Nonsteroidal anti-inflammatory therapy after eccentric exercise in healthy older individuals.

BACKGROUND: Aging is associated with greater susceptibility to muscle injury and soreness after exercise. Although elderly persons regularly consume nonsteroidal anti-inflammatory drugs (NSAIDs), it is not clear that NSAIDs alleviate muscle dysfunction and/or inflammation following injurious exercise. METHODS: In this double-blind crossover study, 10 men and 5 women (aged 60 +/- 2 years, mean +/- SE) consumed naproxen sodium or placebo for 10 days after performing 64 unilateral eccentric (ECC) knee extensions using 75% of the ECC 1-repetition maximum. Strength was measured before, 3 days after, and 10 days after each bout. Injury and soreness were assessed using magnetic resonance images of m. quadriceps femoris (QF) and a visual analog scale. RESULTS: Three days after exercise, concentric strength loss was greater for placebo (-32 +/- 9%) than NSAID (-6 +/- 8%; p =.0064). Likewise, isometric strength declined less for NSAID than placebo (-12 +/- 7% vs -24 +/- 4%; p =.0213), and thigh soreness while rising from a chair was greater for placebo (p < or =.0393) than NSAID (43 +/- 7 mm vs 26 +/- 7 mm). QF cross-sectional area (cm(2)) showing elevated T(2) was 27% and 35% greater (p < or =.0096) for placebo on Days 3 and 10, respectively. CONCLUSIONS: Naproxen sodium attenuated muscle injury, strength loss, and soreness following ECC exercise in older individuals and may be beneficial during the early stages of increased physical activity.

Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion.

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-x(L) expression in beta-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-x(L) transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-x(L) mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses to glucose and KCl. Furthermore, insulin and [Ca(2+)](i) responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-x(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.

Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse.

To determine whether loss of beta-cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, beta-cell mass and rates of beta-cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune beta-cell destruction. Despite an increase in the rate of beta-cell proliferation, beta-cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than beta-cell mass, suggesting the presence of beta-cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, beta-cell destruction begins soon after the onset of insulitis. Despite a compensatory beta-cell proliferative response, beta-cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual beta-cell mass represents 30% of control levels.

Adaptation to hyperglycemia enhances insulin secretion in glucokinase mutant mice.

The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice. Insulin secretion and intracellular calcium ([Ca2+]i) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucokinase (GK)-deficient mice (GK+/-) and their wild-type littermates (GK+/+). Results obtained in islets incubated in 11.6 or 30 mmol/l glucose for 48-96 h were compared. GK+/- islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secretory and [Ca2+]i responses to the standard glucose challenge as well as an enhanced ability to sense small amplitude glucose oscillations. These effects were associated with increased glucokinase activity and protein. In contrast, exposure of GK+/+ islets to 30 mmol/l glucose increased their basal insulin secretion but reduced their incremental secretory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l glucose for 48-96 h enhanced their ability to sense and respond to a glucose stimulus, whereas similar exposure of GK+/+ islets induced evidence of beta-cell dysfunction. These findings provide a mechanistic framework for understanding why glucokinase diabetes results in mild hyperglycemia that tends not to increase over time. In addition, the absence of one allele of the glucokinase gene appears to protect against glucose-induced beta-cell dysfunction (glucose toxicity).

Nitric oxide production by the rat insulinoma cell line, RINm5F, Is specific for IL-1: a spectrophotometric IL-1 bioassay.

Cytokines inhibit glucose-induced insulin secretion from pancreatic beta-cells by stimulating the expression of nitric oxide synthase and the increased production of nitric oxide (NO). We have found that the rat insulinoma cell line, RINm5F, responds specifically and linearly to murine and human interleukin-1beta (IL-1beta) and IL-1alpha in the range of 0.1 to 1 unit/ml to produce nitric oxide. Other cytokines, including IL-2, IL-4, IL-6, IL-9, IL-11, IL-15, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide fail to stimulate nitric oxide formation by RINm5F cells either alone or in combination. In addition, these cytokines do not significantly potentiate or attenuate the IL-1 response. This unprecedented specificity to IL-1 has been further developed as a sensitive and specific assay for IL-1 bioactivity. Quantitation by this new bioassay of human IL-1beta and IL-1 released from activated murine peritoneal macrophages showed a close correlation with the quantitation of IL-1 by enzyme immunoassay (ELISA). This new bioassay, which is specific, nonradioactive and inexpensive, represents a significant improvement over current bioassays for IL-1.

Heterogeneous atmospheric reactions: sulfuric Acid aerosols as tropospheric sinks.

The collisional reaction probabilities of several atmospheric species on bulk sulfuric acid surfaces indicate that heterogeneous processes may be important in tropospheric chemistry.

Thiopentone anaphylaxis.

A fit young mother had a severe anaphylactic response to intravenous injection of sodium thiopentone, having been sensitised nearly 20 years previously.

Anaphylactoid response to intravenous tubocurarine.

A case of severe anaphylactoid reaction to tubocurarine in a 42-year-old female is described. This is particularly notable as there was no history of past allergies or of previous exposure to the drug.