C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies

OBJECTIVE: In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Our objective was to determine whether this mutation causes HD phenocopies. METHODS: A cohort of 514 HD phenocopy patients were analyzed for the C9orf72 expansion using repeat primed PCR. In cases where the expansion was found, Southern hybridization was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases. RESULTS: Ten subjects (1.95%) had the expansion, making it the most common identified genetic cause of HD phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterized by the presence of movement disorders, including dystonia, chorea, myoclonus, tremor, and rigidity. Furthermore, the age at onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion and included one case with pediatric onset. DISCUSSION: This study extends the known phenotype of the C9orf72 expansion in both age at onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy patients based on these data

Inotropic action of the puberty hormone kisspeptin in rat, mouse and human: cardiovascular distribution and characteristics of the kisspeptin receptor

Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [¹²⁵I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (K(D) = 0.12 nM, human; K(D) = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.This work was supported by grants from the Medical Research Council (http://www.mrc.ac.uk) and the British Heart Foundation (http://www.bhf.org.uk). (Grant numbers PS/02/001 and PG/09/050/27734.)

Wake up, wake up! It's me! It's my life! patient narratives on person-centeredness in the integrated care context: a qualitative study

Person-centered care emphasizes a holistic, humanistic approach that puts patients first, at the center of medical care. Person-centeredness is also considered a core element of integrated care. Yet typologies of integrated care mainly describe how patients fit within integrated services, rather than how services fit into the patient's world. Patient-centeredness has been commonly defined through physician's behaviors aimed at delivering patient-centered care. Yet, it is unclear how 'person-centeredness' is realized in integrated care through the patient voice. We aimed to explore patient narratives of person-centeredness in the integrated care context

Epithelial p38α Controls Immune Cell Recruitment in the Colonic Mucosa

Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-κB pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38α in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38α deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4+ T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38α in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells

Physician support for diabetes patients and clinical outcomes

<p>Abstract</p> <p>Background</p> <p>Physician practical support (e.g. setting goals, pro-active follow-up) and communicative support (e.g., empathic listening, eliciting preferences) have been hypothesized to influence diabetes outcomes.</p> <p>Methods</p> <p>In a prospective observational study, patients rated physician communicative and practical support using a modified Health Care Climate Questionnaire. We assessed whether physicians' characteristic level of practical and communicative support (mean across patients) and each patients' deviation from their physician's mean level of support was associated with glycemic control outcomes. Glycosylated haemoglobin (HbA1c) levels were measured at baseline and at follow-up, about 2 years after baseline.</p> <p>Results</p> <p>We analysed 3897 patients with diabetes treated in nine primary care clinics by 106 physicians in an integrated health plan in Western Washington, USA. Physicians' average level of practical support (based on patient ratings of their provider) was associated with significantly lower HbA1c at follow-up, controlling for baseline HbA1c (<it>p </it>= .0401). The percentage of patients with "optimal" and "poor" glycemic control differed significantly across different levels of practical support at follow (<it>p </it>= .022 and <it>p </it>= .028). Communicative support was not associated with differences in HbA1c at follow-up.</p> <p>Conclusion</p> <p>This observational study suggests that, in community practice settings, physician differences in practical support may influence glycemic control outcomes among patients with diabetes.</p

A Reservoir of Drug-Resistant Pathogenic Bacteria in Asymptomatic Hosts

The population genetics of pathogenic bacteria has been intensively studied in order to understand the spread of disease and the evolution of virulence and drug resistance. However, much less attention has been paid to bacterial carriage populations, which inhabit hosts without producing disease. Since new virulent strains that cause disease can be recruited from the carriage population of bacteria, our understanding of infectious disease is seriously incomplete without knowledge on the population structure of pathogenic bacteria living in an asymptomatic host. We report the first extensive survey of the abundance and diversity of a human pathogen in asymptomatic animal hosts. We have found that asymptomatic swine from livestock productions frequently carry populations of Salmonella enterica with a broad range of drug-resistant strains and genetic diversity greatly exceeding that previously described. This study shows how agricultural practice and human intervention may lead and influence the evolution of a hidden reservoir of pathogens, with important implications for human health

A Model of Salmonella Colitis with Features of Diarrhea in SLC11A1 Wild-Type Mice

Background: Mice do not get diarrhea when orally infected with S. enterica, but pre-treatment with oral aminoglycosides makes them susceptible to Salmonella colitis. However, genetically susceptible ItyS mice (Nramp1 G169D allele) die from systemic infection before they develop diarrhea, so a new model is needed to study the pathogenesis of diarrhea. We pretreated ItyR mice (Nramp1 G169) with oral kanamycin prior to infecting them with virulent S. Typhimurium strain 14028s in order to study Salmonella-induced diarrhea. We used both a visual scoring system and the measurement of fecal water content to measure diarrhea. BALB/c.D2 Nramp1 congenic started losing weight 5 days post-infection and they began to die from colitis 10–14 days after infection. A SPI-1 (invA) mutant caused cecal, but not colonic inflammation and did not cause diarrhea. A phoP- mutant did not cause manifestations of diarrhea in either normal or NADPHdeficient (gp91 phox) mice. However, strain 14028s caused severe colitis and diarrhea in gp91 phox-deficient mice on an ItyR background. pmr A and F mutants, which are less virulent in orally infected BALB/c mice, were fully virulent in this model of colitis. Conclusions: S. enterica must be able to invade the colonic epithelium and to persist in the colon in order to cause colitis with manifestations of diarrhea. The NADPH oxidase is not required for diarrhea in Salmonella colitis. Furthermore,

