Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals

The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions.     

Using monoclonal antibodies to characterize a sequential epitope on the group I allergen of Bermuda grass pollen

We measured the incidence of cuff retear and injury to the suprascapular nerve after mobilization and repair of a massive rotator cuff tear. Of one hundred four rotator cuff repairs performed over a 5-year period, 10 patients (7 men and 3 women, age range 22 to 68 years) had primary repairs of massive rotator cuff tears requiring cuff mobilization and an acromioplasty as their only procedure. These patients were evaluated at a mean of 2.5 years (range 2.0 to 3.0 years) after surgery. At follow-up electromyographic examination confirmed that 1 of the 10 patients had an iatrogenic suprascapular nerve injury, whereas ultrasound evaluation revealed that 2 of 10 repairs failed. Pain relief was achieved in the eight patients with intact repairs and not in the two with recurrent tears. All patients had some limitation of active motion or strength, especially in external rotation. Thus 7 of 10 patients had neither evidence of nerve injury nor recurrent rotator cuff tears yet still showed limited active motion or weakness. It appears that operative injury to the suprascapular nerve during cuff mobilization can occur, but other factors such as inadequate cuff muscle function are more frequently responsible for the poor functional outcomes seen after successful repairs of massive rotator cuff tears.     

Effects of veratridine on the action potentials and contractility of right and left ventricles from normo- and hypertensive rats

Induction of nitric oxide synthase and generation of nitric oxide in pancreatic islet beta-cells may mediate cytokine-induced dysfunction leading to insulin-dependent diabetes mellitus. Nitric oxide generation can be regulated by availability of arginine substrate which, in turn, may be affected by substrate utilization in competing pathways such as the arginase-catalysed formation of ornithine and urea. In this study we have investigated the activity of arginase in the rat insulinoma-derived cell line RINm5F and the effect on this of interleukin 1beta, the nitric oxide synthase reaction intermediate NG-hydroxy-l-arginine and the nitric oxide-generating compounds 3-morpholinosydnonimine and S-nitrosoglutathione. Cytosols from RINm5F cells treated with or without interleukin 1beta (0.1nM, 18h) were incubated (45min, 37 degrees C) with [U-14C]arginine. Radiolabelled products ([14C]citrulline from nitric oxide synthase, [14C]ornithine and [14C]urea from arginase) were separated by high-performance liquid chromatography or ion-exchange chromatography. Interleukin 1beta increased citrulline production (from 0.01+/-0.002 to 0.58+/-0.03 pmol/microg cell protein), indicating induction of nitric oxide synthase, and significantly decreased production of both ornithine (from 4.60+/-0.20 to 3.40+/-0.20 pmol/microg) and urea (0.93+/-0.05 to 0.69+/-0.04 pmol/microg) (P<0.001), indicating decreased activity of arginase. Arginase was significantly inhibited by NG-hydroxy-l-arginine (IC50=50 microM), S-nitrosoglutathione (500 microM: 69+/-7% of control) and 3-morpholinosydnonimine (1 mM: 57+/-7% of control) (P<0.05). We conclude that during cytokine-directed beta-cell assault nitric oxide synthase-catalysed production of NG-hydroxy-l-arginine and nitric oxide may inhibit arginase thereby increasing the availability of arginine for nitric oxide production.     

Local-circuit neurones in the medial prefrontal cortex (areas 25, 32 and 24b) in the rat: morphology and quantitative distribution

This paper is a light microscopical study describing the detailed morphology and quantitative distribution of local circuit neurones in areas 25, 32, and 24b of the medial prefrontal cortex (mPFC) in the rat. Cortical interneurones were identified immunocytochemically by their expression of calretinin (CR), parvalbumin (PV), and calbindin D-28k (CB) immunoreactivity. Neurones immunoreactive for gamma-aminobutyric acid (GABA) were also investigated, as were interneurones containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity. Several distinct classes of CR+, PV+, and CB+ neurones were identified; the most frequent were: bipolar/bitufted CR+ cells in upper layer 3; multipolar PV+ neurones in layers 3 and 5; and bitufted/multipolar CB+ neurones in lower layer 3. CB+ neurones resembling Martinotti and neurogliaform cells were also present in layers 5/6. The morphologies and depth distributions of each cell type were consistent across the three areas of mPFC studied. Seven classes of diaphorase-reactive mPFC neurone are described; these cells were composed about 0.8% of the total neurone population and had a peak distribution located in mid- to lower layer 5 in each area. In areas 32 and 25, three defined bands of diffuse NADPH diaphorase staining were located in layer 2 and in upper and deep layer 5. Diaphorase reactivity was very infrequently colocalised with either CR, PV, or CB immunoreactivities. The numerical densities of neurones (N(V), number of cells per mm3) in each layer were calculated stereologically. The mean total neuronal N(V) estimate for areas 25, 32, and 24b was 51,603 +/- 3,324 (mean +/- S.D.; n = 8). Significant interareal differences were detected. From cortical thickness data and neuronal N(V) estimates, the absolute number of neurones under 1 mm2 of cortical surface (N(C)) have been derived. The mean N(C) value for areas 25, 32, and 24b was 57,328 +/- 7,505 neurones. In immunolabelled Nissl-stained sections, CR+ neurones constituted an overall 4.0%, PV+ cells 5.6%, and CB+ 3.4% of the total neurone populations in mPFC. GABA+ cells represented a mean of 16.2% (14.8-17.2%) of neurones in areas 25, 32 and 24b. The absolute numbers of CR+, PV+, CB+, and GABA+ neurones within individual layers in a column of cortex under 1 mm2 of cortical surface (N(L)) have also been derived, with significant interareal differences in N(L) values being detected. The data provide the structural basis for a qualitative and quantitative definition of local cortical circuits in the rat mPFC.     

Electron tomography of large, multicomponent biological structures

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda s = 2.5). It is recognised that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda s = 1.25), cannot account for all of the observed clustering of disease in families (lambda s = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33), IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. The results suggest that the clustering of type 1 diabetes in families is due to the sharing of alleles at multiple loci, and that the as yet unidentified environmental factors are not causing clustering, but instead appear to influence the overall penetrance of genetically programmed susceptibility. The data are consistent with a polygenic threshold model for the inheritance of type 1 diabetes.     

EFFECT OF TIME AND TEMPERATURE ON ACCELERATED CHEMICAL DURABILITY TESTS MADE ON COMMERCIAL GLASS BOTTLES*

Chemical durability results obtained by tests on crushed samples and bottle surfaces on a variety of commercial glass-bottle compositions show the difficulties encountered in attempting to correlate accelerated tests with the actual performance of the bottles toward various solutions under service conditions. The results obtained thus far indicate that the value of accelerated tests conducted with distilled water as a leaching medium is questionable as an aid in predicting resistance of various glass compositions to neutral solutions at room temperature.