Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies

Cardiac muscle contraction occurs through an interaction of the myosin head with the actin filaments, a process which is regulated by the troponin complex together with tropomyosin and is Ca²⁺ dependent. Mutations in genes encoding sarcomeric proteins are a common cause of familial hypertrophic and dilated cardiomyopathies. The scope of this review is to gather information from studies regarding the in vitro characterisation of six HCM and six DCM mutations on the cardiac TnC gene and to suggest, if possible, how they may lead to dysfunction. Since TnC is the subunit responsible for Ca²⁺ binding, mutations in the TnC could possibly have a strong impact on Ca²⁺ binding affinities. Furthermore, the interactions of mutant TnCs with their binding partners could be altered. From the characterisation studies available to date, we can conclude that the HCM mutations on TnC increase significantly the Ca²⁺ sensitivity of force development or of ATPase activity, producing large pCa shifts in comparison to WT TnC. In contrast, the DCM mutations on TnC have a tendency to decrease the Ca²⁺ sensitivity of force development or of ATPase activity in comparison to WT TnC. Furthermore, the DCM mutants of TnC are not responsive to the TnI phosphorylation signal resulting in filaments that preserve their Ca²⁺ sensitivity in contrast to WT filaments that experience a decrease in Ca²⁺ sensitivity upon TnI phosphorylation.     

Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults

Background: Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16-26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2, and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16-26 years and had a favorable safety profile.     

Prevalence of hepatitis C virus antibodies and genotypes in asymptomatic, first-time blood donors in Namibia

Reported is the prevalence of hepatitis C virus (HCV) in Namibia as determined using a third-generation enzyme-linked immunosorbent assay (ELISA) on samples of blood collected from all asymptomatic, first-time blood donors between 1 February and 31 July 1997 (n = 1941). The HCV seroprevalence was 0.9% (95% confidence interval (CI): 0.5-1.5%) and no associations were detected between a positive HCV serostatus and the person's sex, region of residence, or previous hepatitis B exposure or hepatitis B carrier status, as determined by hepatitis B surface antigen (HBsAg). The only significant association in a logistic regression model was an increase in HCV positivity with increasing age (P = 0.04). Viral RNA was amplified from 2 out of 18 (11.1%) specimens that were ELISA positive. Genotyping of these specimens, by restriction fragment length polymorphism (RFLP), showed the presence of genotypes 5 and 1a. The positive predictive value of using HBsAg positivity as a surrogate screening marker for HCV in Namibian blood donors was poor (1.6%), with low sensitivity (16.7%) and specificity (89.3%), and detecting only 3 out of 18 serologically HCV-positive specimens. The results of this first study of the prevalence and epidemiology of HCV infection in Namibia suggest that donor blood should be screened for HCV by ELISA in order to prevent the transmission of hepatitis C virus.     

Viral hepatitis in South African healthcare workers at increased risk of occupational exposure to blood-borne viruses

The prevalence of hepatitis A, B and C antibodies was measured in a group of healthcare workers (HCWs) at increased risk of occupational acquisition of blood-borne viruses (N=402) from a large, urban referral hospital in South Africa. The aims of this study were to determine the immunity of HCWs to these agents and to recommend policy for the protection of HCWs against occupational exposure to viral hepatitis in this country. Race, sex and age were shown to be important factors influencing the presence of hepatitis A (HAV) antibodies. Most black HCWs (96.2%) are protected from HAV infection. Females have significantly higher HAV antibodies compared with males and antibodies increase with increasing age. Hepatitis B antibodies (anti-HBs) were found in 30.6% of HCWs. Anti-HBs levels were significantly associated with a past history of HBV vaccination. However, only a small proportion of HCWs (21.2%) could remember ever being immunized against HBV. For those individuals that did receive HBV vaccination (N=83), the mean number of years since their last vaccine was 6.2 years (SD +/- 3.5). HCV antibodies were found in 1.8% of HCWs at increased risk of occupational exposure. It was not possible to define whether these infections were occupationally acquired but genotyping of the HCV (in two of seven cases) showed genotype 5, the predominant South African genotype. New recommendations for the prevention of viral hepatitis in HCWs in South Africa are made, including pre-employment screening for HAV based on self-selection criteria, universal anti-HBs screening with HBV booster vaccination. HCV recommendations are based on appropriate education of HCWs about this infection and its prevention and a standardized post-exposure testing protocol.     

