Drug points: Neuropsychiatric complications of nevirapine treatment.
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Adult↗
Biomedical subjects
K Mistry
Publications and source records attributed to K Mistry.
An analysis of the relationship between hydration and protein-DNA interactions.
Eleven protein-DNA crystal structures were analyzed to test the hypothesis that hydration sites predicted in the first hydration shell of DNA mark the positions where protein residues hydrogen-bond to DNA. For nine of those structures, protein atoms, which form hydrogen bonds to DNA bases, were found within 1.5 A of the predicted hydration positions in 86% of the interactions. The correspondence of the predicted hydration sites with the hydrogen-bonded protein side chains was significantly higher for bases inside the conserved DNA recognition sequences than outside those regions. In two CAP-DNA complexes, predicted base hydration sites correctly marked 71% (within 1.5 A) of protein atoms, which form hydrogen bonds to DNA bases. Phosphate hydration was compared to actual protein binding sites in one CAP-DNA complex with 78% marked contacts within 2.0 A. These data suggest that hydration sites mark the binding sites at protein-DNA interfaces.
Binding Sites↗
Rebound bilirubin levels in infants receiving phototherapy.
A retrospective medical record review was completed for 264 consecutive newborns receiving phototherapy for hyperbilirubinemia to determine whether a "rebound" increase in total serum bilirubin (TSB) level occurs after termination of phototherapy. The difference between mean TSB levels at discontinuation of phototherapy and at rebound was calculated by paired t test. TSB levels at rebound were significantly lower than at discontinuation of phototherapy for infants weighing > 1800 g (positive and negative Coombs' test results). There were no statistically significant differences among infants in the smaller weight categories, regardless of Coombs' test results. Infants completing phototherapy for hyperbilirubinemia who are otherwise healthy do not require follow-up solely to identify a rebound bilirubin level.
Bilirubin↗
Looking into the future: materials and joining technology.
To improve existing products and create new ones manufacturers of medical devices need to consider the latest technology and materials. This review of recent developments in joining techniques describes alternative joining processes and how to establish best practice when working with adhesives and welding.
Adhesives↗
Comparison of the effects of Zopolrestat and Sorbinil on lens myo-inositol influx.
The effects of two structurally dissimilar aldose reductase inhibitors, Zopolrestat and Sorbinil, were investigated on the sodium-dependent, myo-inositol (MI) cotransporter in rat lenses maintained in either normal (5.5 mmol/l) or high sugar medium (35.5 mmol/l glucose or 30 mmol/l galactose). MI influx was compared to the lens polyol content. The effects of Sorbinil (10, 20 and 40 mumol/l) were determined on normal lens MI influx. At all concentrations, Sorbinil had no effect on normal MI influx; therefore, there was no direct effect on the MI transporter. Acute exposure (4-hour incubation) in either high D- or L-glucose media significantly inhibited lens MI influx, which was attributed to competitive inhibition by either D- or L-glucose with MI cotransporter. Due to the short incubation period and rapid metabolism of D-glucose to fructose, there was a low level of polyol (sorbitol) in these lenses. Thus, concomitant administration of Sorbinil (10, 20 and 40 mumol/l) had no significant effect on MI influx in this short-term experiment. Sorbinil had no effect in the presence of L-glucose because L-glucose was not metabolized; thus the polyol content remained normal. To investigate the effects of large accumulations of polyol, lenses were preincubated for 8, 12 and 16 h in 30 mmol/l galactose medium. Large amounts of polyol (galactitol) rapidly accumulated because galactitol was not metabolized. Galactose served as substrate for aldose reductase, and lens polyol (galactitol) content increased markedly. Inhibition of MI influx directly correlated with the increased lens polyol content. Lens polyol accumulation resulted in noncompetitive inhibition of MI influx. Coadministration of 40 mumol/l Sorbinil inhibited 80% of polyol formation and protected 80% of MI influx. Furthermore, in the presence of Sorbinil, lens galactose increased rapidly and equilibrated with galactose in the medium further indicating that Sorbinil inhibited aldose reductase. The effects of 40 mumol/l Sorbinil were compared to 40 mumol/l Zopolrestat. Zopolrestat was as effective as Sorbinil; both aldose reductase inhibitors maintained MI influx at approximately 80% of control values after 12- and 16-hour incubations in high galactose medium. In conclusion, Sorbinil did not exert a direct effect on the sodium-dependent, MI cotransport system or prevent the direct competitive inhibition of either D- or L-glucose. Sorbinil and Zopolrestat inhibited lens polyol formation, thereby eliminating noncompetitive inhibition of MI influx.
