An Investigation Into the Biosynthesis of Terrein

An investigation has been carried out into the nature of the biosynthesis and the metabolites involved in the production of the natural product, terrein. Terrein, a metabolite of the fungus Aspergillus terreus has been previously shown to be of polyketide origin. It seems likely that terrein may be derived by way of an aromatic intermediate with subsequent oxidative cleavage of the aromatic ring to a five-membered ring. It is the nature of this ring contraction which is of primary interest. Also under investigation was the stereochemistry of the elimination process leading to the propenyl side chain of terrein. 3,4-Dihydro-6,8-dihydroxy-3-methylisocoumarin is already known to be an intermediate on the pathway to terrein and this fact was utilised in the investigation of the side chain modification of terrein. The two deuterium labelled isocoumarins [4,alpha,alpha,alpha -2H4]-3,4-dihydro-6,8-dihydroxy-3-methylisocoumarin and [3,4-2H2] -3,4-dihydro-6,8-dihydroxy-3-methylisocoumarin were synthesised and fed to Aspergillus terreus. Results showed that both were incorporated to some extent but some partial degradation of the isocoumarins to acetate was also observed. In the ring contraction step it is known that C-7 of the isocoumarin is lost. Thus a possible intermediate containing an oxygenated carbon at C-7 was examined. Several synthetic routes to 3,4-dihydro- 6,7,8-trihydroxy-3-methylisocoumarin were investigated since the synthesis used for the 6,8-dihydroxyisocoumarin was not applicable in this case. The intermediacy of 2,3,5-trihydroxyphenylpropene was also explored. Two different synthetic strategies to this compound were employed, one involving the condensation of a phosphonic acid bisamide with an appropriate ester derivative, the other making use of the ortho-Claisen rearrangement

Huntington Disease: The Complexities of Making and Disclosing a Clinical Diagnosis After Premanifest Genetic Testing

The management of patients and families affected by Huntington disease (HD) is complicated by several factors, both practical and ethical. It can be difficult to determine the onset of clinically manifest HD (mHD). In addition, it can be challenging to decide when to disclose the diagnosis to the affected individual. Firstly, the features of HD, an incurable, inherited, neurocognitive disorder that often manifests in young adulthood, influence how the person presents and accepts a diagnosis. Secondly, a positive genetic test for HD may result in a genetic diagnosis, sometimes years before the development of clinical features and the diagnosis of mHD. Thirdly, observational studies of unaffected gene expansion carriers documented HD manifestations up to 10 years before the typical presentation for diagnosis. These developments may permit earlier genetic diagnosis and information regarding the patient’s likely status with respect to the development of clinical disease. Making the genetic diagnosis of HD and providing information regarding disease status, earlier rather than later, respects the person’s right to know and preserves honesty in the doctor/patient relationship. Conversely, delaying the diagnosis respects the right not to know, avoids potential discrimination, and permits the person to live a “normal” life for longer, in the context of a disease without cure. This discussion has implications for other inherited and neurocognitive disorders

Motor onset and diagnosis in Huntington disease using the diagnostic confidence level

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI 27-69%). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models

Socio-demographic and clinical characteristics of re-presentation to an Australian inner-city emergency department: implications for service delivery

BACKGROUND: People who have complex health care needs frequently access emergency departments for treatment of acute illness and injury. In particular, evidence suggests that those who are homeless, or suffer mental illness, or have a history of substance misuse, are often repeat users of emergency departments. The aim of this study was to describe the socio-demographic and clinical characteristics of emergency department re-presentations. Re-presentation was defined as a return visit to the same emergency department within 28 days of discharge from hospital. METHODS: A retrospective cohort study was conducted of emergency department presentations occurring over a 24-month period to an Australian inner-city hospital. Characteristics were examined for their influence on the binary outcome of re-presentation within 28 days of discharge using logistic regression with the variable patient fitted as a random effect. RESULTS: From 64,147 presentations to the emergency department the re-presentation rate was 18.0% (n = 11,559) of visits and 14.4% (5,894/40,942) of all patients. Median time to re-presentation was 6 days, with more than half occurring within one week of discharge (60.8%; n = 6,873), and more than three-quarters within two weeks (80.9%; n = 9,151). The odds of re-presentation increased three-fold for people who were homeless compared to those living in stable accommodation (adjusted OR 3.09; 95% CI, 2.83 to 3.36). Similarly, the odds of re-presentation were significantly higher for patients receiving a government pension compared to those who did not (adjusted OR 1.73; 95% CI, 1.63 to 1.84), patients who left part-way through treatment compared to those who completed treatment and were discharged home (adjusted OR 1.64; 95% CI, 1.36 to 1.99), and those discharged to a residential-care facility compared to those who were discharged home (adjusted OR 1.46: 95% CI, 1.03 to 2.06). CONCLUSION: Emergency department re-presentation rates cluster around one week after discharge and rapidly decrease thereafter. Housing status and being a recipient of a government pension are the most significant risk factors. Early identification and appropriate referrals for those patients who are at risk of emergency department re-presentation will assist in the development of targeted strategies to improve health service delivery to this vulnerable group

