ApoA-I Protects Pancreatic ß-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

BACKGROUND: High cholesterol levels in pancreatic ß-cells cause oxidative stress and decrease insulin secretion. ß-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves ß-cell insulin secretion by reducing oxidative stress. METHODS: Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-ß-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by ß-cells was monitored by flow cytometry. The effects of apoA-I internalization on ß-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the ß-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in ß-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS: An F1-ATPase ß-subunit on the ß-cell surface was identified as the main apoA-I-binding partner. ß-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase ß-subunit-dependent. ß-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase ß-subunit levels than ß-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E ß-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS: These results establish that ß-cells are functionally heterogeneous, and apoA-I restores insulin secretion in ß-cells with elevated cholesterol levels by improving mitochondrial redox balance.

Myeloperoxidase Gene Deletion Causes Drastic Microbiome Shifts in Mice and Does Not Mitigate Dextran Sodium Sulphate-Induced Colitis.

Neutrophil-myeloperoxidase (MPO) is a heme-containing peroxidase which produces excess amounts of hypochlorous acid during inflammation. While pharmacological MPO inhibition mitigates all indices of experimental colitis, no studies have corroborated the role of MPO using knockout (KO) models. Therefore, we investigated MPO deficient mice in a murine model of colitis. Wild type (Wt) and MPO-deficient mice were treated with dextran sodium sulphate (DSS) in a chronic model of experimental colitis with three acute cycles of DSS-induced colitis over 63 days, emulating IBD relapse and remission cycles. Mice were immunologically profiled at the gut muscoa and the faecal microbiome was assessed via 16S rRNA amplicon sequencing. Contrary to previous pharmacological antagonist studies targeting MPO, MPO-deficient mice showed no protection from experimental colitis during cyclical DSS-challenge. We are the first to report drastic faecal microbiota shifts in MPO-deficient mice, showing a significantly different microbiome profile on Day 1 of treatment, with a similar shift and distinction on Day 29 (half-way point), via qualitative and quantitative descriptions of phylogenetic distances. Herein, we provide the first evidence of substantial microbiome shifts in MPO-deficiency, which may influence disease progression. Our findings have significant implications for the utility of MPO-KO mice in investigating disease models.

Identifying the most important research, policy and practice questions for substance use, problematic alcohol use and behavioural addictions in autism (SABA-A): A priority setting partnership.

BACKGROUND: Autistic people are more likely to report problematic alcohol and other substance use when compared to the general population. Evidence suggests that up to one in three autistic adults may have an alcohol or other substance use disorder (AUD/SUD), although the evidence base for behavioural addictions is less clear. Autistic people may use substances or engage in potentially addictive behaviours as a means of coping with social anxiety, challenging life problems, or camouflaging in social contexts. Despite the prevalence and detrimental effects of AUD, SUD and behavioural addictions in community samples, literature focusing on the intersection between autism and these conditions is scarce, hindering health policy, research, and clinical practice. METHODS: We aimed to identify the top 10 priorities to build the evidence for research, policy, and clinical practice at this intersection. A priority-setting partnership was used to address this aim, comprising an international steering committee and stakeholders from various backgrounds, including people with declared lived experience of autism and/or addiction. First, an online survey was used to identify what people considered key questions about Substance use, alcohol use, or behavioural addictions in autistic people (SABA-A). These initial questions were reviewed and amended by stakeholders, and then classified and refined to form the final list of top priorities via an online consensus process. OUTCOMES: The top ten priorities were identified: three research, three policy, and four practice questions. Future research suggestions are discussed.

Pharmacological interventions for the treatment of disordered and problem gambling.