Abnormal heart rate recovery immediately after treadmill testing: Correlation with clinical, exercise testing, and myocardial perfusion parameters

BACKGROUND: The increase in heart rate during exercise is considered to be attributed to sympathetic system activation combined with parasympathetic withdrawal. The prognostic importance of the chronotropic response to exercise and heart rate recovery 1 minute after exercise has already been established. The purpose of this study was to evaluate heart rate recovery as an index of myocardial ischemia, by correlating heart rate recovery with known parameters of myocardial ischemia. METHODS AND RESULTS: Included in the study were 304 consecutive patients (73% men), aged 34 to 82 years. Patients whose heart rate recovery value or myocardial perfusion imaging could have been influenced by factors other than ischemic disease were excluded from the study. The patients underwent single photon emission computed tomography myocardial perfusion imaging combined with symptom-limited exercise testing with thallium 201 or technetium 99m tetrofosmin. The value for heart rate recovery was defined as the decrease in heart rate from peak exercise to 1 minute after termination of exercise. For semiquantitation of the scintigram, the uptake of the radiotracer was graded on a scale from 0 to 4. Twenty-one beats per minute was defined as the lowest normal value for heart rate recovery. We found 74 patients (24%) with an abnormal value. We also found a significant correlation between heart rate recovery 1 minute after exercise and stress myocardial perfusion score. In addition, there was a statistically significant relationship between heart rate recovery and chronotropic variables. Patients with an abnormal value of heart rate recovery were generally of an older age, were more likely men, had a higher frequency of risk factors for coronary artery disease, were mostly taking cardioactive medications, had lower efficiency during treadmill testing, and had more pathologic findings on the scintigram. CONCLUSIONS: Myocardial ischemia, as assessed by myocardial perfusion imaging, is an important correlate of heart rate recovery. There is a significant correlation between chronotropic variables during exercise testing and heart rate recovery 1 minute after exercise. It seems that the heart rate recovery value 1 minute after peak exercise may be considered a reliable index of the severity of myocardial ischemia.     

Update of the guidelines on sudden cardiac death of the European Society of Cardiology.

One of the most important challenges forscientific societiesresponsible for the development of guidelines, is to provideregular update of recommendations when new data become available.The Committee for Practice Guidelines of the ESC has set thegoal of producing an update of guidelines every 12–24months from the publication of the initial document (http://www.escardio.org). The guidelines for the prevention of suddencardiac death (SCD)were published in the August issue of the European Heart Journalin 2001¹ and the Executive Summary was published in theJanuaryissue of Europace.² In the last 12 months, the release of importantdata has affected risk stratification and management of patientsat riskof dying suddenly. Based on this evidence, the membersof the Task Force on     

Training Patterns and Lifetime Career Achievements of US Academic Cardiothoracic Surgeons

Background

We aimed to investigate the impact of taking dedicated time for research (DTR) during training and/or getting a PhD on subsequent career achievements of US academic cardiothoracic surgeons.

Methods

Online resources (institutional Web sites, CTSNet, Scopus, NIH RePORTER) were queried to collect training information (timing of medical school/residency/fellowship graduation, DTR, PhD) and academic metrics (publications, citations, research funding) for 694 academic cardiothoracic surgeons practicing at 56 premiere US institutions.

Results

Excluding missing data, 464 (75 %) surgeons took DTR and 156 (25 %) did not; 629 (91 %) were MD only and 65 (9 %) also had a PhD. DTR was associated with higher number of ongoing publications (~5.6/year vs. ~3.8/year), with no difference for accrued number of total citations. History of DTR was more prevalent among surgeons with versus without NIH funding (87 vs. 71 %; p < 0.001), but no difference was seen across academic ranks and among those who were division/department chiefs. No overall increase in publications/citations, academic rank advancement, NIH funding, or leadership roles was found for those with a PhD.

Conclusions

Among cardiothoracic surgeons, devoting time during the training years exclusively to research might be associated with higher career-long academic productivity in terms of annual number new publications and ability to get NIH funding, but without significant impact in terms of academic rank or institutional role advancement. No significant difference was found between those with versus without a PhD in terms of career-long number of publications/citations, academic rank, NIH funding, or leadership role, even though sample size might have been insufficient to identify any such potential difference.