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations

Supportive care for older people with frailty in hospital: An integrative review

BACKGROUND: Growing numbers of older people living with frailty and chronic health conditions are being referred to hospitals with acute care needs. Supportive care is a potentially highly relevant and clinically important approach which could bridge the practice gap between curative models of care and palliative care. However, future interventions need to be informed and underpinned by existing knowledge of supportive care. AIM: To identify and build upon existing theories and evidence about supportive care, specifically in relation to the hospital care of older people with frailty, to inform future interventions and their evaluation. DESIGN: An integrative review was used to identify and integrate theory and evidence. Electronic databases (Cochrane Medline, EMBASE and CIHAHL) were searched using the key term 'supportive care'. Screening identified studies employing qualitative and/or quantitative methods published between January 1990 and December 2015. Citation searches, reference checking and searches of the grey literature were also undertaken. DATA SOURCES: Literature searches identified 2733 articles. After screening, and applying eligibility criteria based on relevance to the research question, studies were subject to methodological quality appraisal. Findings from included articles (n=52) were integrated using synthesis of themes. RESULTS: Relevant evidence was identified across different research literatures, on clinical conditions and contexts. Seven distinct themes of the synthesis were identified, these were: Ensuring fundamental aspects of care are met, Communicating and connecting with the patient, Carer and family engagement, Building up a picture of the person and their circumstances, Decisions and advice about best care for the person, Enabling self-help and connection to wider support, and Supporting patients through transitions in care. A tentative integrative model of supportive care for frail older people is developed from the findings. CONCLUSION: The findings and model developed here will inform future interventions and can help staff and hospital managers to develop appropriate strategies, staff training and resource allocation models to improve the quality of health care for older people

Prevention of delirium (POD) for older people in hospital: study protocol for a randomised controlled feasibility trial

Background: Delirium is the most frequent complication among older people following hospitalisation. Delirium may be prevented in about one-third of patients using a multicomponent intervention. However, in the United Kingdom, the National Health Service has no routine delirium prevention care systems. We have developed the Prevention of Delirium Programme, a multicomponent delirium prevention intervention and implementation process. We have successfully carried out a pilot study to test the feasibility and acceptability of implementation of the programme. We are now undertaking preliminary testing of the programme. Methods/Design: The Prevention of Delirium Study is a multicentre, cluster randomised feasibility study designed to explore the potential effectiveness and cost-effectiveness of the Prevention of Delirium Programme. Sixteen elderly care medicine and orthopaedic/trauma wards in eight National Health Service acute hospitals will be randomised to receive the Prevention of Delirium Programme or usual care. Patients will be eligible for the trial if they have been admitted to a participating ward and are aged 65 years or over. The primary objectives of the study are to provide a preliminary estimate of the effectiveness of the Prevention of Delirium Programme as measured by the incidence of new onset delirium, assess the variability of the incidence of new-onset delirium, estimate the intracluster correlation coefficient and likely cluster size, assess barriers to the delivery of the Prevention of Delirium Programme system of care, assess compliance with the Prevention of Delirium Programme system of care, estimate recruitment and follow-up rates, assess the degree of contamination due to between-ward staff movements, and investigate differences in financial costs and benefits between the Prevention of Delirium Programme system of care and standard practice. Secondary objectives are to investigate differences in the number, severity and length of delirium episodes (including persistent delirium); length of stay in hospital; inhospital mortality; destination at discharge; health-related quality of life and health resource use; physical and social independence; anxiety and depression; and patient experience. Discussion: This feasibility study will be used to gather data to inform the design of a future definitive randomised controlled trial. Trial registration: ISRCTN01187372. Registered 13 March 2014

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD