Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus

Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine-sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral-CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action.     

Cardiovascular health and economic effects of smoke-free workplaces

PURPOSE: Smoking is the leading controllable risk factor for heart disease. Only about 69% of U.S. indoor workers are currently covered by a smoke-free workplace policy. This analysis projects the cardiovascular health and economic effects of making all U.S. workplaces smoke free after 1 year and at steady state. METHODS: We estimated the number of U.S. indoor workers not covered by smoke-free workplace policies, and the effects of making all workplaces smoke free on smoking behavior and on the relative risks of acute myocardial infarctions and strokes. One-year and steady-state results were calculated using an exponential decline model. A Monte Carlo simulation was performed for a sensitivity analysis. RESULTS: The first-year effect of making all workplaces smoke free would produce about 1.3 million new quitters and prevent over 950 million cigarette packs from being smoked annually, worth about 2.3 billion dollars in pretax sales to the tobacco industry. In 1 year, making all workplaces smoke free would prevent about 1500 myocardial infarctions and 350 strokes, and result in nearly $60 [corrected] in savings in direct medical costs. At steady state, 6250 myocardial infarctions and 1270 strokes would be prevented, and $279 million [corrected] would be saved in direct medical costs annually. Reductions in passive smoking would account for 60% of effects among acute myocardial infarctions. CONCLUSION: Making all U.S. workplaces smoke free would result in considerable health and economic benefits within 1 year. Reductions in passive smoking would account for a majority of these savings. Similar effects would occur with enactment of state or local smoke-free policies.     

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CA1 pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxia-induced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodium-dependent action potentials and low-threshold transient calcium conductances. These findings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable.     

GTP-binding proteins inhibit cAMP activation of chloride channels in cystic fibrosis airway epithelial cells.

Cystic fibrosis (CF) is a genetic disease characterized, in part, by defective regulation of Cl- secretion by airway epithelial cells. In CF, cAMP does not activate Cl- channels in the apical membrane of airway epithelial cells. We report here whole-cell patch-clamp studies demonstrating that pertussis toxin, which uncouples heterotrimeric GTP-binding proteins (G proteins) from their receptors, and guanosine 5'-[beta-thio]diphosphate, which prevents G proteins from interacting with their effectors, increase Cl- currents and restore cAMP-activated Cl- currents in airway epithelial cells isolated from CF patients. In contrast, the G protein activators guanosine 5'-[gamma-thio]triphosphate and AlF4- reduce Cl- currents and inhibit cAMP from activating Cl- currents in normal airway epithelial cells. In CF cells treated with pertussis toxin or guanosine 5'-[beta-thio]diphosphate and in normal cells, cAMP activates a Cl- conductance that has properties similar to CF transmembrane-conductance regulator Cl- channels. We conclude that heterotrimeric G proteins inhibit cAMP-activated Cl- currents in airway epithelial cells and that modulation of the inhibitory G protein signaling pathway may have the therapeutic potential for improving cAMP-activated Cl- secretion in CF.     

Novel Approaches to Improve the Intrinsic Microbiological Safety of Powdered Infant Milk Formula

Human milk is recognised as the best form of nutrition for infants. However; in instances where breast-feeding is not possible, unsuitable or inadequate, infant milk formulae are used as breast milk substitutes. These formulae are designed to provide infants with optimum nutrition for normal growth and development and are available in either powdered or liquid forms. Powdered infant formula is widely used for convenience and economic reasons. However; current manufacturing processes are not capable of producing a sterile powdered infant formula. Due to their immature immune systems and permeable gastro-intestinal tracts, infants can be more susceptible to infection via foodborne pathogenic bacteria than other age-groups. Consumption of powdered infant formula contaminated by pathogenic microbes can be a cause of serious illness. In this review paper, we discuss the current manufacturing practices present in the infant formula industry, the pathogens of greatest concern, Cronobacter and Salmonella and methods of improving the intrinsic safety of powdered infant formula via the addition of antimicrobials such as: bioactive peptides; organic acids; probiotics and prebiotics.     

Sexual and Relationship Benefits of a Safer Conception Intervention Among Men with HIV Who Seek to Have Children with Serodifferent Partners in Uganda

AIDS and Behavior - Many men with HIV (MWH) in Uganda desire children, yet seldom receive reproductive counseling related to HIV care. Because men are under engaged in safer conception programming,...