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The polymerase delta interacting protein 2 (Poldip2) is a nuclear-encoded mitochondrial protein required for oxidative metabolism. Under hypoxia, Poldip2 expression is repressed by an unknown mechanism. Therefore, low levels of Poldip2 are required to maintain glycolytic metabolism. The Cellular Communication Network Factor 2 (CCN2, Connective tissue growth factor, CTGF) is a profibrogenic molecule highly expressed in cancer and vascular inflammation in advanced atherosclerosis. Because CCN2 is upregulated under hypoxia and is associated with glycolytic metabolism, we hypothesize that Poldip2 downregulation is responsible for the upregulation of profibrotic signaling under hypoxia. Here, we report that Poldip2 is repressed under hypoxia by a mechanism that requires the activation of the enhancer of zeste homolog 2 repressive complex (EZH2) downstream from the Cyclin-Dependent Kinase 2 (CDK2). Importantly, we found that Poldip2 repression is required for CCN2 expression downstream of metabolic inhibition of the ubiquitin-proteasome system (UPS)-dependent stabilization of the serum response factor. Pharmacological or gene expression inhibition of CDK2 under hypoxia reverses Poldip2 downregulation, the inhibition of the UPS, and the expression of CCN2, collagen, and fibronectin. Thus, our findings connect cell cycle regulation and proteasome activity to mitochondrial function and fibrotic responses under hypoxia. [Display omitted] • In hypoxia, Poldip2 is repressed by EZH2-mediated signaling downstream of the cell cycle. • Poldip2 expression under hypoxia controls the activity of the Ubiquitin proteasome system. • Cell cycle regulation controls pro-fibrotic signaling under hypoxia. • Poldip2 deficiency exacerbates hypoxia-induced vascular hypoxia. [ABSTRACT FROM AUTHOR]

Objective We describe Veterans Affairs (VA) primary care received by veterans with mental health symptoms in the year prior to suicide to identify opportunities to improve care. Method Death certificate data from 11 states were linked to VA national patient care data for veterans who died by suicide in 2009 and had received VA care. We identified 118 age-, sex- and clinician-matched case–control pairs (suicide decedents and living controls) with mental health symptoms. Using McNemar's chi-square and paired t tests, we compare primary care follow-up received during the year prior to death. Results Cases and controls received similar primary care clinician follow-up and treatment for mental health symptoms. Cases were less likely than controls to fill 90 or more total days of an antidepressant during the year ( P = .02), despite no differences in prescription orders from clinicians ( P = .05). Cases and controls were equally likely to fill 90 or more consecutive days of an antidepressant ( P = .47). Across both groups, 48% ( n = 113) received assessment for suicidal ideation in primary care. Conclusion We identified two areas to improve primary care for veterans at risk for suicide: monitoring antidepressant treatment adherence and improving suicidal ideation assessment and follow-up for veterans with mental health symptoms. [ABSTRACT FROM AUTHOR]

In 1996, Social Science & Medicine published a review of treatment seeking for malaria (McCombie, 1996). Since that time, a significant amount of socio-behavioral research on the home management of malaria has been undertaken. In addition, recent initiatives such as Roll Back Malaria have emphasized the importance of social science inputs to malaria research and control. However, there has been a growing feeling that the potential contributions that social science could and should be making to malaria research and control have yet to be fully realized. To address these issues, this paper critically reviews and synthesizes the literature (published, unpublished and technical reports) pertaining to the home management of illness episodes of malaria in sub-Saharan Africa from 1996 to the end of 2000, and draws conclusions about the use of social science in malaria research and control.The results suggest that while we have amassed increasing quantities of descriptive data on treatment seeking behavior, we still have little understanding of the rationale of drug use from the patient perspective and, perhaps more importantly, barely any information on the rationale of provider behaviors. However, the results underline the dynamic and iterative nature of treatment seeking with multiple sources of care frequently being employed during a single illness episode; and highlight the importance in decision making of gender, socio-economic and cultural position of individuals within households and communities. Furthermore, the impact of political, structural and environmental factors on treatment seeking behaviors is starting to be recognised. Programs to address these issues may be beyond single sector (malaria control programme) interventions, but social science practice in malaria control needs to reflect a realistic appraisal of the complexities that govern human behavior and include critical appraisal and proposals for practical action. Major concerns arising from the review were the lack of evidence of ‘social scientist’ involvement (particularly few from endemic countries) in much of the published research; and concerns with methodological rigor. To increase the effective use of social science, we should focus on a new orientation for field research (including increased methodological rigor), address the gaps in research knowledge, strengthen the relationship between research, policy and practice; and concentrate on capacity strengthening and advocacy. [Copyright &y& Elsevier]

