The genetics of aging

We present a case of a patient who is HIV positive and developed both thrombotic thrombocytopenia purpura and visceral Kaposi's sarcoma (KS) with hemorrhage. This case presents a difficult management problem in that the patient's bleeding originated from KS lesions and did not quickly abate with plasmapheresis therapy despite both clinical and laboratory improvement after 2-4 days. Chemotherapy was initiated on day 13 and the patient's condition improved markedly afterward. We believe the addition of chemotherapy to plasmapheresis hastened the improvement of our patient's thrombotic thrombocytopenic purpura (TTP) and KS-related bleeding. Therefore, under similar conditions, we recommend combining plasmapheresis and chemotherapy at the onset of therapy.     

Dose of hemodialysis and survival: differences by race and sex

CONTEXT: Although blacks receive lower doses of hemodialysis than whites, their survival when receiving dialysis treatment is better than that for whites. Previous studies of the relationship between the dose of dialysis and patient survival have not controlled for differences in patient characteristics. OBJECTIVE: To examine the association of mortality with the dose of hemodialysis for clusters of patients categorized by race and sex. DESIGN: Retrospective analysis of laboratory data and mortality outcomes from 1994, using a national database of hemodialysis patients. PATIENTS: A total of 18144 black and white patients receiving hemodialysis 3 times weekly who either lived the entire year receiving hemodialysis or died. MAIN OUTCOME MEASURES: The fractional reduction of urea in a single dialysis session as the measured hemodialysis dose (urea reduction ratio [URR]) after controlling for race, sex, age, and diabetes mellitus. Mortality was determined by strata of URRs and albumin and creatinine levels. RESULTS: Across all age categories, blacks had lower URRs than whites, and men had lower URRs than women. In an age-adjusted model for evaluating interactions among URRs, race, sex, and diabetes, the association of URR with mortality risk was weak among blacks, particularly black men. After adjustment for age and diabetes, death probability curves were most steep for white women with URR values less than 60%. The death probability curves were least steep for black men. There was no meaningful difference between death probability and albumin or creatinine concentration among the race by sex clusters. CONCLUSION: Using URR, the usual measure of hemodialysis dose, the assumption that the association between dialysis dose and survival is uniform across demographic groups appears incorrect. Comparisons of the quality of dialysis patient care should not rely on URR alone to predict patient survival.     

Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis

Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg/kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-gamma receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.     

Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands

PURPOSE: To evaluate the usefulness of Doppler ultrasonography (US) in the diagnosis of hyperfiltration in patients with insulin-dependent diabetes mellitus (IDDM). MATERIALS AND METHODS: Eighty-one consecutive patients with IDDM were studied. All patients were normotensive and had normal creatinine and blood urea nitrogen levels. The glomerular filtration rate (GFR) was evaluated by means of plasma clearance of chromium-51 ethylenediaminetetraacetic acid, urinary albumin excretion, US evaluation of renal volume, and Doppler evaluation of resistance index (RI) in the renal interlobar arteries. The patients were divided according to GFR into the following groups: those with hyperfiltering kidneys (group 1, n = 40) and those with normofiltering kidneys (group 2, n = 41). RESULTS: The median renal volume was 351 mL (95% CI = 337 mL, 379 mL) in group 1 and 318 mL (95% CI = 300 mL, 335 mL) in group 2 (P = .005). The number of patients with microalbuminuria was significantly lower in group 1 than in group 2 (P = .02). The median RI was significantly lower in group 1 (0.55; 95% CI = 0.53, 0.57) than in group 2 (0.57; 95% CI = 0.56, 0.59) (P = .04). An RI of less than 0.5, a renal volume greater than 410 mL/m2, and the absence of microalbuminuria were independent predictors of hyperfiltration. An RI of less than 0.5 and a renal volume greater than 410 mL/m2 showed high specificity (98% and 95%, respectively) and poor sensitivity (25% and 23%, respectively) in the diagnosis of hyperfiltration in IDDM patients. CONCLUSION: Both RI and renal volume showed correlation with GFR, but neither parameter is sufficiently sensitive in screening for hyperfiltration in IDDM patients.     

Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor

When stimulated through their antigen receptor without requisite costimulation, T cells enter a state of antigen-specific unresponsiveness termed anergy. In this study, signaling through the common gamma chain of the interleukin-2 (IL-2), IL-4, and IL-7 receptors in the presence of antigen was found to be sufficient to prevent the induction of anergy. After culture with IL-2, IL-4, or IL-7, Jak3 kinase was tyrosine-phosphorylated, which correlated with the prevention of anergy. Therefore, a signal through the common gamma chain may regulate the decision of T cells to either clonally expand or enter a state of anergy.     

Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells

The soluble IL-6 receptor (sIL-6R) is generated through either proteolytic shedding of the cognate receptor (PC-sIL-6R), or released as the product of differential mRNA splicing (DS-sIL-6R). Using monocytic THP-1 cells, we demonstrate that both mechanisms are independently regulated, and that each process contributes to sIL-6R production. Shedding of the IL-6R was activated by the Ca2+ ionophore, ionomycin, and inhibited by the TNF-alpha protease inhibitor (TAPI). In contrast, basal sIL-6R release was unaffected by Ca2+ depletion and largely insensitive to TAPI. Moreover, although IL-6R shedding was inactivated by serum starvation, non-stimulated production remained intact. Basal sIL-6R production via differential mRNA splicing was shown through the inhibitory action of brefeldin A and an enzyme-linked immunosorbent assay specific for DS-sIL-6R. Release of this isoform was unaffected by ionomycin or TAPI, indicating that Ca2+ mobilization activates PC-sIL-6R generation, but not DS-sIL-6R. The divergent control of these sIL-6R isoforms indicates that they may independently influence the inflammatory response.     

Proximal locking screw repositioning in reconstruction femoral nails

Chard (Beta vulgaris L. var. cicla) is one of the plants used as hypoglycaemic agent by diabetics in Turkey and it has been reported to reduce blood glucose. The purpose of this study was to investigate the effect of feeding chard on diabetes induced impairments in rat skins. Uncontrolled induced diabetes caused significant increases in nonenzymatic glycosylation of skin proteins, lipid peroxidation and blood glucose. Administration of chard extract inhibited these effects except the increase in lipid peroxidation. SDS-polyacrylamide gel electrophoresis revealed no significant differences in any protein bands between any of the groups. The data indicate that the use of chard may be effective in preventing or at least retarding the development of some diabetic complications.     

Isolated agenesis of the mastoid antrum

The first isolated case of agenesis of the mastoid antrum, previously only described in association with the congenital syndromes trisomy 13 and mandibulofacial dysostosis, is reported. The loss of this important surgical landmark may result in disorientation and iatrogenic trauma. The surgeon must be aware of its existence, and where it is suspected the middle fossa dura should be exposed and followed posteriorly until the lateral sinus is encountered.     

Developmental regulation of the brain polyamine-stress-response

A transient increase in brain polyamine metabolism, termed the polyamine-stress-response is a common response to stressful stimuli. Previous studies have implicated an over-reactive polyamine response as a component of the maladaptive brain response to stressful events, and as a novel molecular mechanism involved in the pathophysiology of affective disorders. Ample evidence indicates that stressful experiences during early life can alter normal developmental processes and may result in pathophysiological and behavioral changes in the adult. Additionally, an important characteristic of affective disorders is their age dependency, a phenomenon that may be correlated with a maladaptive regulation of the hypothalamic-pituitary-adrenocortical (HPA) neuroendocrine system. In the present study we measured the activities of the enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase as markers of polyamine synthesis and found that unlike adults, immature rats do not show the characteristic brain polyamine-stress-response. Instead of the characteristic increase observed in adults, ornithine decarboxylase activity in immature animals was reduced or remained unchanged (for up to 16 days of age) after a dexamethasone injection or restraint stress application. The ontogenesis of this ornithine decarboxylase response was brain region-specific, indicating its dependence on the stage of neuronal maturation. Animals treated with dexamethasone at 7 days of age, showed increased behavioral reactivity in the open-field test as adults and an attenuated increase in ornithine decarboxylase activity after a re-challenge with dexamethasone at age 60 days. The results indicate that: (1) the brain polyamine-stress-response is developmentally regulated and its ontogenesis is brain region-specific, indicating dependence on the stage of neuronal maturation; (2) the switch to a mature polyamine-stress-response pattern coincides with the cessation of the stress hyporesponsive period in the HPA system: (3) activation of the polyamine-stress-response, as in the mature brain, appears to be a constructive reaction, while its down-regulation, as in the developing brain, may be implicated in neuronal cell death; (4) an attenuated dexamethasone-induced increase in ornithine decarboxylase activity implicates an altered polyamine-stress-response in the maladaptive response of the brain to stressful events.