Aldehyde Reductase↗
Effect of pyruvate on lens myo-inositol transport and polyol formation in diabetic cataract.
In diabetic cataract, sorbitol pathway flux perturbs intracellular metabolism by two putative mechanisms. The osmolyte hypothesis implicates the aldose reductase enzyme, increased rate of reduction of glucose of sorbitol and reciprocal osmoregulatory depletion of organic osmolytes (myo-inositol). Redox hypothesis favors alterations in the ratios (NADP+/NADPH and/or NADH/NAD+ as the primary cause of glucose-induced aldose reductase related defects. Increase in NADH/NAD+ promotes increased oxidation of sorbitol to fructose by polyol dehydrogenase; potential normalization of this ratio by coadministration of pyruvate (which reoxidizes NADH to NAD+ via lactate dehydrogenases reaction) was investigated. Effects of exogenous pyruvate on lens polyol formation and sodium-dependent myo-inositol (MI) cotransporter using two in vitro models of sugar cataract were determined. Rat lenses were incubated for 16 h in either normal (5.5 mM) or high sugar medium, 35.5 mM glucose or 30 mM galactose. Then lens MI influx was compared to polyol, MI and fructose content. Pyruvate did not affect MI influx or sorbitol content in lenses incubated in control medium. In 35.5 mM glucose, coadministration of pyruvate maintained lens MI influx at 76% of control values vs. 43% for lenses without pyruvate. Furthermore, pyruvate treatment diminished lens sorbitol content by 50% and increased lens sugar content (myo-inositol, fructose, lactate) and media lactate levels. Lenses incubated in high galactose medium formed galactitol with a corresponding decreased MI content. Coadministration of pyruvate had no effect on either lens sugar content (galactitol, myo-inositol, fructose) or MI influx, consistent with the fact that galactitol was not metabolized to fructose. In conclusion, pyruvate did not exert a direct effect on the MI co-transporter or prevent galactitol inhibition of MI influx. Coadministration of pyruvate with high glucose altered lens metabolism and promoted reduction of pyruvate to lactate, increased fructose, decreased sorbitol, enhanced MI influx, maintained lens MI content, implicating both osmotic and redox systems.
Animals↗
Glial growth factors I-III are specific mitogens for glial cells.
Recently we identified three novel Schwann cell mitogens named GGF (glial growth factor)-I (34 kDa), GGF-II (59 kDa), and GGF-III (45 kDa), and provided evidence that they are three distinct but structurally related members of a larger family of factors, which includes heregulin, neu differentiation factor, and acetylcholine receptor-inducing activity (ARIA). We report here the characterization of the mitogenic and trophic activities for all three forms of GGF on rat Schwann cells and several other cell types. GGF-I, GGF-II, and GGF-III are potent mitogens for rat Schwann cells in vitro at nanomolar concentrations, whereas at lower concentrations they promote Schwann cell survival, in the absence of cAMP elevating agents. Forskolin, an adenylate cyclase activator, potently synergizes with the GGFs by an indirect mechanism, possibly involving transcriptional activation of GGF receptor(s). In addition, the GGFs stimulate DNA synthesis in rat glioma C6 cells, and in SK-BR-3 cells, which overexpress the p185 neu/erbB2. Fibroblasts obtained from different sources are weakly stimulated by GGFs, whereas PC12 cells are unable to respond under a variety of experimental conditions. These observations are consistent with the proposal that GGF-I, GGF-II, and GGF-III are a set of potent glial cell mitogens and putative ligands of members of the EGF receptor family, namely p185 neu/erbB2, p160/erbB3, and p180/erbB4, which may play important roles in the development, regeneration, and tumor biology of the peripheral nervous system.
Animals↗
Zopolrestat prevention of proteinuria, albuminuria and cataractogenesis in diabetes mellitus.
The aldose reductase inhibitor, Zopolrestat, reduced proteinuria and albuminuria in streptozocin-induced diabetic rats compared with both untreated diabetic and age-matched controls. Daily administration of Zopolrestat (100 mg/kg) for 4 months decreased 24 h total protein excretion to 15.07 +/- 2.17 mg from 49.97 +/- 7.94 mg/day in untreated diabetic rats. Zopolrestat protected against excretion of any array of urinary proteins with molecular weights between 30 and 100 kD. These effects were sustained throughout the 5th and 6th months of treatment. At the end of 6 months, Zopolrestat-treated diabetic rats excreted 22.77 +/- 4.39 mg/day compared to untreated diabetic rats (67.05 +/- 14.03 mg/day), a 6-fold increase in urinary protein excretion compared to age-matched nondiabetic controls (11.65 +/- 1.71 mg/day). Zopolrestat treatment for 6 months produced therapeutic effects in the lens: transparency and myo-inositol content were maintained and lens sorbitol diminished, despite elevated lens glucose. In contrast, untreated diabetic rats had opaque lenses which exhibited a 40-fold increase in sorbitol and myo-inositol depletion. In opaque lenses, ouabain-sensitive Rb influx, an index of Na-K-ATPase activity, decreased to only 53.8% of mean values in age-matched controls; the ouabain-insensitive component increased by 63.6%. Zopolrestat treatment prevented these diabetic-induced changes and maintained ouabain-sensitive and ouabain-insensitive Rb influx. Collectively, these results suggest that Zopolrestat exerts a protective effect on the slowly developing diabetic cataract, as well as reducing albuminuria and proteinuria.
Albuminuria↗
Kinetics of myo-inositol transport in rat ocular lens.
Myo-inositol (MI) influx as a function of concentration in rat lens consisted of a saturable component, fit by a rectangular hyperbola, and a linear component which was more distinct at high myo-inositol concentrations suggesting passive diffusion. The hyperbolic component was half-maximally saturated (Kt) at 61.3 microM and had a maximal transport rate (Jmax) of 44.6 mumol/kg wet wt/h. The linear component had an apparent permeability coefficient of 1.44 x 10(-6) s-1. Sorbitol, which distributed rapidly in the extracellular space (6.83 ml/100 g wet wt), also appeared to enter the intracellular space with a permeability coefficient of 1.37 x 10(-6) s-1, similar to that of myo-inositol. The influx of myo-inositol was critically dependent on the concentration of extracellular sodium consistent with a sodium-myo-inositol cotransport. The kinetics of influx activation by sodium suggested an apparent 2:1 coupling ratio for sodium and myo-inositol. When potassium was used as sodium substitute, a significantly stronger influx inhibition was observed than with nondepolarizing sodium substitutes, indicating that myo-inositol was driven by the electrochemical gradient of sodium rather than the chemical gradient only. Reducing the extracellular Na concentration increased the MI concentration at which transport was half-maximally activated, suggesting an ordered binding sequence of Na followed by MI. Myo-inositol influx was competitively inhibited by phlorizin with an inhibitory coefficient (Ki) of 35 microM. Phloretin also was capable of inhibition but with a much lesser efficacy. Myo-inositol desaturates from the lens at a rate of 0.00862 h-1. Approximately 19% of the efflux can be inhibited with phlorizin, suggesting that it represents carrier-mediated flux. The phlorizin insensitive flux has a rate of 0.00695 h-1 or 1.93 x 10(-6) s-1, similar to the Na-independent passive influx. MI influx is due to a Na-dependent, phlorizin-sensitive active transport while the efflux consists largely of a phlorizin-independent passive leakage.
Animals↗
Purification of multiple forms of glial growth factor.
Glial growth factors (GGFs) were purified from bovine pituitaries using an in vitro rat Schwann cell mitogenesis assay. In addition to an approximately 34-kDa species termed GGF-I, similar in molecular mass to a previously identified molecule (Lemke, G. E., and Brockes, J. P. (1984) J. Neuroscience 4, 75-83), two species named GGF-II and GGF-III were characterized with apparent molecular masses of approximately 59 and approximately 45 kDa, respectively. Highly purified preparations of all species share a similar dose-dependent stimulation of Schwann cell DNA synthesis at nanomolar concentrations. Forskolin synergizes with all three GGFs, shifting their dose dependence 3-8-fold into the sub-nanomolar range. The GGFs, which contain N-linked carbohydrate groups not essential for their in vitro mitogenic effects, are three distinct members of a novel family of glial cell mitogens.
Animals↗
Myo-inositol transport in the lens of galactose-maintained rats.
Lens myo-inositol (MI) content is regulated by a pump-leak system consisting of an active Na-dependent MI transport and its passive permeability through the membrane. We measured the active MI uptake and membrane permeability in lenses of rats maintained on a 50% galactose diet for 1, 3 and 7 days. After only 1 day of galactose feeding, active MI uptake in the lens was reduced dramatically by 74% compared to age-matched control lenses; by day 3, active MI transport was decreased by 89% and it was undetectable by day 7. The passive membrane permeability was determined by measuring (a) the passive MI influx and (b) the 3H-sorbitol flux. After 1 day of galactose feeding, the membrane permeability increased such that within 3 days it increased to 5-6 fold. Galactose feeding also led to a rapid increase in lens polyol content. After 1 day, lens polyol increased to 53 mumol/g wet wt compared to a control value of 0.35 mumol/g wet wt and increased further to 65 and 72 mumol/g wet wt after 3 and 7 days of galactose feeding respectively. Lens galactose accumulation was low (3 mumol/g wet wt) up to 7 days; however, it was rapidly increased after 7 days. Our results indicate that galactose feeding rapidly interfered with MI homeostasis by a severe depression of active MI transport and a rapid increase in membrane permeability. These interferences of MI homeostasis correlate with the appearance of high polyol levels.
