Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.

Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70-/- mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70-/- mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70-/- mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (-99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70-/- mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70-/- mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70-/- mice. In conclusion, depletion of gut microbiota in Cyp2c70-/- mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.

Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70-/- Mice with a Human-like Bile Acid Composition.

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids.

BACKGROUND: Cyp2c70-/- mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70-/- mice and reduces cholangiopathy development later in life. METHODS: Cyp2c70+/- males were crossed with Cyp2c70+/- females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70-/- and wild-type offspring at 3 and 8 weeks of age. RESULTS: Three-week-old Cyp2c70-/- pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70-/- pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70-/- pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment. CONCLUSION: Perinatal exposure of Cyp2c70-/- mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70-/- mice has no long-lasting effects on liver pathophysiology. IMPACT: This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70-/- mice. Perinatal UDCA exposure of Cyp2c70-/- pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids. Perinatal UDCA exposure of Cyp2c70-/- pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment. The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70-/- mice by reducing fat absorption.

Bile acids (BAs) play important roles in lipid homeostasis, and BA signaling pathways serve as therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Recently, we generated cytochrome P450, family 2, subfamily C, polypeptide 70 (Cyp2c70-/-) mice with a human-like BA composition lacking mouse-/rat-specific muricholic acids to accelerate translation from mice to humans. We employed this model to assess the consequences of a human-like BA pool on diet-induced obesity and NAFLD development. Male and female Cyp2c70-/- mice and WT littermates were challenged with a 12-week high-fat Western-type diet (WTD) supplemented with 0.25% cholesterol. Cyp2c70 deficiency induced a hydrophobic BA pool with high abundances of chenodeoxycholic acid, particularly in females, because of sex-dependent suppression of sterol 12α-hydroxylase (Cyp8b1). Plasma transaminases were elevated, and hepatic fibrosis was present in Cyp2c70-/- mice, especially in females. Surprisingly, female Cyp2c70-/- mice were resistant to WTD-induced obesity and hepatic steatosis, whereas male Cyp2c70-/- mice showed similar adiposity and moderately reduced steatosis compared with WT controls. Both intestinal cholesterol and FA absorption were reduced in Cyp2c70-/- mice, the latter more strongly in females, despite unaffected biliary BA secretion rates. Intriguingly, the biliary ratio 12α-/non-12α-hydroxylated BAs significantly correlated with FA absorption and hepatic triglyceride content as well as with specific changes in gut microbiome composition. The hydrophobic human-like BA pool in Cyp2c70-/- mice prevents WTD-induced obesity in female mice and NAFLD development in both genders, primarily because of impaired intestinal fat absorption. Our data point to a key role for 12α-hydroxylated BAs in control of intestinal fat absorption and modulation of gut microbiome composition.

Gender differences between adolescents with autism in emergency psychiatry.

LAY ABSTRACT: Among adolescents seen for psychiatric emergency consultation, the percentage of adolescents with autism is increasing over the years. This applies even more to girls than to boys. We collected data of 1378 adolescents aged 12-18 years who were seen for urgent consultation by mobile psychiatric emergency services in the Netherlands. Among these, there were 64 autistic girls and 125 autistic boys. We wanted to know more about differences in problems between autistic and typical developing adolescents in crisis, both to prevent crisis and to improve services. The percentage of adolescents with autism increased over the years studied. Autistic adolescents experienced more severe impairment in functioning compared to typically developing adolescents. Compared to other adolescents, both boys and girls on the autism spectrum were diagnosed less frequently with mood disorders, behavioral disorders, relational problems, and abuse. Autistic girls had a higher suicide risk and suffered more often from anxiety disorders than autistic boys, while autistic boys had a longer history of problems. Outpatient care for children with autism should include easy access to specialized professionals who aim to reduce anxiety and help young people with autism to cope with the challenges of adolescence. Because possibly signs were missed during the emergency consultation, we recommend that as part of the routine procedure in crisis situations adolescents with autism are asked about mood and behavioral problems explicitly, as well as about negative life events.

Increased prevalence of intellectual disabilities in higher-intensity mental healthcare settings.

