Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene

BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life

Non-evidence-based antipsychotic drug prescribing in the treatment of adult schizophrenia

The extent of combination antipsychotic prescribing (CAP), or polypharmacy, in the treatment of schizophrenia is high, with evidence of prevalence exceeding 40% nationally and 30% across Greater Manchester. CAP increases the incidence of adverse drug events and inadvertent high dosage, whilst elevating treatment costs. Guidance against CAP is contained in both local and national evidence-based treatment guidelines. Few previous studies have attempted to alter this antipsychotic prescribing practice. The aims of the studies described here were to develop and evaluate an intervention to reduce rates of CAP in a mental health services catchment area in Greater Manchester, alongside an investigation of the main aspects of CAP: whether rates of CAP are as high as those recorded previously across the city; whether CAP is associated with other non-evidence-based antipsychotic prescribing; whether some patients are more likely to be treated with CAP than others; and what it is like, from the patient's perspective, to take antipsychotic drugs, including those taken in combination.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Second Generation Antipsychotics Improve Sexual Dysfunction in Schizophrenia: A Randomised Controlled Trial

The impact of antipsychotic drug treatment on sexual function was investigated during a randomised trial comparing first generation antipsychotics (FGAs) to (nonclozapine) second generation antipsychotics (SGAs). Sexual function and quality of life were (rater-blind) assessed in 42 patients with DSM-IV schizophrenia (aged 18-65) using the self-report version of the Derogatis Interview for Sexual Function (DISF-SR) and the Heinrichs Quality of Life Scale (QLS), prior to, and 12 weeks following, a change in medication from an FGA drug to either an FGA or SGA drug. SGAs significantly improved sexual function compared to FGAs. Change in sexual function was associated with change in quality of life. Where impaired sexual functioning is a distressing adverse effect of treatment with an FGA agent, consideration should be given to switching to an SGA

Second Generation Antipsychotics Improve Sexual Dysfunction in Schizophrenia: A Randomised Controlled Trial

The impact of antipsychotic drug treatment on sexual function was investigated during a randomised trial comparing first generation antipsychotics (FGAs) to (nonclozapine) second generation antipsychotics (SGAs). Sexual function and quality of life were (rater-blind) assessed in 42 patients with DSM-IV schizophrenia (aged 18–65) using the self-report version of the Derogatis Interview for Sexual Function (DISF-SR) and the Heinrichs Quality of Life Scale (QLS), prior to, and 12 weeks following, a change in medication from an FGA drug to either an FGA or SGA drug. SGAs significantly improved sexual function compared to FGAs. Change in sexual function was associated with change in quality of life. Where impaired sexual functioning is a distressing adverse effect of treatment with an FGA agent, consideration should be given to switching to an SGA

Short-Term Outcomes for Opiate and Crack Users Accessing Treatment:The Effects of Criminal Justice Referral and Crack Use

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; The English drug treatment population doubled in size between 1998 and 2008, increasingly characterised by crack cocaine use and criminal justice system (CJS) referral. We assessed short-term (median 3.5 month) behaviour changes following participation in drug treatment and the moderating effect of CJS referral/crack use. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Opiate and/or crack cocaine users (n = 1,267) were recruited from 342 agencies. Outcome effects were assessed via interaction term regression, clustered at participant level, controlling for client characteristics. Treatment retention effects were tested via Cox proportional hazard models. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Statistically significant improvements in health, drug use and offensive behaviour were observed (e.g. heroin use from 87 to 51%, acquisitive offending from 47 to 23%). Referral route was not associated with variation in outcomes. Crack use at baseline was associated with a greater chance of non-fatal overdose at follow-up (p = 0.035, 95% CI 1.08-8.20) but a greater reduction in offending income (p = 0.002, 95% CI £104-£419). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Despite changes in the English drug treatment population, equivalent short-term improvements in client behaviour were observed a decade earlier. Outcomes for CJS-referred clients were comparable to non-CJS. Crack use at treatment entry offered some scope for greater improvements in offending but may be a barrier to cessation of mortality-associated risky behaviour.</jats:p