Inactivated influenza vaccine reduced proven influenza illness by 63% in infants up to 6 months of age and averted approximately a third of all febrile respiratory illnesses in mothers and young infants. Maternal influenza immunization is a strategy with substantial benefits for both mothers and infants. (ClinicalTrials.gov number, NCT00142389.)

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.

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Study objective: To assess prevalence of arsenic exposure through drinking water and skin lesions, and their variation by geographical area, age, sex, and socioeconomic conditions. Design, setting, and participants: Skin lesion cases were identified by screening the entire population above 4 years of age (n = 166 934) living in Matlab, a rural area in Bangladesh, during January 2002 and August 2003. The process of case identification involved initial skin examinations in the field, followed by verification by physicians in a clinic, and final confirmation by two independent experts reviewing photographs. The tubewell water arsenic concentrations (n = 13 286) were analysed by atomic absorption spectrometry. Drinking water history since 1970 was obtained for each person. Exposure information was constructed using drinking water histories and data on water arsenic concentrations. Main results: The arsenic concentrations ranged from ,1 to 3644 mg/l, and more than 70% of functioning tubewells exceeded the World Health Organisation guideline of 10 mg/l. Arsenic exposure had increased steadily from 1970s to the late 1990s, afterwards a decrease could be noted. In total, 504 skin lesions cases were identified, and the overall crude prevalence was 3/1000. Women had significantly higher cumulative exposure to arsenic, while men had significantly higher prevalence of skin lesions (SMR 158, 95% CI 133 to 188). The highest prevalence occurred in 35-44 age groups for both sexes. Arsenic exposure and skin lesions had a positive association with socioeconomic groups and achieved educational level. Conclusions: The result showed sex, age, and socioeconomic differentials in both exposure and skin lesions. Findings clearly showed the urgency of effective arsenic mitigation activities.

Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion-induced oxidative stress or the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics.

The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in ΔF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of ΔF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on ΔF508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects ΔF508 CFTR trafficking by inhibiting Hop expression, and that combination therapiesusing differing mechanisms of action-may have additive benefits in treating CF.cystic fibrosis transmembrane conductance regulator | S-nitrosoglutathione corrector | treatment

The activities of certain nuclear regulatory proteins are modified by high concentrations of S-nitrosothiols associated with nitrosative stress. In the present study, we have studied the effect of physiological (low microM) concentrations of the endogenous S-nitrosothiol, GSNO (S-nitrosoglutathione), on the activities of nuclear regulatory proteins Sp3 and Sp1 (specificity proteins 3 and 1). Low concentrations of GSNO increased Sp3 binding, as well as Sp3-dependent transcription of the cystic fibrosis transmembrane conductance regulatory gene, cftr. However, higher GSNO levels prevented Sp3 binding, augmented Sp1 binding and prevented both cftr transcription and CFTR (cystic fibrosis transmembrane conductance regulator) expression. We conclude that low concentrations of GSNO favour Sp3 binding to 'housekeeping' genes such as cftr, whereas nitrosative stress-associated GSNO concentrations shut off Sp3-dependent transcription, possibly to redirect cellular resources. Since low micromolar concentrations of GSNO also increase the maturation and activity of a clinically common CFTR mutant, whereas higher concentrations have the opposite effect, these observations may have implications for dosing of S-nitrosylating agents used in cystic fibrosis clinical trials.