Finleyschwartz8201

This paper addresses a novel putative mechanism by which atypical antipsychotic agents induce clinically significant neuroprotective effects that may be viable in the treatment of schizophrenia - and perhaps other neuropsychiatric disorders. Based upon experimental studies with multiple in vitro models (i.e., PC 12 cells, NSC-34 hybrid cells, SH-SY5Y cells, the immune cell line U-937) and several rodent in vivo models, six atypical antipsychotic drugs, within direct experimental comparisons and/or preconditioning protocol studies with six different stressor/toxic agents (i.e. rotenone, hydrogen peroxide, MPP+, serum withdrawal, beta-amyloid, and corticosterone) were demonstrated to induce neuroprotective effects with consistently hormetic dose response patterns. These findings suggest that some of the reported neuroprotective effects of atypical human antipsychotic agents are likely to be mediated by hormetic mechanisms. These findings may have important implications for both experimental study design and clinical therapeutics.Nicotine exposure increases the release of glutamate in part through stimulatory effects on pre-synaptic nicotinic acetylcholine receptors (nAChRs). To assess the impact of chronic electronic (e)-cigarette use on these drug dependence pathways, we exposed C57BL/6 mice to three types of inhalant exposures for 3 months; 1) e-cigarette aerosol generated from liquids containing nicotine (ECN), 2) e-cigarette aerosol generated from liquids containing vehicle chemicals without nicotine (Veh), and 3) air only (AC). We investigated the effects of daily e-cigarette exposure on protein levels of α7 nAChR and α4/β2 nAChR, gene expression and protein levels of astroglial glutamate transporters, including glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT), in the frontal cortex (FC), striatum (STR) and hippocampus (HIP). We found that chronic inhalation of ECN increased α4/β2 nAChR in all brain regions, and increased α7 nAChR expression in the FC and STR. The total GLT-1 relative mRNA and protein expression were decreased in the STR. Moreover, GLT-1 isoforms (GLT-1a and GLT-1b) were downregulated in the STR in ECN group. However, inhalation of e-cigarette aerosol downregulated xCT expression in STR and HIP compared to AC and Veh groups. ECN group had increased brain-derived neurotrophic factor in the STR compared to control groups. Finally, mass spectrometry detected high concentrations of the nicotine metabolite, cotinine, in the FC and STR in ECN group. This work demonstrates that chronic inhalation of nicotine within e-cigarette aerosols significantly alters the expression of nAChRs and astroglial glutamate transporters in specific mesocorticolimbic brain regions.Lead (Pb) is one of the most common heavy metal contaminants in the environment. Pb can cause pathophysiological changes in several organ systems, including the cardiovascular system, but the molecular mechanism remains elusive. The study aimed to study the effects of Pb on Gap junction intercellular communication (GJIC) and its role in Pb-induced apoptosis. The present study aims to determine whether Pb-induced autophagy promotes apoptosis of rat cardiac myocytes (H9c2 cells) by downregulating GJIC using CCK-8 Kit, scrape loading/dye transfer assay, Annexin V/PI assays, Western blot analysis and double-immunofluorescence experiments. The results showed that Pb elicited cytotoxicity in a time- and concentration-dependent manner and led to increased apoptosis in a concentration-dependent manner in H9c2 cells. Pb also reduced GJIC in H9c2 cells in a concentration-dependent manner through the downregulation of connexin (Cx) 43. Inhibition of gap junctions by gap junction blocker carbenoxolone disodium (CBX) resulted in increased apoptosis. Furthermore, Pb increased autophagy in a concentration-dependent manner in H9c2 cells, decreasing the distribution of Cx43 on the cell membrane, and targeted Cx43 to autophagosome via light chain 3 (LC3). Elexacaftor However, autophagy inhibitor 3-Methyladenine (3-MA) can slow down the downregulation of Cx43 induced by Pb in H9c2 cells. In conclusion, our results provide evidence that Pb-decreased GJIC promotes apoptosis in cardiomyocytes. This is probably because of the fact that Pb-induced autophagy exacerbates GJIC inhibition and downregulation of Cx43.

With increasing intention to treat HIV as early as possible, evidence to confirm the safety and therapeutic drug concentrations of a nevirapine-based antiretroviral regimen in the early neonatal period is needed. This study aims to establish dosing of nevirapine for very early treatment of HIV-exposed neonates at high risk of HIV acquisition.

IMPAACT P1115 is a multinational phase 1/2 proof-of-concept study in which presumptive treatment for in-utero HIV infection is initiated within 48 h of birth in HIV-exposed neonates at high risk of HIV acquisition. Participants were neonates who were at least 34 weeks gestational age at birth and enrolled within 48 h of birth, born to women with presumed or confirmed HIV infection who had not received antiretrovirals during this pregnancy. The regimen consisted of two nucleoside reverse transcriptase inhibitors plus nevirapine dosed at 6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafte of 349 neonates at week 1 and 174 (87%, 81-91) of 201 at week 2. In Monte-Carlo simulations, week 1 nevirapine concentrations exceeded 3 μg/mL in 80% of term neonates and 82% of preterm neonates. DAIDS grade 3 or 4 adverse events at least possibly related to antiretrovirals occurred in 30 (7%, 95% CI 5-10) of 438 infants but did not lead to nevirapine cessation in any neonates; neutropenia (25 [6%] neonates) and anaemia (six [1%]) were most common.

Nevirapine at the dose studied was confirmed to be safe and provides therapeutic exposure concentrations. These data support nevirapine as a component of presumptive HIV treatment in high-risk neonates.

National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.