 2005, the authors surveyed 200 residents who trained both before and after duty hours reform at six residency programs (three internal medicine, three general surgery) at five academic medical centers in the United States. Residents' attitudes about the effects of the duty hours regulations on the quality of patient care, residency education, and quality of life were measured using a survey instrument containing 19 Likert scale questions on a scale of 1 to 5. Survey responses were compared using the Student's t-test. RESULTS: The response rate was 80% (159 residents). Residents reported that whereas fatigue-related errors decreased slightly, errors related to reduced continuity of care significantly increased. Additionally, duty hours regulations somewhat decreased opportunities for formal education, bedside learning, and procedures, but there was no consensus that graduates would be less well trained after duty hours reform. Residents, particularly surgical trainees, reported improvements in quality of life and reduced burnout. CONCLUSIONS: Residents in medicine and surgery had similar opinions about the effects of duty hours reform, including improved quality of life. However, resident opinions suggest that reduced fatigue-related errors have been offset by errors related to decreased continuity of care and that the quality of the educational experience may have declined. Quantifying the degree to which regulating duty hours affected errors related to discontinuity of care should be a focus of future research.     

Glomerular Hypertrophy in Offspring of Subtotally Nephrectomized Ewes

We have shown that fetuses whose mothers underwent subtotal nephrectomy (STNx) before pregnancy had high urine flow rates and sodium excretions, but lower hematocrits, plasma chloride, and plasma renin levels compared with controls. To see if these functional differences in utero persist after birth and are the result of altered renal development, we studied 8 lambs born to STNx mothers (STNxL) and 10 controls (ConL) in the second week of life. These lambs were of similar body weights, nose–rump lengths and abdominal girths. Their kidney weights were not different (ConL 36.1 ± 1.9 vs. STNxL 39.8 ± 3.3 g), nor were kidney dimensions or glomerular number (ConL 423,520 ± 22,194 vs. STNxL 429,530 ± 27,471 glomeruli). However, STNxL had 30% larger glomerular volumes (both mean and total, P < 0.01) and there was a positive relationship between total glomerular volume and urinary protein excretion (P < 0.05) in STNxL. Despite this change in glomerular morphology, glomerular filtration rate, tubular function, urine flow, and sodium excretion rates were not different between STNxL and ConL, nor were plasma electrolytes, osmolality, and plasma renin levels. Thus while many of the functional differences seen in late gestation were not present at 1–2 weeks after birth, the alteration in glomerular size and its relationship to protein excretion suggests that exposure to this altered intrauterine environment may predispose offspring of mothers with renal dysfunction to renal disease in adult life. Anat Rec, 291:318–324, 2008. © 2008 Wiley‐Liss, Inc.     

Electromyography of oral-facial musculature in craniocarpaltarsal dysplasia (Freeman-Sheldon syndrome)

Electromyography and biopsy of the oral-facial musculature of a patient with craniocarpaltarsal dysplasia (Freeman-Sheldon syndrome) supports the thesis that facial muscle hypoplasia is a significant component of this evolving syndrome complex.