BACKGROUND: It has been suggested that people with intellectual disabilities have a higher likelihood to develop psychiatric disorders, and that their treatment prognosis is relatively poor. AIMS: We aimed to establish the prevalence of intellectual disability in different mental healthcare settings, and estimate percentage of cognitive decline. We hypothesised that the prevalence of intellectual disabilities increases with intensity of care. METHOD: A cross-sectional study was conducted in different settings in a mental healthcare trust in the Netherlands. We used the Screener for Intelligence and Learning Disabilities (SCIL) to identify suspected mild intellectual disability (MID) or borderline intellectual functioning (BIF). We identified patients with a high level of education and low SCIL score to estimate which patients may have had cognitive decline. RESULTS: We included 1213 consecutive patients. Over all settings, 41.4% of participating patients were positive for MID/BIF and 20.2% were positive for MID only. Prevalence of suspected MID/BIF increased by setting, from 27.1% in out-patient settings to 41.9% in flexible assertive community treatment teams and admission wards, to 66.9% in long-stay wards. Only 85 (7.1%) of all patients were identified as possibly having cognitive decline. Of these, 25.9% were in long-stay wards and had a diagnosis of schizophrenia or substance use disorder. CONCLUSIONS: Low intellectual functioning is common in Dutch mental healthcare settings. Only a modest number of patients were identified as suffering from cognitive decline rather than suspected MID/BIF from birth. Therefore, we recommend improved screening of psychiatric patients for intellectual functioning at the start of treatment.

The Impact of Antipsychotic Formulations on Time to Medication Discontinuation in Patients with Schizophrenia: A Dutch Registry-Based Retrospective Cohort Study.

BACKGROUND: Many patients with schizophrenia discontinue antipsychotic medication, frequently with adverse outcomes. Although different antipsychotic formulations are associated with different times to discontinuation, not much is known about discontinuation rates with oral-weekly formulations. Such a formulation of penfluridol is available in both the Netherlands and several other countries. OBJECTIVES: We aimed to investigate the impact of antipsychotic formulations on time to discontinuation, especially the oral-weekly formulation. METHODS: In a large, registry-based, retrospective cohort study from 1 January 2013 to 31 December 2016, we determined the time to medication discontinuation during the follow-up period with antipsychotic formulations, including oral-daily, oral-weekly, depot, or a combination of these. Patients with schizophrenia aged between 18 and 69 years were included and stratified according to the duration of recent antipsychotic use (taking the same formulation for ≤ 60 days or > 60 days before follow-up: short-term or long-term recent antipsychotic use). Medication discontinuation was defined as discontinuation of current antipsychotic formulation. RESULTS: Overall, 8257 patients were included for analyses, with 80% of patients discontinuing antipsychotic medication. Time to discontinuation was longer in those with long-term recent antipsychotic use before the follow-up period and longest for oral-daily formulations. Patterns for discontinuation of oral-weekly and depot formulations were similar, regardless of the duration of recent antipsychotic use before follow-up. More prior discontinuations were associated with shorter time to discontinuation. CONCLUSIONS: Time to discontinuation differed considerably between formulations. The duration of recent antipsychotic use was a strong predictor of time to discontinuation. While oral-daily formulations had the longest time to discontinuation in the long-term recent antipsychotic use group, discontinuation trends were similar for oral-weekly and depot formulations. An oral-weekly formulation, whose administration route is noninvasive, might therefore be considered an alternative to depot formulations.

Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1d/- mice.

BACKGROUND: Type 2 diabetes (T2DM) is an age-associated disease characterized by hyperglycemia due to insulin resistance and decreased beta-cell function. DNA damage accumulation has been associated with T2DM, but whether DNA damage plays a role in the pathogenesis of the disease is unclear. Here, we used mice deficient for the DNA excision-repair gene Ercc1 to study the impact of persistent endogenous DNA damage accumulation on energy metabolism, glucose homeostasis and beta-cell function. METHODS: ERCC1-XPF is an endonuclease required for multiple DNA repair pathways and reduced expression of ERCC1-XPF causes accelerated accumulation of unrepaired endogenous DNA damage and accelerated aging in humans and mice. In this study, energy metabolism, glucose metabolism, beta-cell function and insulin sensitivity were studied in Ercc1d/- mice, which model a human progeroid syndrome. RESULTS: Ercc1d/- mice displayed suppression of the somatotropic axis and altered energy metabolism. Insulin sensitivity was increased, whereas, plasma insulin levels were decreased in Ercc1d/- mice. Fasting induced hypoglycemia in Ercc1d/- mice, which was the result of increased glucose disposal. Ercc1d/- mice exhibit a significantly reduced beta-cell area, even compared to control mice of similar weight. Glucose-stimulated insulin secretion in vivo was decreased in Ercc1d/- mice. Islets isolated from Ercc1d/- mice showed increased DNA damage markers, decreased glucose-stimulated insulin secretion and increased susceptibility to apoptosis. CONCLUSION: Spontaneous DNA damage accumulation triggers an adaptive response resulting in improved insulin sensitivity. Loss of DNA repair, however, does negatively impacts beta-cell survival and function in Ercc1d/- mice.

