Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Key points• We recently showed that orexin neurons in the hypothalamus are indispensable for stress-induced thermogenesis.• In this study we examined whether the orexin neurons are also important for other forms of thermogenic processes, including brain prostaglandin E 2 (PGE 2 ) injection that mimics inflammatory fever and environmental cold exposure.• As was the case with stress-induced thermogenesis, orexin neuron-ablated (ORX-AB) mice exhibited a blunted PGE 2 -induced fever and intolerance to cold (5 • C) exposure.• Injection of retrograde tracer into the medullary raphe nucleus, where sympathetic premotor neurons regulating thermogenesis by the brown adipose tissue are located, revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice.• These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. AbstractWe recently showed using prepro-orexin knockout (ORX-KO) mice and orexin neuron-ablated (ORX-AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress-induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E 2 (PGE 2 ) injections which mimic inflammatory fever and environmental cold exposure, to ORX-KO mice, ORX-AB mice and their wild-type (WT) litter mates. ORX-AB mice, but not ORX-KO mice, exhibited a blunted PGE 2 -induced fever and intolerance to cold (5 • C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE 2 -induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39• C). In WT and ORX-KO mice, the administration of PGE 2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c-fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice. In addition, we found that glutamate receptor antagonists (D-(-)-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE 2 -induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE 2 -induced fever.

Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H 2 O 2 ) to generate the reactive metabolite and compared reactive metaboliteinduced cytotoxicity between HL-60 cells undergoing granulocytic differentiation and differentiated HL-60 cells. In addition, we examined the role of oxidative stress in this type of cytotoxicity. The reactive metabolite of clozapine induced rapid cytotoxicity in HL-60 cells undergoing granulocytic differentiation, but not in differentiated HL-60 cells, with the metabolite exhibiting more potent cytotoxicity than clozapine. No cytotoxicity was observed following incubation with olanzapine, a structural analog of clozapine, even after exposure of the drug to H 2 O 2 . The reactive metabolite of clozapine decreased the levels of reduced glutathione, while addition of reduced glutathione attenuated the reactive metabolite-induced cytotoxicity. These findings indicate that glutathione metabolism plays a role in the hematopoietic toxicity induced by the reactive metabolite of clozapine. Oxidative stress may potentially increase susceptibility to the hematopoietic toxicity induced by the reactive metabolite of clozapine.

Renal and bone marrow involvements in sarcoidosis are rare. We experienced the case of a 67-year-old man with systemic sarcoidosis, with bone marrow involvement, hepatic involvement and a unique constellation of renal lesion with cellular crescent formation. Immunosuppressive therapy was helpful for maintaining the stability of his pancytopenia, hepatic function and renal function. To the best of our knowledge, the association between sarcoidosis, bone marrow involvement and crescentic glomerulonephritis has been reported in only few cases in literature.

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