Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.     

Selective pair recognition memory impairment with no response bias in schizophrenia

Memory is one of the cognitive functions most affected in schizophrenia, but the severity of deficits varies from one task to another. In particular, greater impairments have been reported for pair recognition than item recognition. However, decision biases and how they could affect memory dysfunction in schizophrenia have received scant attention. In this study, 26 people with schizophrenia and 28 healthy controls were administrated an association item recognition task. During encoding, participants studied pairs of visual objects, and they had to memorise objects and their pairing. In a subsequent retrieval task, participants performed an item recognition test (old/new items) and a pair recognition test (intact/rearranged pairs). Results showed that both groups were better at recognizing items than pairs, with lower performance for pair recognition, but not for item recognition, in people with schizophrenia. Analyses of response biases revealed that patients had a conservative response bias for items but not for pairs. The study also provides evidence that associative impairment may not result from decisional bias but rather from impairments in mnesic processes.     

Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice

Obstructive sleep apnoea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. Obstructive sleep apnoea has been associated with liver injury. Acetaminophen (APAP; known as paracetamol outside the USA) is one of the most commonly used drugs which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. Adult C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg kg⁻¹) or normal saline daily. A combination of CIH and APAP caused liver injury, with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. Acetaminophen alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a fivefold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. Acetaminophen or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.     

Syk-deficient eosinophils show normal interleukin-5-mediated differentiation, maturation, and survival but no longer respond to FcgammaR activation

The tyrosine kinase Syk has been proposed to play a critical role in the antiapoptotic effect of interleukin (IL)-5 in human eosinophils. However, little is known about the involvement of Syk in other IL-5-mediated activation events. To further address these questions, the role of Syk in IL-5-induced eosinophil differentiation, activation, and survival was analyzed using cells obtained from Syk-deficient mice. We could demonstrate that Syk-deficient fetal liver cells differentiate into mature eosinophils in response to IL-5 at the same rate as wild-type fetal liver cells and generate the same total number of eosinophils. Moreover, no difference in IL-5-induced survival of mature eosinophils between Syk(-/-) and wild-type eosinophils could be demonstrated, suggesting that the antiapoptotic effect of IL-5 does not require Syk despite the activation of this tyrosine kinase upon IL-5 receptor ligation. In contrast, eosinophils derived from Syk-deficient but not wild-type mice were incapable of generating reactive oxygen intermediates in response to Fcgamma receptor (FcgammaR) engagement. Taken together, these data clearly demonstrate no critical role for Syk in IL-5-mediated eosinophil differentiation or survival but underline the importance of this tyrosine kinase in activation events induced by FcgammaR stimulation.     

Studies on the uptake of low molecular weight monomeric tris-galactosyl conjugates by the rat liver.

We have attempted to direct low molecular weight compounds to the liver via the internalizing asialoglycoprotein receptor on parenchymal cells by conjugation to a monomeric triantennary galactosyl cluster. Acetate and a hypolipidaemic ansamycin were derivatized and the biodistribution of the conjugates was determined 250 sec and 30 min after administration to Wistar rats. The ansamycin conjugate (CGH46) was rapidly cleared from the circulation by the liver; after 250 sec, 64% of the radiolabelled dose was found in the liver compared to 18% in the blood. However, the distribution of the conjugate did not differ significantly from that of unconjugated ansamycin (CGH45). Tris-galactosyl acetate showed no capacity to localize in the liver, with only 2% recovered from that organ 250 sec after administration compared to 38% in the blood and 13-18% in the kidneys, skin and muscle. Extraction efficiency of CGH46 by isolated perfused rat livers was almost 20% of the administered dose and this value was not significantly changed by co-administration of specific inhibitors of the uptake process. It is concluded that derivatization of low molecular weight molecules with monomeric triantennary galactosyl residues is unlikely to increase their affinity for the liver.     

Organizational analysis of Canadian supported employment programs for people with psychiatric disabilities

Supported employment (SE) is widely considered to be the most effective intervention for helping people with psychiatric disabilities integrate into the competitive workforce. While fidelity to principles and standards of evidence-based SE, i.e., the Individual Placement and Support model, is positively associated with vocational outcomes, studies have revealed significant heterogeneity in SE programs implemented in Canada. This qualitative study thus aimed to shed light on organizational and contextual factors influencing SE implementation in three Canadian provinces (British Columbia, Ontario and Quebec). The study adopted several key concepts from the field of organizational studies (e.g., coalitions, archetypes, isomorphism) to guide data collection and analysis. Overall, 20 SE programs provided by 15 different agencies were examined. Findings revealed that agencies' exposure to different institutional pressures, their interactions and relationships with other groups and organizations, as well as their values, beliefs and ideologies played determining roles in shaping the evolution of SE services in each province.