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

BACKGROUND AND AIMS: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. METHODS: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages. RESULTS: Cyp2c70-/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70-/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70-/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70-/- mice up to 8 months of age. In female Cyp2c70-/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70-/- mice. CONCLUSION: Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet.

Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype.

A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice.

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Cytochrome P450 family 2 subfamily c polypeptide 70 (CYP2C70) was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 knockout mouse model (Cyp2c70ako) to clarify the role of CYP2C70 in BA metabolism in vivo and evaluate whether its activity modulates effects of pharmacologic FXR activation on cholesterol homeostasis. In Cyp2c70ako mice, chenodeoxycholic acid (CDCA) increased at the expense of ßMCA, resulting in a more hydrophobic human-like BA pool. Tracer studies demonstrated that, in vivo, CYP2C70 catalyzes the formation of ßMCA primarily by sequential 6ß-hydroxylation and C7-epimerization of CDCA, generating αMCA as an intermediate metabolite. Physiologically, the humanized BA composition in Cyp2c70ako mice blunted the stimulation of fecal cholesterol disposal in response to FXR activation compared with WT mice, predominantly due to reduced stimulation of transintestinal cholesterol excretion. Thus, deletion of hepatic Cyp2c70 in adult mice translates into a human-like BA pool composition and impacts the response to pharmacologic FXR activation. This Cyp2c70ako mouse model may be a useful tool for future studies of BA signaling and metabolism that informs human disease development and treatment.

A Qualitative Study of the Working Alliance between Patient and Community Mental Health Nurse during Interpersonal Community Psychiatric Treatment.

In the Netherlands, long-term community psychiatric treatment for patients with a severe mental illness (SMI) is poorly developed and lacks a structured, goal-centered approach. Often this form of treatment is provided by community mental health nurses (CMHN's).Especially in the group of nonpsychotic patients with SMI, it often leads to care-as-usual with limited proven interventions and an unstructured treatment. Interpersonal Community Psychiatric Treatment (ICPT) was developed to provide this group of patients a focus, a theoretical view, and a methodological structure. A pilot study has been conducted on ICPT. As a result, a randomized controlled trial (RCT) was recently conducted in which this study is part. The pilot study showed improvement on a number of treatment outcomes. However, the working alliance (WA) experienced by the patients, although not significant, was considered to be decreased. The aim of study was to gain insight into how the ICPT-elements shape the WA and the possible self-determination of patients in general.The main part of this mixed-methods study was a qualitative study with a Grounded Theory approach. For the selection of the participants, quantitative data from the current RCT has been used. Semistructured interviews have been conducted with 13 participants, divided over three mental health institutions throughout the Netherlands. Interviews and analysis were alternated, so that the interview topics were developed by constant comparison.Eleven participants were female and 11 participants received social benefit. Six of the participants were above 50 years of age. Four participants suffered either from a depressive or anxiety disorder. Seven participants had a borderline personality disorder. The results are linked to Bordin's theory of the therapeutic alliance, which is agreement on therapeutic tasks, agreement on therapeutic goals, and the quality of the personal bond. The WA could be analyzed from three different perspectives: mutually agreed on goals, tasks, and experienced interpersonal relationship. ICPT had limited influence on the mutually agreed on goals and interpersonal relationship but mainly on the mutually agreed on tasks. In daily practice, ICPT may have a positive influence on the perceived WA.The main factors that affected the perceived WA during ICPT were the tasks that had been mutually agreed on, the use of an agenda, the structure of the sessions, the alliance between the CMHN and the patient, and the patient's own self-determination. There was a limited influence on the mutually agreed on goals and the quality of the personal relationship between the CMHN and the patient. The present research revealed valuable information about the significance of the WA in ICPT and the opinions of the respondents about ICPT and information about what might be helpful or unhelpful in their relationship with their CMHN.

Mental health professionals' knowledge, skills and attitudes on domestic violence and abuse in the Netherlands: cross-sectional study.

BACKGROUND: Despite the high prevalence of domestic violence and abuse (DVA) among patients with psychiatric conditions, detection rates are low. Limited knowledge and skills on DVA in mental healthcare (MHC) professionals might contribute to poor identification.AimsTo assess the level of, and factors associated with, DVA knowledge and skills among MHC professionals. METHOD: A total of 278 professionals in Dutch MHC institutions completed a survey assessing factual knowledge, perceived knowledge, perceived skills and attitudes about DVA. RESULTS: On average, low scores were reported for perceived skills and knowledge. MHC professionals in primary care scored higher than those working with individuals with severe mental illness (P<0.005). Levels of factual knowledge were higher; levels of attitudes moderate. Previous training was positively associated with skills (odds ratios (OR) = 3.0) and attitudes (OR = 2.7). Years of work was negatively associated with factual knowledge (OR = 0.97). Larger case-loads predicted higher scores on skills (OR = 2.1). CONCLUSIONS: Training is needed, particularly for clinicians working with patients with severe mental illness.Declaration of interestNone.

Glucose-6-Phosphate Regulates Hepatic Bile Acid Synthesis in Mice.

It is well established that, besides facilitating lipid absorption, bile acids act as signaling molecules that modulate glucose and lipid metabolism. Bile acid metabolism, in turn, is controlled by several nutrient-sensitive transcription factors. Altered intrahepatic glucose signaling in type 2 diabetes associates with perturbed bile acid synthesis. We aimed to characterize the regulatory role of the primary intracellular metabolite of glucose, glucose-6-phosphate (G6P), on bile acid metabolism. Hepatic gene expression patterns and bile acid composition were analyzed in mice that accumulate G6P in the liver, that is, liver-specific glucose-6-phosphatase knockout (L-G6pc-/- ) mice, and mice treated with a pharmacological inhibitor of the G6P transporter. Hepatic G6P accumulation induces sterol 12α-hydroxylase (Cyp8b1) expression, which is mediated by the major glucose-sensitive transcription factor, carbohydrate response element-binding protein (ChREBP). Activation of the G6P-ChREBP-CYP8B1 axis increases the relative abundance of cholic-acid-derived bile acids and induces physiologically relevant shifts in bile composition. The G6P-ChREBP-dependent change in bile acid hydrophobicity associates with elevated plasma campesterol/cholesterol ratio and reduced fecal neutral sterol loss, compatible with enhanced intestinal cholesterol absorption. Conclusion: We report that G6P, the primary intracellular metabolite of glucose, controls hepatic bile acid synthesis. Our work identifies hepatic G6P-ChREBP-CYP8B1 signaling as a regulatory axis in control of bile acid and cholesterol metabolism.

Employment Rates in Flexible Assertive Community Treatment Teams in The Netherlands: An Observational Study.

We determined the proportions of clients treated in Flexible Assertive Community Treatment teams who were unemployed and gained employment and who were employed and lost employment. Secondly, we explored the demographical and clinical factors associated with employment. Data were collected during routine outcome monitoring. We calculated differences in employment rates over a year and explored differences in demographic characteristics at baseline between patient groups. Logistic regression analysis was used to estimate the role of clinical predictor variables on employment status. Over time, 10% remained employed, 5% lost their employment, 3% gained employment and 82% remained unemployed. Clients who found employment were younger, more often male, and had significantly fewer psychosocial problems and a higher subjective quality of life during follow-up than those who remained unemployed. Problems with motivation for treatment at baseline were related to losing employment or remaining unemployed. Better implementation of vocational services is very important for increasing the number of clients gaining employment.

AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet.

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta cells improves beta cell function in mice in response to a high-fat diet. This suggests that increased miR-132 expression is beneficial for beta cell function during hyperglycemia and obesity.

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic ß Cell Death and May Contribute to Type 1 Diabetes Development.

Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the ß cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to ß cells favoring apoptosis. Inactivation of these miRNAs in recipient ß cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in ß cells. The induction of these genes may promote the recruitment of immune cells and exacerbate ß cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells.

Treatment results for severe psychiatric illness: which method is best suited to denote the outcome of mental health care?

