P300/CBP Regulates HIF-1-Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.

Obstructive sleep apnea (OSA), a widespread breathing disorder, leads to intermittent hypoxia (IH). Patients with OSA and IH-treated rodents exhibit heightened sympathetic nerve activity and hypertension. Previous studies reported transcriptional activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) by HIF-1 (hypoxia-inducible factor-1) contribute to autonomic dysfunction in IH-treated rodents. Lysine acetylation, regulated by KATs (lysine acetyltransferases) and KDACs (lysine deacetylases), activates gene transcription and plays an important role in several physiological and pathological processes. This study tested the hypothesis that acetylation of HIF-1α by p300/CBP (CREB-binding protein) (KAT) activates Nox transcription, leading to sympathetic activation and hypertension. Experiments were performed on pheochromocytoma-12 cells and rats treated with IH. IH increased KAT activity, p300/CBP protein, HIF-1α lysine acetylation, HIF-1 transcription, and HIF-1 binding to the Nox4 gene promoter in pheochromocytoma-12 cells, and these responses were blocked by CTK7A, a selective p300/CBP inhibitor. Plasma norepinephrine (index of sympathetic activation) and blood pressures were elevated in IH-treated rats. These responses were associated with elevated p300/CBP protein, HIF-1α stabilization, transcriptional activation of Nox2 and Nox4 genes, and reactive oxygen species, and all these responses were absent in CTK7A-treated IH rats. These findings suggest lysine acetylation of HIF-1α by p300/CBP is an important contributor to sympathetic excitation and hypertension by IH.

Maximizing patient safety when prescribing opioids for pain management.

ABSTRACT: Cytochrome P450 enzyme metabolism is altered by environmental and genetic factors, which can affect the efficacy and safety of opioids. This article describes CYP polymorphisms and how pharmacogenetic testing could be used to help clinicians make safer decisions about opioid use in patients.

Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCß, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.

I'll See You in Court Again: Psychopathology and Hyperlitigious Litigants.

Persistent litigation is a problem in many legal jurisdictions and is costly at individual and systemic levels. This phenomenon is referred to as "querulous" behavior in psychiatric literature, whereas legal discourse refers to it as "vexatious litigation." We refer to this phenomenon as "hyperlitigious behavior" and those who engage in these actions as "hyperlitigious litigants." Hyperlitigious litigants and hyperlitigious behavior were once the focus of a considerable amount of psychiatric literature, but research devoted to these topics has declined over the past half century. A review of the published literature on hyperlitigious behavior in European and English-speaking countries highlights geographic differences in the conceptualization and management of this behavior. We provide an alternative framework to consider the motivation to engage in hyperlitigious behavior and suggest three strategies for mental health professionals who interact with these individuals. Finally, we call for a revival of discussions and research within the English-speaking psychiatric community to facilitate more informed decisions regarding the management and treatment of hyperlitigious behavior.

Novel environment influences the effect of paradoxical sleep deprivation upon brain and peripheral cytokine gene expression.

Sleep loss increases inflammatory mediators in brain and peripheral tissues, but the mechanisms underlying this association are not fully understood. Male C57BL/6j mice were exposed to paradoxical sleep deprivation (PSD) for 24h using the modified multiple platform (MMP) technique (platforms over water) or two different controls: home cage or a dry platform cage, which constituted a novel environment. PSD mice exhibited increased IL-1ß and TNF-α pro-inflammatory gene expression in brain (hypothalamus, hippocampus, pre-frontal cortex), as well as in peripheral tissues (liver, spleen), when compared with home-cage controls. In addition, among PSD mice, TGFß1, an anti-inflammatory cytokine, was increased in pre-frontal cortex, liver, and spleen in conjunction with elevated serum corticosterone concentration relative to home-cage controls. However, these differences were nearly abolished when PSD mice were compared with control mice subjected to a dry MMP cage, suggesting that simply exposing mice to a novel environment can induce an acute inflammatory response.

Hypothetical constructs, hypothetical questions, and the expert witness.

Professor John Henry Wigmore in 1940 described the hypothetical question as an intolerable obstruction of truth. Since that time, the nature and application of the hypothetical question in the courtroom, as well as responses to this line of questioning during expert testimony, have been sources of controversy. Governed by legal philosophical foundations, the hypothetical construct addresses what there is, in a general sense, and what can or ought to be. Alexy (2004) has described the nature of legal philosophy as the epistemological question of what we can know. This article begins by examining the philosophical underpinnings, legal parameters, and teaching purposes of posing hypothetical queries. A social-psychological backdrop for the use of hypothetical questions is then discussed followed by a broader discussion of the hypothetical question's role in court procedures. This paper identifies hypothetical questions used in court as devices to elicit information, or as predictions that potentially change underlying factual interpretations of evidence. In particular, on cross examination hypothetical questions seek to make opposing experts assume facts that are incongruent with their conclusions or opinions. Sometimes in these situations, experts are led to re-evaluate opinions based on alternative understandings of events and behaviors. Thus, this paper's final aim is to explore a foundational understanding of hypothetical questions asked of expert witnesses with special reference to mental health issues. Options for responding to hypothetical questions on the stand are considered along the dimensions of assertiveness-passivity, compliance-resistance, and possible redefinitions of the hypothetical issues.