The role of Zap70 in naïve T cell homeostasis

TCR signalling is crucial to both T cell development and naive T cell homeostasis. Naïve T cell survival in the periphery is thought to depend on both cytokine signalling and constitutive TCR signalling. The nature of this TCR dependent survival signal remains controversial. The tyrosine kinase, Zap70, is essential for TCR signalling. The aim of this project is to investigate the role of Zap70 in the transduction of survival signals in naïve T cells. Using mice that conditionally express Zap70 by means of a tetracycline-inducible system, we found that Zap70 is absolutely required for the maintenance of naïve T cells in the periphery. Loss of Zap70 resulted in a dramatic and rapid reduction in mature naive CD8 T cells in the blood and peripheral organs consistent with a naïve T cell survival defect. This survival defect could not be accounted for by cell-intrinsic differences in IL-7Rα or Bcl-2 expression. Analysis of T cell survival in vitro revealed no differences in responses to IL-7 between F5 T cells with or without Zap70. Survival in vitro was found to be enhanced by the presence of CD1 1 c+ enriched splenocytes but not T or B cells. Survival of F5 T cells in these cultures was dependent on Zap70 expression and also required intact MEK signalling. In addition, we also tested the ability of previously described Zap70 mutants, Zap70 SKG and Zap70YYAA, to transduce homeostatic TCR survival signals in vivo. Both mutants were unable to support the development, survival or antigen-induced expansion of F5 T cells. Additionally, we found evidence that Zap70Y YAA had a dominant negative effect on T cell development and reconstitution in F5 TetZap70 mice. In conclusion, we find that Zap70 is essential for transmission of signals required for naive T cell survival and requires both full expression and functionality of Zap70

Estrogen receptor polymorphism predicts the onset of natural and surgical menopause

Age at menopause and risk of hysterectomy have strong genetic components, but the genes involved remain ill defined. We investigated whether genetic variation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 postmenopausal women, aged 55-80 yr, of the Rotterdam Study, a population-based cohort study in The Netherlands. Gynecological information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1-yr (P &lt; 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5-yr (P &lt; 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia. We conclude that genetic variations of the ER gene are related to the onset of natural menopause and the risk of surgical menopause, especially hysterectomy.</p

Hip fracture incidence in the elderly in Austria: An epidemiological study covering the years 1994 to 2006

Mann E, Icks A, Haastert B, Meyer G. Hip fracture incidence in the elderly in Austria: an epidemiological study covering the years 1994 to 2006. BMC Geriatrics. 2008;8(1): 35.Background: Hip fractures in the elderly are a major public health burden. Data concerning secular trends of hip fracture incidence show divergent results for age, sex and regions. In Austria, the hip fracture incidence in the elderly population and trends have not been analysed yet. Methods: Hip fractures in the population of 50 years and above were identified from 1994 to 2006 using the national hospital discharge register. Crude incidences (IR) per 100,000 person years and standardised incidences related to the European population 2006 were analysed. Estimate of age-sex-adjusted changes was determined using Poisson regression (incidence rate ratios, IRRs). Results: The number of hospital admissions due to hip fracture increased from a total number of 11,694 in 1994 to 15,987 in 2006. Crude incidences rates (IR) per 100.000 for men increased from 244.3 (95% confidence interval (CI) 234.8 to 253.7) in 1994 to IR 330.8 (95% CI 320.8 to 340.9) in 2006 and for women from 637.3 (95% CI 624.2 to 650.4) in 1994 to IR 758.7 (95% CI 745.0 to 772.4) in 2006. After adjustment for age and sex the annual hip fracture incidence increase was only small but statistically significant (IRR per year 1.01, 95% CI 1.01 to 1.01, p < 0.01). Change of IRR over the 12 years study period was 13%. It was significantly higher for men (IRR over 12 years 1.21, 95% CI 1.16 to 1.27) than for women (IRR over 12 years 1.10, 95% CI 1.06 to 1.14) (interaction: p = 0.03). Conclusion: In contrast to findings in other countries there is no levelling-off or downward trend of hip fracture incidence from 1994 to 2006 in the Austrian elderly population. Further investigations should aim to evaluate the underlying causes in order to plan effective hip fracture reduction programmes