The polymerase delta interacting protein 2 (Poldip2) is a nuclear-encoded mitochondrial protein of unknown function. We recently reported that Poldip2 is repressed under hypoxia and that its deficiency results in repressed mitochondrial function and increased glycolytic activity. However, the mechanisms responsible for this metabolic reprograming and its consequences are unknown. In this study, we show that Poldip2 controls the lipoylation and consequently the activity of the pyruvate and α-ketoglutarate dehydrogenase complexes by a mechanism that involves Clp-protease complex-mediated degradation of Acyl-CoA Synthetase Medium-Chain Family Member 1 (ACSM1), a lipoate-activating enzyme required for the utilization of lipoic acid derived from the salvage pathway. With regards to the increased glycolytic activity, we found that Poldip2 deficiency inhibits PHDs inducing HIF-1α-dependent upregulation of Hexokinase 2. As a result, we observed an increase in the flux through the Hexosamine biosynthetic pathway (HBP), a glucose metabolic pathway that produces uridine diphosphate N-acetylglucosamine, the sugar donor for the O-GlcNAc transferase (OGT). The OGT-catalyzed transfer of O-GlcNAc is a post-translational modification implicated in cell signaling. Interestingly we found that Poldip2 deficiency induces the inhibition of the ubiquitin proteasome system (UPS) by OGT-dependent O-GlcNAcylation of the 19S regulatory unit of the 26S proteasome regulatory subunit 4 (PRS4). Additionally, we demonstrated that Poldip2-mediated inhibition of the UPS is required for the hypoxia-induced expression of connective tissue growth factor (CTGF), a cytokine that participates in multiple pathologies including fibrotic diseases and cancer. In all, we demonstrate that Poldip2 is an oxygen sensitive protein that regulates the activity of key enzymes of the Krebs cycle by coupling proteasome activity to mitochondrial function and fibrotic responses under hypoxia. [ABSTRACT FROM AUTHOR]

The second annual meeting of the Partnership for Social Sciences in Malaria Control was held at the London School of Hygiene and Tropical Medicine, UK, from 8 to 10 January 2002. [Copyright &y& Elsevier]

Abstract: While exposure to chemical mixtures is an everyday reality, an understanding of their combined effects, and any potential prediction thereof, is extremely limited. Realistic exposures potentially consist of hundreds to thousands of chemicals per day, but even relatively simple binary mixture interactions can be inherently difficult to predict based upon the lack of temporal and spatial mechanisms for the individual constituents. To this end, we explore the concept of capitalizing on downstream convergence of intracellular signal transduction to experimentally simplify the means of determining xenobiotics that, when combined, could result in increased or unexpected toxicity. In a proof of principle study, we exposed HepG2 cells to deguelin, a natural isoflavonoid, alone and in combination with KCN, and determined the relative post-translational phosphorylation responses to several key proteins related to mitochondrial outer membrane permeabilization. Dose-dependent phosphorylation activity provides a clear identification of threshold response to low-level exposures, and crosstalk amongst selected proteins correctly forecasts mixtures interactions that may lead to increased toxicity. We then used Bliss Independence to determine if the experimentally measured mixture phosphorylation responses could be predicted with individual responses. Independence accurately predicted mixture interactions for deguelin and KCN (87.5%). To more fully exhaust independence as a model for determining potential pharmacodynamic interactions, we exposed HepG2 cells to deguelin and staurosporine, a broad kinase inhibitor; independence accurately predicted these mixture responses (77.5%). In this study, we demonstrate the potential of a new in vitro approach for the prediction of toxic mixtures interactions that is fundamentally driven by the interdependence of signal transduction and apoptosis. [Copyright &y& Elsevier]

Objective To describe Department of Veterans Affairs (VA) mental health clinician attitudes toward and experiences with OpenNotes (also known as Blue Button ), which provides patients direct access to clinical notes online. Method A 35-item online survey was administered to 263 mental health clinicians and nurses from one VA Medical Center. Results Seventy-nine percent of eligible subjects participated. Most respondents agreed or somewhat agreed that OpenNotes is a good idea in general, but only half agreed that making mental health notes available online is a good idea. Most believed that patients will better remember plans of care and be better prepared for visits. Most also felt that patients will worry more and request changes in notes. Many clinicians reported being less detailed and changing the tone of their notes. Conclusion As a group, mental health clinicians are positive about OpenNotes in general but ambivalent about the use of OpenNotes in mental health care. The results call for research on outcomes of OpenNotes use in mental health and to develop education and support to help clinicians adapt to OpenNotes. [ABSTRACT FROM AUTHOR]

Abstract: The nitric acid oxidation of d-glucose was reinvestigated in an effort to better understand and improve the oxidation and subsequent work up steps. The oxidation was carried out using a computer controlled reactor employing a closed reaction flask under an atmosphere of oxygen which allowed for a catalytic oxidation process with oxygen as the terminal oxidant. Removal of nitric acid from product included the use of both diffusion dialysis and nanofiltration methodologies. Product analysis protocols were developed using ion chromatography. [Copyright &y& Elsevier]