BACKGROUND: Pharmacological interventions for disordered and problem gambling have been employed in clinical practice. Despite the availability of several reviews of the efficacy of pharmacological interventions for disordered or problem gambling, few have employed systematic search strategies or compared different categories of pharmacological interventions. Systematic reviews of high-quality evidence are therefore essential to provide guidance regarding the efficacy of different pharmacological interventions for disordered or problem gambling. OBJECTIVES: The primary aims of the review were to: (1) examine the efficacy of major categories of pharmacological-only interventions (antidepressants, opioid antagonists, mood stabilisers, atypical antipsychotics) for disordered or problem gambling, relative to placebo control conditions; and (2) examine the efficacy of these major categories relative to each other.  SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase, and PsycINFO (all years to 11 January 2022). SELECTION CRITERIA: We included randomised trials evaluating a pharmacological intervention for the treatment of disordered or problem gambling. Eligible control conditions included placebo control groups or comparisons with another category of pharmacological intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures, including systematic extraction of included study characteristics and results and risk of bias assessment. Our primary outcome was reduction in gambling symptom severity. Our secondary outcomes were reduction in gambling expenditure, gambling frequency, time spent gambling, depressive symptoms, anxiety symptoms, and functional impairment; and responder status. We evaluated treatment effects for continuous and dichotomous outcomes using standardised mean difference (SMD) and risk ratios (RR), respectively, employing random-effects meta-analyses. A minimum of two independent treatment effects were required for a meta-analysis to be conducted (with only meta-analytic findings reported in this abstract). MAIN RESULTS: We included 17 studies in the review (n = 1193 randomised) that reported outcome data scheduled for end of treatment. Length of treatment ranged from 7 to 96 weeks.  Antidepressants: Six studies (n = 268) evaluated antidepressants, with very low to low certainty evidence suggesting that antidepressants were no more effective than placebo at post-treatment: gambling symptom severity (SMD -0.32, 95% CI -0.74 to 0.09, n = 225), gambling expenditure (SMD -0.27, 95% CI -0.60 to 0.06, n = 144), depressive symptoms (SMD -0.19, 95% CI -0.60 to 0.23, n = 90), functional impairment (SMD -0.15, 95% CI -0.53 to 0.22, n = 110), and responder status (RR 1.24, 95% CI 0.93 to 1.66, n = 268). Opioid antagonists: Four studies (n = 562) evaluated opioid antagonists, with very low to low certainty evidence showing a medium beneficial effect of treatment on gambling symptom severity relative to placebo at post-treatment (SMD -0.46, 95% CI -0.74 to -0.19, n = 259), but no difference between groups in responder status (RR 1.65, 95% CI 0.86 to 3.14, n = 562). Mood stabilisers: Two studies (n = 71) evaluated mood stabilisers (including anticonvulsants), with very low certainty evidence suggesting that mood stabilisers were no more effective than placebo at post-treatment: gambling symptom severity (SMD -0.92, 95% CI -2.24 to 0.39, n = 71), depressive symptoms (SMD -0.15, 95% CI -1.14 to 0.83, n = 71), and anxiety symptoms (SMD -0.17, 95% CI -0.64 to 0.30, n = 71). Atypical antipsychotics:Two studies (n = 63) evaluated the atypical antipsychotic olanzapine, with very low certainty evidence showing a medium beneficial effect of treatment on gambling symptom severity relative to placebo at post-treatment (SMD -0.59, 95% CI -1.10 to -0.08, n = 63). Comparative effectiveness: Two studies (n = 62) compared antidepressants with opioid antagonists, with very low certainty evidence indicating that antidepressants were no more effective than opioid antagonists on depressive symptoms (SMD 0.22, 95% CI -0.29 to 0.72, n = 62) or anxiety symptoms (SMD 0.21, 95% CI -0.29 to 0.72, n = 62) at post-treatment. Two studies (n = 58) compared antidepressants with mood stabilisers (including anticonvulsants), with very low certainty evidence indicating that antidepressants were no more effective than mood stabilisers on depressive symptoms (SMD 0.02, 95% CI -0.53 to 0.56, n = 58) or anxiety symptoms (SMD 0.16, 95% CI -0.39 to 0.70, n = 58) at post-treatment. Tolerability and adverse events: Several common adverse effects were reported by participants receiving antidepressants (e.g. headaches, nausea, diarrhoea/gastrointestinal issues) and opioid antagonists (e.g. nausea, dry mouth, constipation). There was little consistency in the types of adverse effects experienced by participants receiving mood stabilisers (e.g. tiredness, headaches, concentration difficulties) or atypical antipsychotics (e.g. pneumonia, sedation, increased hypomania). Discontinuation of treatment due to these adverse events was highest for opioid antagonists (10% to 32%), followed by antidepressants (4% to 31%), atypical antipsychotics (14%), and mood stabilisers (13%). AUTHORS' CONCLUSIONS: This review provides preliminary support for the use of opioid antagonists (naltrexone, nalmefene) and atypical antipsychotics (olanzapine) to produce short-term improvements in gambling symptom severity, although a lack of available evidence precludes a conclusion regarding the degree to which these pharmacological agents can improve other gambling or psychological functioning indices. In contrast, the findings are inconclusive with regard to the effects of mood stabilisers (including anticonvulsants) in the treatment of disordered or problem gambling, and there is limited evidence to support the efficacy of antidepressants. However, these conclusions are based on very low to low certainty evidence characterised by a small number of included studies, high risk of bias, modest pooled sample sizes, imprecise estimates, moderate between-study heterogeneity, and exclusion of participants with psychiatric comorbidities. Moreover, there were insufficient studies to conduct meta-analyses on many outcome measures; to compare efficacy across and within major categories of interventions; to explore dosage effects; or to examine effects beyond post-treatment. These limitations suggest that, despite recommendations related to the administration of opioid antagonists in the treatment of disordered or problem gambling, pharmacological interventions should be administered with caution and with careful consideration of patient needs. A larger and more methodologically rigorous evidence base with longer-term evaluation periods is required before definitive conclusions can be drawn about the effectiveness and durability of pharmacological treatments for disordered or problem gambling.

Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase.

The heme enzyme myeloperoxidase (MPO) is a key mediator of endothelial dysfunction and a therapeutic target in cardiovascular disease. During inflammation, MPO released by circulating leukocytes is internalized by endothelial cells and transcytosed into the subendothelial extracellular matrix of diseased vessels. At this site, MPO mediates endothelial dysfunction by catalytically consuming nitric oxide (NO) and producing reactive oxidants, hypochlorous acid (HOCl) and the nitrogen dioxide radical (•NO2). Accordingly, there is interest in developing MPO inhibitors that effectively target endothelial-localized MPO. Here we studied a series of piperidine nitroxides conjugated to polyamine moieties as novel endothelial-targeted MPO inhibitors. Electron paramagnetic resonance analysis of cell lysates showed that polyamine conjugated nitroxides were efficiently internalized into endothelial cells in a heparan sulfate dependent manner. Nitroxides effectively inhibited the consumption of MPO's substrate hydrogen peroxide (H2O2) and formation of HOCl catalyzed by endothelial-localized MPO, with their efficacy dependent on both nitroxide and conjugated-polyamine structure. Nitroxides also differentially inhibited protein nitration catalyzed by both purified and endothelial-localized MPO, which was dependent on •NO2 scavenging rather than MPO inhibition. Finally, nitroxides uniformly inhibited the catalytic consumption of NO by MPO in human plasma. These studies show for the first time that nitroxides effectively inhibit local oxidative reactions catalyzed by endothelial-localized MPO. Novel polyamine-conjugated nitroxides, ethylenediamine-TEMPO and putrescine-TEMPO, emerged as efficacious nitroxides uniquely exhibiting high endothelial cell uptake and efficient inhibition of MPO-catalyzed HOCl production, protein nitration, and NO oxidation. Polyamine-conjugated nitroxides represent a versatile class of antioxidant drugs capable of targeting endothelial-localized MPO during vascular inflammation.

Evaluating a low-intensity cognitive behavioural program for young people in regional Australia.

NewAccess is a low-intensity cognitive behavioural program which was recently trialled for the first time in Australia for clients aged under 18. Given that accessing support earlier tends to result in better outcomes for people with mild-to-moderate mental health issues, having NewAccess available for young people has the potential to reduce the likelihood of mild-to-moderate mental health concerns developing into more serious, or chronic mental illness over time for some clients, while also freeing up resources for those with more severe support needs. This mixed methods approach presents the findings of an independent evaluation of the program delivered out of two regional headspace centres in 2017-2019. From an initial sample of 165 young participants aged between 12 and 25, 109 completed the program. Of those who completed the program 60 were under the age of 18. The standardised assessment and outcome measures indicated a very good response to the program, with the majority showing significant improvements in their depression, anxiety and psychological distress scores. The overall 'reliable improvement' and 'recovery rates' were 64.2% and 72.3% respectively. Overall, the results indicated this program was an acceptable and efficacious intervention for young people in rural settings, when delivered in a 'youth-friendly' service environment.