Animals↗
Characterisation of the in vitro responsiveness of lymphocyte subsets to locomotor stimuli by immunocytochemical methods.
The in vitro locomotion of lymphocyte subsets has previously been determined by use of highly purified cell populations. A method is now described in which mixed peripheral blood lymphocytes (PBL) migrate to the undersurface of polycarbonate filters in a 48 well microassay, the responding cells being characterised by alkaline phosphatase-anti-alkaline phosphatase immunocytochemistry. Recombinant interleukin (rIL)-1 alpha, zymosan activated plasma (ZAP) and rIL-8 were shown to induce concentration-related migration of mixed PBL in the 48 well assay and were therefore used as reference agonists. Total T cells, B cells, T helper/inducer and T suppressor/cytotoxic cells, as well as lymphocytes stained with the monoclonal antibodies UCHL1 and SN130, have now been quantified after migration to the undersurface of 8 microns pore size polycarbonate filters, in response to optimal concentrations of rIL-1 alpha, ZAP and rIL-8. The value of the analytical method was demonstrated by the selective responses seen. rIL-1 alpha selectively stimulated the migration of T helper/inducer and a small number of B cells without affecting T suppressor/cytotoxic cell locomotion. ZAP and rIL-8 significantly stimulated the migration of T helper/inducer, T suppressor/cytotoxic and B cells. ZAP and rIL-1 alpha also stimulated the migration of both UCHL1 and SN130 positively stained cells. This method may therefore be used to investigate the selective actions of lymphocyte locomotor stimuli on PBL sub-populations without the need to purify specific cell subsets, and to study the specificity of certain inhibitors or drugs on lymphocyte responses.
Antigens, Differentiation, B-Lymphocyte↗
Chemotactic cytokines in inflammatory skin disease.
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Chemotaxis, Leukocyte↗
The in vitro 5-lipoxygenase and cyclo-oxygenase inhibitor L-652,343 does not inhibit 5-lipoxygenase in vivo in human skin.
1 3-hydroxy-5-trifluoromethyl-N-[2-(2-thienyl)-2-phenyl-ethenyl]-benzo(B) thiophene-2-carboxamide (L-652,343) is a 5-lipoxygenase and cyclo-oxygenase inhibitor in vitro. 2 In psoriasis increased concentrations of arachidonic acid transformation products are found in the lesional skin which may be important in the pathogenesis of the disease. We have measured the effect of orally administered L-652,343 on the concentration of LTB4 and prostaglandins in the lesional skin. 3 Eight patients with stable chronic plaque psoriasis received 500 and 250 mg of L-652,343, 12 h apart. A chamber technique was used to collect skin exudate samples from abraded plaques before and at 4, 24 and 48 h after the first dose. Exudates were analysed for LTB4 by a neutrophil chemokinesis assay and for PGE2 and PGD2 by RIA. 4 PGE2 and PGD2 levels were significantly reduced at 4 and 24 h after the first dose of L-652,343 but LTB4 levels were not affected indicating inhibition of the cyclo-oxygenase pathway but not of the 5-lipoxygenase pathway. This shows the importance of confirming that the action of 5-lipoxygenase inhibiting drugs in vitro occurs in vivo.
Adult↗
Topical steroid treatment reduces arachidonic acid and leukotriene B4 in lesional skin of psoriasis.
Topical clobetasol propionate or vehicle ointment was applied daily for 3 days to psoriatic plaques on eight patients. Skin chamber exudates from untreated, steroid and vehicle treated lesions were assayed for arachidonic acid (AA), leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) before, and at 24 h and 72 h after treatment. Significant reductions in AA and LTB4 were observed at 72 h in steroid treated lesions. The reduction in 12-HETE levels observed after steroid treatment was not statistically significant. PGE2 levels in lesional psoriatic skin were unaltered. The reduction of AA, and LTB4 was associated with clinical improvement of psoriasis.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Interference in a two-site immunoradiometric assay for thyrotropin in a child.
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Antibody Specificity↗