Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes

Background: Variants in the cardiac myosin-binding protein C gene (MYBPC3) are a common cause of hypertrophic cardiomyopathy (HCM) in adults and have been associated with late-onset disease, but there are limited data on their role in paediatric-onset HCM. The objective of this study was to describe natural history and clinical outcomes in a large cohort of children with HCM and pathogenic/likely pathogenic (P/LP) MYBPC3 variants. / Methods and results: Longitudinal data from 62 consecutive patients diagnosed with HCM under 18 years of age and carrying at least one P/LP MYBPC3 variant were collected from a single specialist referral centre. The primary patient outcome was a major adverse cardiac event (MACE). Median age at diagnosis was 10 (IQR: 2–14) years, with 12 patients (19.4%) diagnosed in infancy. Forty-seven (75%) were boy and 31 (50%) were probands. Median length of follow-up was 3.1 (IQR: 1.6–6.9) years. Nine patients (14.5%) experienced an MACE during follow-up and five (8%) died. Twenty patients (32.3%) had evidence of ventricular arrhythmia, including 6 patients (9.7%) presenting with out-of-hospital cardiac arrest. Five-year freedom from MACE for those with a single or two MYBPC3 variants was 95.2% (95% CI: 78.6% to 98.5%) and 68.4% (95% CI: 40.6% to 88.9%), respectively (HR 4.65, 95% CI: 1.16 to 18.66, p=0.03). / Conclusions: MYBPC3 variants can cause childhood-onset disease, which is frequently associated with life-threatening ventricular arrhythmia. Clinical outcomes in this cohort vary substantially from aetiologically and genetically mixed paediatric HCM cohorts described previously, highlighting the importance of identifying specific genetic subtypes for clinical management of childhood HCM

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy. © 1989 Plenum Publishing Corporation

Resilience and physical and mental well-being in adults with and without HIV

Resilience has been related to improved physical and mental health, and is thought to improve with age. No studies have explored the relationship between resilience, ageing with HIV, and well-being. A cross sectional observational study performed on UK HIV positive (N = 195) and HIV negative adults (N = 130). Associations of both age and ‘time diagnosed with HIV’ with resilience (RS-14) were assessed, and the association of resilience with depression, anxiety symptoms (PHQ-9 and GAD-7), and problems with activities of daily living (ADLs) (Euroqol 5D-3L). In a multivariable model, HIV status overall was not related to resilience. However, longer time diagnosed with HIV was related to lower resilience, and older age showed a non-significant trend towards higher resilience. In adults with HIV, high resilience was related to a lower prevalence of depression, anxiety, and problems with ADLs. It may be necessary to consider resilience when exploring the well-being of adults ageing with HIV

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3>2.1×10-12¿¿s/eV at 90% C.L

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989–2003

<p>Abstract</p> <p>Background</p> <p>Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003.</p> <p>Methods</p> <p>We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway).</p> <p>Results</p> <p>Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy.</p> <p>Conclusion</p> <p>This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.</p

HIV Infection and Gut Mucosal Immune Function: Updates on Pathogenesis with Implications for Management and Intervention

HIV is primarily a sexually transmitted infection. However, given that the gastrointestinal tract (GIT) houses most of the body’s lymphocytes, including activated memory CD4+ T cells that are preferential targets for HIV, recent research has focused on the role of the GIT in transmission and pathogenesis. In health, the GIT maintains a balance between immune tolerance and rapid responsiveness. A complex network of innate and adaptive responses maintains this balance, which is severely perturbed in HIV infection. Recent studies have focused on mechanisms of GIT CD4+ T-cell depletion and epithelial disruption in HIV infection, the role of inflammation in accelerating viral dissemination, the kinetics of the adaptive response following transmission, and the extent of T-cell reconstitution following antiretroviral therapy. This review summarizes the results of recent investigations that may have important implications for the development of vaccines, microbicides, and therapeutic interventions for HIV and other mucosal pathogens

Comfort and utility of school-based weight screening: the student perspective

<p>Abstract</p> <p>Background</p> <p>Weight screening in schools has been proposed as one strategy to address childhood obesity. Students' response to such screening is unexplored, however. In this study we evaluated the perceived comfort, utility and impact of school-based weight screening from the perspective of middle school-aged students.</p> <p>Methods</p> <p>A cross-sectional study of 852 ethnically diverse 5^th–8^thgrade students. Associations were investigated between measured height and weight screening data and responses to a self-administered questionnaire completed immediately following weight screening in physical education class. BMI categories were based on the revised 2000 CDC growth chart and definitions: 5^th–85^thBMI percentile = healthy weight, 85^th–95^thBMI percentile = at risk for overweight, and >95^thpercentile BMI = overweight.</p> <p>Results</p> <p>Overall, students' comfort level with weight screening varied depending on the student's own weight status. More overweight students (38.1%) reported being uncomfortable than healthy weight students (8.1%) (p < 0.001). In particular, overweight female students (54.8%) compared to healthy weight female students (21.6%) reported being uncomfortable (p < 0.01). About half (54.9%) of all students reported knowing their weight prior to screening, and 58.9% reported that it was useful to learn their height and weight. Compared to healthy weight students, overweight students were significantly more likely to report the intention to perform weight modification related activities such as visiting a doctor (Odds ratio (OR) = 2.0, 95% CI = 1.3, 3.1), eating more fruits and vegetables (OR = 2.7, 95% CI = 1.7, 4.1), and increasing physical activity (OR = 4.3, 95% CI = 2.7, 7.0).</p> <p>Conclusion</p> <p>Overall, the majority of the middle school students did not report discomfort with school-based weight screening, did report that receiving height and weight information was useful, and generally report appropriate weight control intentions. These proportions varied across weight status categories, however, with students who were at risk for overweight or overweight reporting higher levels of discomfort. For schools that conduct weight screening, it is essential that they also provide comfortable and private settings as well as education or counseling regarding healthy weight control practices.</p