To test or not to test: A cross-sectional survey of the psychosocial determinants of self-testing for cholesterol, glucose, and HIV

Contains fulltext : 97466.pdf (publisher's version ) (Open Access)BACKGROUND: Although self-tests are increasingly available and widely used, it is not clear whether their use is beneficial to the users, and little is known concerning the determinants of self-test use. The aim of this study was to identify the determinants of self-test use for cholesterol, glucose, and HIV, and to examine whether these are similar across these tests. Self-testing was defined as using in-vitro tests on body materials, initiated by consumers with the aim of diagnosing a particular disorder, condition, or risk factor for disease. METHODS: A cross-sectional Internet survey was conducted among 513 self-testers and 600 non-testers, assessing possible determinants of self-test use. The structured questionnaire was based on the Health Belief Model, Theory of Planned Behavior, and Protection Motivation Theory. Data were analyzed by means of logistic regression. RESULTS: The results revealed that perceived benefits and self-efficacy were significantly associated with self-testing for all three conditions. Other psychosocial determinants, e.g. gender, cues to action, perceived barriers, subjective norm, and moral obligation, seemed to be more test-specific. CONCLUSIONS: Psychosocial determinants of self-testing are not identical for all tests and therefore information about self-testing needs to be tailored to a specific test. The general public should not only be informed about advantages of self-test use but also about the disadvantages. Designers of information about self-testing should address all aspects related to self-testing to stimulate informed decision making which, in turn, will result in more effective self-test use

Extended and standard duration weight-loss programme referrals for adults in primary care (WRAP): a randomised controlled trial

$\textit{Background}$ Evidence exist that primary care referral to an open-group behavioural programme is an effective strategy for management of obesity, but little evidence on optimal intervention duration is available. We aimed to establish whether 52-week referral to an open-group weight-management programme would achieve greater weight loss and improvements in a range of health outcomes and be more cost-effective than the current practice of 12-week referrals. $\textit{Methods}$ In this non-blinded, parallel-group, randomised controlled trial, we recruited participants who were aged 18 years or older and had body-mass index (BMI) of 28 kg/m² or higher from 23 primary care practices in England. Participants were randomly assigned (2:5:5) to brief advice and self-help materials, a weight-management programme (Weight Watchers) for 12 weeks, or the same weight-management programme for 52 weeks. We followed-up participants over 2 years. The primary outcome was weight at 1 year of follow-up, analysed with mixed-effects models according to intention-to-treat principles and adjusted for centre and baseline weight. In a hierarchical closed-testing procedure, we compared combined behavioural programme arms with brief intervention, then compared the 12-week programme and 52-week programme. We did a within-trial cost-effectiveness analysis using person-level data and modelled outcomes over a 25-year time horizon using microsimulation. This study is registered with Current Controlled Trials, number ISRCTN82857232. $\textit{Findings}$ Between Oct 18, 2012, and Feb 10, 2014, we enrolled 1269 participants. 1267 eligible participants were randomly assigned to the brief intervention (n=211), the 12-week programme (n=528), and the 52-week programme (n=528). Two participants in the 12-week programme had been found to be ineligible shortly after randomisation and were excluded from the analysis. 823 (65%) of 1267 participants completed an assessment at 1 year and 856 (68%) participants at 2 years. All eligible participants were included in the analyses. At 1 year, mean weight changes in the groups were –3·26 kg (brief intervention), –4·75 kg (12-week programme), and –6·76 kg (52-week programme). Participants in the behavioural programme lost more weight than those in the brief intervention (adjusted difference –2·71 kg, 95% CI –3·86 to –1·55; p<0·0001). The 52-week programme was more effective than the 12-week programme (–2·14 kg, –3·05 to –1·22; p<0·0001). Differences between groups were still significant at 2 years. No adverse events related to the intervention were reported. Over 2 years, the incremental cost-effectiveness ratio (ICER; compared with brief intervention) was £159 per kg lost for the 52-week programme and £91 per kg for the 12-week programme. Modelled over 25 years after baseline, the ICER for the 12-week programme was dominant compared with the brief intervention. The ICER for the 52-week programme was cost-effective compared with the brief intervention (£2394 per quality-adjusted life-year [QALY]) and the 12-week programme (£3804 per QALY). $\textit{Interpretation}$ For adults with overweight or obesity, referral to this open-group behavioural weight-loss programme for at least 12 weeks is more effective than brief advice and self-help materials. A 52-week programme produces greater weight loss and other clinical benefits than a 12-week programme and, although it costs more, modelling suggests that the 52-week programme is cost-effective in the longer term.This trial was funded by the National Prevention Research Initiative grant MR/J000493/1. The cost of the Weight Watchers® programme and the costs of blood sampling and analysis were funded by Weight Watchers International as part of an MRC Industrial Collaboration Award