Human Indoleamine 2,3-Dioxygenase 1 Is an Efficient Mammalian Nitrite Reductase.

The heme enzyme indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the first reaction of l-tryptophan oxidation along the kynurenine pathway. IDO1 is a central immunoregulatory enzyme with important implications for inflammation, infectious disease, autoimmune disorders, and cancer. Here we demonstrate that IDO1 is a mammalian nitrite reductase capable of chemically reducing nitrite to nitric oxide (NO) under hypoxia. Ultraviolet-visible absorption and resonance Raman spectroscopy showed that incubation of dithionite-reduced, ferrous-IDO1 protein (FeII-IDO1) with nitrite under anaerobic conditions resulted in the time-dependent formation of an FeII-nitrosyl IDO1 species, which was inhibited by substrate l-tryptophan, dependent on the concentration of nitrite or IDO1, and independent of the concentration of the reductant, dithionite. The bimolecular rate constant for IDO1 nitrite reductase activity was determined as 5.4 M-1 s-1 (pH 7.4, 23 °C), which was comparable to that measured for myoglobin (3.6 M-1 s-1; pH 7.4, 23 °C), an efficient and biologically important mammalian heme-based nitrite reductase. IDO1 nitrite reductase activity was pH-dependent but differed with myoglobin in that it showed a reduced proton dependency at pH >7. Electron paramagnetic resonance studies measuring NO production showed that the conventional IDO1 dioxygenase reducing cofactors, ascorbate and methylene blue, enhanced IDO1's nitrite reductase activity and the time- and IDO1 concentration-dependent release of NO in a manner inhibited by l-tryptophan or the IDO inhibitor 1-methyl-l-tryptophan. These data identify IDO1 as an efficient mammalian nitrite reductase that is capable of generating NO under anaerobic conditions. IDO1's nitrite reductase activity may have important implications for the enzyme's biological actions when expressed within hypoxic tissues.

Patterns of Family and Intimate Partner Violence in Problem Gamblers.

While the evidence about the statistical co-occurrence of family violence and problem gambling is growing, the mechanism by which the two behaviours are related is less clear. This study sought to clarify the dynamics of the problem behaviours, including the role of gender in victimisation and perpetration of violence in the family. Two-hundred-and-twelve treatment seeking problem gamblers (50.5% females) were recruited for interviews about past year FV and IPV experiences. The interviews included questions about the types of FV and IPV using the HITS tool (Sherin et al. in Fam Med Kans City 30:508-512, 1998). The questions addressed multiple family members, the temporal order of violence and gambling and the perceived associations between the two behaviours. The result show that well over half (60.8%; 95 CI = 54.1-67.2) of the participants reported some form of violence in the past 12 months, with no gender differences in relation to perpetration and victimisation. Bidirectional violence (43.9%; 95 CI = 37.4-50.6) was significantly more common than 'perpetration only' (11.3%; 95 CI = 7.7-16.3) or 'victimisation only' (5.7%; 95 CI = 3.3-9.6). Violence was mostly verbal, although considerable rates of physical violence also featured in the responses. 'Participants' own gambling preceded violence in a majority of the interviews but a small group of IPV victims reported that being a victim had led to their problematic gambling. These results can be used inform prevention, better treatment matching and capacity building in family violence and problem gambling services, where a significant focus should be on situational IPV.

Identification of Native and Posttranslationally Modified HLA-B*57:01-Restricted HIV Envelope Derived Epitopes Using Immunoproteomics.

The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified. HIVenv peptides are present at a very small percentage of the overall HLA-B*57:01 peptidome (<0.1%) and both native and posttranslationally modified forms of two distinct HIV peptides are identified. Notably, a peptide bearing a natively encoded C-terminal tryptophan residue is also present in a modified form containing a kynurenine residue. Kynurenine is a major product of tryptophan catabolism and is abundant during inflammation and infection. Binding of these peptides at a molecular level and their immunogenicity in preliminary functional studies are examined. Modest immune responses are observed to the modified HIVenv peptide, highlighting a potential role for kynurenine-modified peptides in the immune response to HIV and other viral infections.

Responsible gambling among older adults: a qualitative exploration.