BACKGROUND: The present study investigates the suitability of various treatment outcome indicators to evaluate performance of mental health institutions that provide care to patients with severe mental illness. Several categorical approaches are compared to a reference indicator (continuous outcome) using pretest-posttest data of the Health of Nation Outcome Scales (HoNOS). METHODS: Data from 10 institutions and 3189 patients were used, comprising outcomes of the first year of treatment by teams providing long-term care. RESULTS: Findings revealed differences between continuous indicators (standardized pre-post difference score ES and ΔT) and categorical indicators (SEM, JTRCI, JTCS, JTRCI&CS, JTrevised) on their ranking of institutions, as well as substantial differences among categorical indicators; the outcome according to the traditional JT approach was most concordant with the continuous outcome indicators. CONCLUSIONS: For research comparing group averages, a continuous outcome indicator such as ES or ΔT is preferred, as this best preserves information from the original variable. Categorical outcomes can be used to illustrate what is accomplished in clinical terms. For categorical outcome, the classical Jacobson-Truax approach is preferred over the more complex method of Parabiaghi et al. with eight outcome categories. The latter may be valuable in clinical practice as it allows for a more detailed characterization of individual patients.

Associations between psychiatric symptoms and seclusion use: Clinical implications for care planning.

Findings from an increasing number of studies suggest that incorporating systematic short-term risk assessments in treatment planning could lead to safer practice on psychiatric admissions wards. The aim of the present study was to investigate the associations between the scores of three structured observation tools - the Kennedy Axis V (K-Axis-V), the Brief Psychiatric Rating Scale (BPRS), and the Social Dysfunction and Aggression Scale (SDAS) - and seclusion. In total, 1840 weekly risk assessments with these observation scales were collected over 2342 admission weeks. These assessment scores related to 370 acutely-admitted psychiatric patients and were subjected to a multilevel analysis. It was found that several dynamic and static factors were related to seclusion. Dynamic factors included violent behaviour, current substance abuse, suspiciousness, and negativism. Static factors included ethnicity and having been diagnosed with a substance abuse disorder. The findings suggest that the incorporation of the Kennedy-Axis V, the BPRS, and the SDAS into standard practice might be helpful in identifying patients at high risk of seclusion, and could be supportive to treatment planning and clinical decision-making in the prevention of seclusion use in acute psychiatric settings.

Different Perspectives of Clinicians and Patients with Severe Mental Illness on Motivation for Treatment.

The present study assessed motivation for engaging in treatment as rated by clinicians (n = 57) and patients with severe mental illness (SMI, n = 294) using measures based on three different motivation theories. Questionnaires were derived from self-determination theory, the transtheoretical model and the integral model of treatment motivation. It was investigated to which extent clinicians of patients with SMI were able to estimate their patient's perspective on motivation for engaging in treatment, to which extent they agreed on the patient's motivation and which factors were associated with estimation and agreement on treatment motivation. It was found that clinicians were poorly to moderately capable of estimating their patient's type of motivation and readiness for change. Further, agreement on the level of motivation between patients and clinicians was moderate. These findings were consistent across diagnostic groups (psychotic and personality disorders). A higher quality therapeutic relationship was generally associated with higher clinician-rated motivation. The patient's ethnicity and socially desirable responding were factors that differentiated between scales of different motivation theories. It is concluded that patients with SMI and their clinicians have different perceptions on the patient's motivation for engaging in psychiatric treatment, regardless of the theoretical framework that is used to measure motivation. The findings imply that a negotiated approach is needed where both perceptions of clinicians and patients on motivation for treatment are considered to ensure effective mental health interventions. Copyright © 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Clinicians show poor to moderate capability in estimating how patients perceive their motivation for engaging in treatment, especially so when the patient's motives revolve around feelings of shame and guilt. Clinicians generally give higher motivation ratings for patients where they experience a higher quality therapeutic relationships with, whereas-depending on the scale that is used to measure motivation-they give lower ratings to patients who respond in socially desirable ways and to ethnic minority patients. As patients with SMI and their clinicians have different perceptions on the patient's motivation for engaging in psychiatric treatment (regardless of the theoretical framework that is used to assess motivation), this implies that a negotiated approach is needed where both perceptions of clinicians and patients on motivation for treatment are considered to ensure effective mental health interventions.