The mortality of patients with diabetes mellitus in Latvia 2000-2012

Publisher Copyright: © 2014 Lithuanian University of Health Sciences.Background and objective: In Latvia, like in other European countries, the incidence of diabetes mellitus is increasing and so it is important to find out what the trends in the mortality of diabetes mellitus in Latvia are. The aim of this study was to calculate the mortality indicators of diabetes patients in Latvia from 2000 to 2012 and compare mortality among diabetes mellitus patients with mortality among the population of Latvia. Materials and methods: The study was carried out with a quantitative statistical analysis approach. In the study, all the registered patients with diabetes mellitus from 2000 to 2012 were included. Results: Mortality in a population with diabetes decreased statistically significantly from 57.76 per 1000 py in 2000 to 45.33 per 1000 py in 2012. In the general population of Latvia, there were no statistically significant changes; the mortality in 2000 was 13.56 per 1000 py, in 2012 - 14.24 per 1000 py. The age-standardised mortality ratio of the population with diabetes and the population of Latvia decreased from 1.71 (95% CI = 1.62-1.81) in 2000 to 1.23 (95% CI = 1.19-1.27) in 2012. Conclusions: In Latvia the mortality of patients with diabetes exceeds mortality in the general population. Mortality rates are higher for men and older patients, however, compared to mortality in the general population, diabetes increases the risk of death; especially for women and for younger patients. There is a tendency that the mortality indicators of patients with diabetes and mortality indicators in the general population are becoming closer.publishersversionPeer reviewe

Cardiodesfibrilador Automático Implantable: Desfibrilación Ventricular. Resultados de la Experiencia del ICD-LABOR

En la presente publicación se expone la experiencia acumulada por el ICD-LABOR, un registro latinoamericano de cardiodesfibriladores implantables, en relación a la inducción de fibrilación ventricular y los valores de umbral de desfibrilación durante el procedimiento del implante. Sobre un total de 857 pacientes implantados entre Enero de 1995 y Octubre de 2004, se indujo fibrilación ventricular (FV) en 818 de ellos (95%), con el propósito de comprobar la eficacia del sistema de detección y el nivel de energía requerido para revertir la arritmia. De los 39 pacientes restantes, en 2 individuos (0.23%) la FV no pudo ser inducida; mientras que en los otros 37 (4.77%), el test de inducción no fue realizado. En el 74% de los pacientes, una energía de 15 J o menos fue suficiente para revertir la FV. En 42 sujetos fue empleada la máxima energía (30 J), con fracaso de la reversión en 7 pacientes, que fueron rescatados mediante un choque externo. Los umbrales reales o verdaderos entre los tres principales grupos de patologías (enfermedad coronaria, enfermedad de Chagas y miocardiopatía dilatada idiopática), fueron semejantes y no pudo establecerse relaciones entre patología de base y necesidades de energía para la reversión de la FV. Tampoco se demostró relación entre el umbral real ó verdadero de desfibrilación y la sobrevida durante el tiempo que duró el seguimiento (28 ± 26 meses)

Cardiodesfibrilador Automático Implantable: Desfibrilación Ventricular. Resultados de la Experiencia del ICD-LABOR

En la presente publicación se expone la experiencia acumulada por el ICD-LABOR, un registro latinoamericano de cardiodesfibriladores implantables, en relación a la inducción de fibrilación ventricular y los valores de umbral de desfibrilación durante el procedimiento del implante. Sobre un total de 857 pacientes implantados entre Enero de 1995 y Octubre de 2004, se indujo fibrilación ventricular (FV) en 818 de ellos (95%), con el propósito de comprobar la eficacia del sistema de detección y el nivel de energía requerido para revertir la arritmia. De los 39 pacientes restantes, en 2 individuos (0.23%) la FV no pudo ser inducida; mientras que en los otros 37 (4.77%), el test de inducción no fue realizado. En el 74% de los pacientes, una energía de 15 J o menos fue suficiente para revertir la FV. En 42 sujetos fue empleada la máxima energía (30 J), con fracaso de la reversión en 7 pacientes, que fueron rescatados mediante un choque externo. Los umbrales reales o verdaderos entre los tres principales grupos de patologías (enfermedad coronaria, enfermedad de Chagas y miocardiopatía dilatada idiopática), fueron semejantes y no pudo establecerse relaciones entre patología de base y necesidades de energía para la reversión de la FV. Tampoco se demostró relación entre el umbral real ó verdadero de desfibrilación y la sobrevida durante el tiempo que duró el seguimiento (28 ± 26 meses)