BACKGROUND: Responsible gambling (RG) is defined as gambling for pleasure and entertainment but with an awareness of the likelihood of losing, an understanding of the associated risks and the ability to exercise control over one's gambling activity. The current study describes a qualitative approach to explore RG among older adults (aged 60 years and above) in Singapore and reports on the cognitive and behavioural strategies employed by them to regulate their gambling. METHODS: Inclusion criteria included Singapore residents aged 60 years and above, who could speak in English, Chinese, Malay or Tamil and were current or past regular gamblers. Participants were recruited using a combination of network and purposive sampling. Socio-demographic information on age, age of onset of gambling, gender, ethnicity, marital status, education and employment was collected. The South Oaks Gambling Screen (SOGS) was used to collect information on gambling activities and problems associated with gambling behaviour. Qualitative interviews were conducted with 25 older adults (60 years and above) who currently gambled. The data was analyzed using thematic network analysis. RESULTS: This global theme of RG comprised two organising themes: self -developed strategies to limit gambling related harm and family interventions to reduce gambling harm. The basic themes included delayed gratification, perception of futility of gambling, setting limits, maintaining balance, help-seeking and awareness of disordered gambling in self or in others. Family interventions included pleading and threatening, compelling help-seeking as well as family exclusion order. CONCLUSIONS: The study highlights the significant role that families play in Asian societies in imposing RG. Education of family members both in terms of the importance of RG, and communication of the ways in which older adults can incorporate RG behaviours including the use of exclusion in specific scenarios is important.

The intergenerational transmission of at-risk/problem gambling: The moderating role of parenting practices.

BACKGROUND AND OBJECTIVES: Although parenting practices are articulated as underlying mechanisms or protective factors in several theoretical models, their role in the intergenerational transmission of gambling problems has received limited research attention. This study therefore examined the degree to which parenting practices (positive parenting, parental involvement, and inconsistent discipline) moderated the intergenerational transmission of paternal and maternal problem gambling. METHODS: Students aged 12-18 years (N = 612) recruited from 17 Australian secondary schools completed a survey measuring parental problem gambling, problem gambling severity, and parenting practices. RESULTS: Participants endorsing paternal problem gambling (23.3%) were 4.3 times more likely to be classified as at-risk/problem gamblers than their peers (5.4%). Participants endorsing maternal problem gambling (6.9%) were no more likely than their peers (4.0%) to be classified as at-risk/problem gamblers. Paternal problem gambling was a significant predictor of offspring at-risk/problem gambling after controlling for maternal problem gambling and participant demographic characteristics. The relationship between maternal problem gambling and offspring at-risk/problem gambling was buffered by parental involvement. DISCUSSION AND CONCLUSIONS: Paternal problem gambling may be important in the development of adolescent at-risk/problem gambling behaviours and higher levels of parental involvement buffers the influence of maternal problem gambling in the development of offspring gambling problems. Further research is therefore required to identify factors that attenuate the seemingly greater risk of transmission associated with paternal gambling problems. SCIENTIFIC SIGNIFICANCE: Parental involvement is a potential candidate for prevention and intervention efforts designed to reduce the intergenerational transmission of gambling problems. (Am J Addict 2017;26:707-712).

The impact of Saudi hospital accreditation on quality of care: a mixed methods study.

In 2005, the Central Board for Accreditation of Healthcare Institutions (CBAHI) was launched in Saudi Arabia in order to improve the quality of care. By 2010, the first hospital was accredited by CBAHI, followed by many hospitals in following years. The aim of this study is to examine the impact of CBAHI on quality of care. In this study we used a mixed methods approach involving surveys, documentary analyses and semi-structure interviews. Surveys data were collected from 669 staff. Documentary analyses included mortality, infection and length of stay. The semi-structure interview data were gathered from 12 senior managers. Data were collected from three accredited public hospitals. Although some improvements in procedure were recognised, CBAHI does not monitor the continuity of health care delivery and had no effect on quality outcomes in our analysis. This study illustrates a need to sustain improvements over time in the accreditation cycle. Copyright © 2016 John Wiley & Sons, Ltd.

Design and Rationale for the Endothelin-1 Receptor Antagonism in the Prevention of Microvascular Injury in Patients with non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (ENDORA-PCI) Trial.

PURPOSE: Peri-procedural myocardial infarction (PMI) occurs in a small but significant portion of patients undergoing percutaneous intervention (PCI). The underlying mechanisms are complex and may include neurohormonal activation and release of vasoactive substances resulting in disruption of the coronary microcirculation. Endothelin in particular has been found in abundance in atherosclerotic plaques and in systemic circulation following PCI, and may be a potential culprit for PMI through its action on microvascular vasoconstriction, and platelet and neutrophil activation. In this study we aim to characterize the behavior of the coronary microcirculation during a PCI with the index of microvascular resistance (IMR) and the effect of peri-procedural endothelin antagonism. METHODS: The ENDORA-PCI trial is a randomized, double-blind, placebo-controlled, single-center clinical trial designed to evaluate the efficacy of endothelin antagonism in attenuating the peri-procedural rise in IMR as a surrogate marker for PMI. The patients of interest are those with non-ST elevation acute coronary syndrome (NSTEACS) undergoing PCI, and we aim to recruit 52 patients overall to give the study a power of 80 % at an α level of 5 %. Patients will be randomized in a 1:1 fashion to either Ambrisentan, an endothelin antagonist, or placebo, prior to their PCI. IMR will be measured before and after PCI. The primary endpoint is the difference in peri-procedural changes in patients' IMR between the two groups. CONCLUSION: The ENDORA-PCI study will investigate whether endothelin antagonism with Ambrisentan attenuates the peri-procedural rise in IMR in patients with NSTEACS undergoing PCI, and thus potentially the risk of PMI.

Barriers and enablers to the delivery of psychological care in the management of patients with type 2 diabetes mellitus in China: a qualitative study using the theoretical domains framework.

BACKGROUND: China has the largest number of type 2 diabetes mellitus (T2DM) cases globally and individuals with T2DM have an increased risk of developing mental health disorders and functional problems. Despite guidelines recommending that psychological care be delivered in conjunction with standard T2DM care; psychological care is not routinely delivered in China. Community Health Centre (CHC) doctors play a key role in the management of patients with T2DM in China. Understanding the behavioural determinants of CHC doctors in the implementation of psychological care recommendations allows for the design of targeted and culturally appropriate interventions. As such, this study aimed to examine barriers and enablers to the delivery of psychological care to patients with T2DM from the perspective of CHC doctors in China. METHODS: Two focus groups were conducted with 23 CHC doctors from Shenzhen, China. The discussion guide applied the Theoretical Domains Framework (TDF) that examines current practice and identifies key barriers and enablers perceived to influence practice. Focus groups were conducted with an interpreter, and were digitally recorded and transcribed. Two researchers independently coded transcripts into pre-defined themes using deductive thematic analysis. RESULTS: Barriers and enablers perceived by doctors as being relevant to the delivery of psychological care for patients with T2DM were primarily categorised within eight TDF domains. Key barriers included: CHC doctors' knowledge and skills; time constraints; and absence of financial incentives. Other barriers included: societal perception that treating psychological aspects of health is less important than physical health; lack of opinion leaders; doctors' intentional disregard of psychological care; and doubts regarding the efficacy of psychological care. In contrast, perceived enablers included: training of CHC doctors in psychological skills; identification of afternoon/evening clinic times when recommendations could be implemented; introduction of financial incentives; and the creation of a professional role (e.g. diabetes educator), that could implement psychological care recommendations to patients with T2DM. CONCLUSIONS: The utilisation of the TDF allowed for the comprehensive understanding of barriers and enablers to the implementation of psychological care recommendations for patients with T2DM, and consequently, has given direction to future interventions strategies aimed at improving the implementation of such recommendations.

Role of indoleamine 2,3-dioxygenase in health and disease.

IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

Apolipoprotein A-I increases insulin secretion and production from pancreatic ß-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism.

OBJECTIVE: Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal ß-cell lines. This study identifies the signaling pathways that mediate these effects. APPROACH AND RESULTS: Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A-specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I-treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels. CONCLUSIONS: ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1-dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and ß-cell survival genes.

Performance of screening tools in detecting major depressive disorder among patients with coronary heart disease: a systematic review.

