Objective-To determine the outcome of administration of neuroleptics to Results-16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2-70 (95% confidence interval 2

No abstract

Abstract:Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to date it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal cortex of 14 AD cases and 15 age-matched control subjects was compared using immunoblotting with antibodies against recombinant peptides specific for ␣3, ␣4, and ␣7 subunits, in conjunction with [3 H]epibatidine binding. Antibodies to ␣3, ␣4, and ␣7 produced one major band on western blots at 59, 51, and 57 kDa, respectively. [ 3 H]Epibatidine binding and ␣4-like immunoreactivity (using antibodies against the extracellular domain and cytoplasmic loop of the ␣4 subunit) were reduced in AD cases compared with control subjects ( p Ͻ 0.02) and with a subgroup of control subjects (n ϭ 9) who did not smoke prior to death ( p Ͻ 0.05) for the former two parameters. [ 3 H]Epibatidine binding and cytoplasmic ␣4-like immunoreactivity were significantly elevated in a subgroup of control subjects (n ϭ 4) known to have smoked prior to death ( p Ͻ 0.05). There were no significant changes in ␣3-or ␣7-like immunoreactivity associated with AD or tobacco use. The selective involvement of ␣4 has implications for understanding the role of nicotinic receptors in AD and potential therapeutic targets. Key Words: Nicotinic acetylcholine receptors-␣3 subunit-␣4 subunit-␣7 subunit-Alzheimer's disease-Tobacco smoking.

Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.