Haematological toxicity of clozapine and some other drugs used in psychiatry

OBJECTIVE: To review recent work on the haematological toxicity of clozapine and some other drugs used in psychiatry concerning especially (i) the mechanism of antipsychotic-induced neutropenia/agranulocytosis, (ii) criteria for clozapine prescribing in benign ethnic neutropenia, (iii) options in the event of worrying falls in white cell count (WCC), including measures to boost WCC with or without continued clozapine administration, (iv) criteria for clozapine rechallenge in the event that treatment was suspended because of a fall in WCC and (v) safety concerns regarding clozapine in children/adolescents. CONCLUSIONS: There remain several difficult areas, including the criteria for clozapine rechallenge. Experience has emphasised (i) the role of appropriate timing of WCC sample collection to ensure that clozapine is not withdrawn unnecessarily and (ii) the success of agents such as filgrastim in promoting rapid production of granulocytes if the situation so demands. On the other hand, the use of lithium to promote a leucocytosis has taken hold without a clear risk: benefit analysis. Be this as it may, should patients decide that they no longer wish to undergo WCC monitoring after 12 months on clozapine, cessation of monitoring is probably preferable to stopping the drug since overall mortality is decreased in patients treated with clozapine.     

Improvement in medical risk factors and quality of life in women and men with coronary artery disease in the Multicenter Lifestyle Demonstration Project

This study examined medical and psychosocial characteristics of 440 patients (mean age 58 years, 21% women) with coronary artery disease at baseline and at 3-month and 12-month follow-ups. All patients were participants in the Multicenter Lifestyle Demonstration Project, aimed at improving diet (low fat, whole foods, plant-based), exercise, stress management, and social support. Spousal participation was encouraged. Both genders evidenced significant improvements in their diet, exercise, and stress management practices, which they maintained over the course of the study. Both women and men also showed significant medical (e.g., plasma lipids, blood pressure, body weight, exercise capacity) and psychosocial (e.g., quality of life) improvement. Despite their worse medical, psychosocial, and sociodemographic status at baseline, women's improvement was similar to that of men's. These results demonstrate that a multi-component lifestyle change program focusing on diet, exercise, stress management, and social support can be successfully implemented at hospitals in diverse regions of the United States. Furthermore, this program may be particularly beneficial for women with coronary artery disease who generally have higher mortality and morbidity than men after a heart attack, angioplasty, or bypass surgery.     

Toll-like receptor 4 deficiency causes pulmonary emphysema

TLRs have been studied extensively in the context of pathogen challenges, yet their role in the unchallenged lung is unknown. Given their direct interface with the external environment, TLRs in the lungs are prime candidates to respond to air constituents, namely particulates and oxygen. The mechanism whereby the lung maintains structural integrity in the face of constant ambient exposures is essential to our understanding of lung disease. Emphysema is characterized by gradual loss of lung elasticity and irreversible airspace enlargement, usually in the later decades of life and after years of insult, most commonly cigarette smoke. Here we show Tlr4(-/-) mice exhibited emphysema as they aged. Adoptive transfer experiments revealed that TLR4 expression in lung structural cells was required for maintaining normal lung architecture. TLR4 deficiency led to the upregulation of what we believe to be a novel NADPH oxidase (Nox), Nox3, in lungs and endothelial cells, resulting in increased oxidant generation and elastolytic activity. Treatment of Tlr4(-/- )mice or endothelial cells with chemical NADPH inhibitors or Nox3 siRNA reversed the observed phenotype. Our data identify a role for TLR4 in maintaining constitutive lung integrity by modulating oxidant generation and provide insights into the development of emphysema.     

Ontogeny stage-independent and high-level clonal expansion in vitro of mouse hematopoietic stem cells stimulated by an engineered NUP98-HOX fusion transcription factor

Achieving high-level expansion of hematopoietic stem cells (HSCs) in vitro will have an important clinical impact in addition to enabling elucidation of their regulation. Here, we couple the ability of engineered NUP98-HOXA10hd expression to stimulate > 1000-fold net expansions of murine HSCs in 10-day cultures initiated with bulk lin(-)Sca-1(+)c-kit(+) cells, with strategies to purify fetal and adult HSCs and analyze their expansion clonally. We find that NUP98-HOXA10hd stimulates comparable expansions of HSCs from both sources at ～ 60% to 90% unit efficiency in cultures initiated with single cells. Clonally expanded HSCs consistently show balanced long-term contributions to the lymphoid and myeloid lineages without evidence of leukemogenic activity. Although effects on fetal and adult HSCs were indistinguishable, NUP98-HOXA10hd-transduced adult HSCs did not thereby gain a competitive advantage in vivo over freshly isolated fetal HSCs. Live-cell image tracking of single transduced HSCs cultured in a microfluidic device indicates that NUP98-HOXA10hd does not affect their proliferation kinetics, and flow cytometry confirmed the phenotype of normal proliferating HSCs and allowed reisolation of large numbers of expanded HSCs at a purity of 25%. These findings point to the effects of NUP98-HOXA10hd on HSCs in vitro being mediated by promoting self-renewal and set the stage for further dissection of this process.     

The role of endogenous heme oxygenase in the initiation of liver injury following limb ischemia/reperfusion

BACKGROUND/AIMS: Heme oxygenase (HO) derived liver protection was tested in mice following 1 h bilateral hindlimb ischemia and either 1.5 or 3 h reperfusion. METHODS: Groups consisted of limb ischemia/reperfusion (I/R), sham (no I/R), I/R+chromium mesoporphyrin (I/R+CrMP;40 micromol/kg, i.p.), or I/R+hemin (10 mg/kg, i.p.). The vital dye propidium iodide (PI), was used to measure hepatocellular death (#/0.1 mm(3)), while the number of sinusoids perfused by red blood cells (SP(RBC)) were measured from the periportal (Pp) and pericentral (Pc) zones of liver acini using intravital microscopy. Whole organ injury was estimated from serum alanine aminotransferase (ALT). RESULTS: SP(RBC) reduced within 1.5 h with no further decline following 3 h. CrMP resulted in a dramatic loss of SP(RBC) following 3 h only. Hemin restored perfusion in both zones. Hepatocellular death and organ injury increased at 1.5 and 3 h. At 1.5 h, CrMP further increased cell death in the Pc zone, as well as whole organ injury, while hemin restored cell viability. Increased HO mRNA, protein and activity suggested induction within 3 h. CONCLUSIONS: HO does not protect perfusion during the early stage (1.5 h), but becomes increasingly important in preserving liver perfusion and cell viability during the later stage (3 h) of liver injury.     

Academic Detailing to Teach Aging and Geriatrics

Geriatric education is a required component of internal medicine training. Work hour rules and hectic schedules have challenged residency training programs to develop and utilize innovative teaching methods. In this study, the authors examined the use of academic detailing as a teaching intervention in their residents’ clinic and on the general medicine inpatient wards to improve clinical knowledge and skills in geriatric care. The authors found that this teaching method enables efficient, directed education without disrupting patient care. We were able to show improvements in medical knowledge as well as self-efficacy across multiple geriatric topics.