BACKGROUND: Eligible studies published before 31 Dec 2013 were identified from the following databases: Ovid Medline, EMBASE, PsycINFO, Scopus, Cochrane Library, CINAHL Plus, and Web of Science. MATERIAL AND METHODS: Eligible studies published before 31, Dec 2013 were identified from the following databases: Ovid Medline, EMBASE, psycINFO, Scopus, Cochrane Library, CINAHL Plus, and Web of Science. RESULTS: Eight studies aiming to identify MDD in CHD patients were included, and there were 10 self-reporting questionnaires (such as PHQ-2, PHQ-9, PHQ categorical algorithm, HADS-D, BDI, BDI-II, BDI-II-cog, CES-D, SCL-90, 2 simple yes/no items) and 1 observer rating scale (Ham-D). For MDD alone, the sensitivity and specificity of various screening tools at the validity and optimal cut-off point varied from 0.34 [0.19, 0.52] to 0.96 [0.78, 1.00] and 0.69 [0.65, 0.73] to 0.97 [0.93, 0.99]. Results showed PHQ-9 (≥10), BDI-II (³14 or ≥16), and HADS-D (≥5 or ≥4) were widely used for screening MDD in CHD patients. CONCLUSIONS: There is no consensus on the optimal screening tool for MDD in CHD patients. When evaluating the performance of a screening tool, balancing the high sensitivity and negative predictive value (NPV) between specificity and positive predictive value (PPV) for screening or diagnostic purpose should be considered. After screening, further diagnosis, appropriate management, and necessary referral may also improve cardiovascular outcomes.

Gambling Participation and Problem Gambling Severity in a Stratified Random Survey: Findings from the Second Social and Economic Impact Study of Gambling in Tasmania.

Demographic characteristics associated with gambling participation and problem gambling severity were investigated in a stratified random survey in Tasmania, Australia. Computer-assisted telephone interviews were conducted in March 2011 resulting in a representative sample of 4,303 Tasmanian residents aged 18 years or older. Overall, 64.8% of Tasmanian adults reported participating in some form of gambling in the previous 12 months. The most common forms of gambling were lotteries (46.5%), keno (24.3%), instant scratch tickets (24.3%), and electronic gaming machines (20.5%). Gambling severity rates were estimated at non-gambling (34.8%), non-problem gambling (57.4%), low risk gambling (5.3%), moderate risk (1.8%), and problem gambling (.7%). Compared to Tasmanian gamblers as a whole significantly higher annual participation rates were reported by couples with no children, those in full time paid employment, and people who did not complete secondary school. Compared to Tasmanian gamblers as a whole significantly higher gambling frequencies were reported by males, people aged 65 or older, and people who were on pensions or were unable to work. Compared to Tasmanian gamblers as a whole significantly higher gambling expenditure was reported by males. The highest average expenditure was for horse and greyhound racing ($AUD 1,556), double the next highest gambling activity electronic gaming machines ($AUD 767). Compared to Tasmanian gamblers as a whole problem gamblers were significantly younger, in paid employment, reported lower incomes, and were born in Australia. Although gambling participation rates appear to be falling, problem gambling severity rates remain stable. These changes appear to reflect a maturing gambling market and the need for population specific harm minimisation strategies.

An Examination of a Proposed DSM-IV Pathological Gambling Hierarchy in a Treatment Seeking Population: Similarities with Substance Dependence and Evidence for Three Classification Systems.

Toce-Gerstein et al. (Addiction 98:1661-1672, 2003) investigated the distribution of Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) pathological gambling criteria endorsement in a U.S. community sample for those people endorsing a least one of the DSM-IV criteria (n = 399). They proposed a hierarchy of gambling disorders where endorsement of 1-2 criteria were deemed 'At-Risk', 3-4 'Problem gamblers', 5-7 'Low Pathological', and 8-10 'High Pathological' gamblers. This article examines these claims in a larger Australian treatment seeking population. Data from 4,349 clients attending specialist problem gambling services were assessed for meeting the ten DSM-IV pathological gambling criteria. Results found higher overall criteria endorsement frequencies, three components, a direct relationship between criteria endorsement and gambling severity, clustering of criteria similar to the Toce-Gerstein et al. taxonomy, high accuracy scores for numerical and criteria specific taxonomies, and also high accuracy scores for dichotomous pathological gambling diagnoses. These results suggest significant complexities in the frequencies of criteria reports and relationships between criteria.