Antiarrhythmic Effect of Reverse Ventricular Remodeling Induced by Cardiac Resynchronization Therapy The InSync ICD (Implantable Cardioverter-Defibrillator) Italian Registry

Objectives: We investigated whether the reverse remodeling after cardiac resynchronization therapy (CRT) might reduce the occurrence of ventricular arrhythmias (VAs). Background: It is currently debated whether CRT has an effect on the burden of VAs. Methods: The study included 398 patients treated with a CRT defibrillator and with a follow-up of at least 12 months. Spontaneous VAs detected by the device were reviewed and validated. Results: A significant reduction in VA episodes and shock therapies was evident during the follow-up with greater decrease after 1 month. After 6 months of CRT, 227 patients (57%) showed a reduction in end-systolic volume of ≥10% and were defined as "responders." The baseline characteristics were similar between the responders and the nonresponders. Nonetheless, the proportion of patients with recurrence of VA after 1 month of CRT was significantly lower in responders (32% vs. 43%, p = 0.024). Among baseline variables no parameters emerged as predictors of tachyarrhythmia recurrence. However, receiver-operating curve analysis recognized a reduction of left ventricular end-systolic volume at 6 months of 13% as the best cutoff to identify the reduction of VAs (with a sensitivity of 58% and a specificity of 54%). Conclusions: In patients treated with CRT defibrillators, a reduction in ventricular arrhythmic events occurs during the initial 12 months after implant and is correlated with the degree of ventricular remodeling induced by the therapy. Patients demonstrating reverse remodeling at midterm follow-up show a reduction in arrhythmias soon after the implant, pronounced improvements at long-term, and a better survival. © 2008 American College of Cardiology Foundation

An investigation of factors associated with the health and well-being of HIV-infected or HIV-affected older people in rural South Africa

BackgroundDespite the severe impact of HIV in sub-Saharan Africa, the health of older people aged 50+ is often overlooked owing to the dearth of data on the direct and indirect effects of HIV on older people's health status and well-being. The aim of this study was to examine correlates of health and well-being of HIV-infected older people relative to HIV-affected people in rural South Africa, defined as participants with an HIV-infected or death of an adult child due to HIV-related cause. MethodsData were collected within the Africa Centre surveillance area using instruments adapted from the World Health Organization (WHO) Study on global AGEing and adult health (SAGE). A stratified random sample of 422 people aged 50+ participated. We compared the health correlates of HIV-infected to HIV-affected participants using ordered logistic regressions. Health status was measured using three instruments: disability index, quality of life and composite health score. ResultsMedian age of the sample was 60 years (range 50-94). Women HIV-infected (aOR 0.15, 95% confidence interval (CI) 0.08-0.29) and HIV-affected (aOR 0.20, 95% CI 0.08-0.50), were significantly less likely than men to be in good functional ability. Women's adjusted odds of being in good overall health state were similarly lower than men's; while income and household wealth status were stronger correlates of quality of life. HIV-infected participants reported better functional ability, quality of life and overall health state than HIV-affected participants. Discussion and Conclusions The enhanced healthcare received as part of anti-retroviral treatment as well as the considerable resources devoted to HIV care appear to benefit the overall well-being of HIV-infected older people; whereas similar resources have not been devoted to the general health needs of HIV uninfected older people. Given increasing numbers of older people, policy and programme interventions are urgently needed to holistically meet the health and well-being needs of older people beyond the HIV-related care system. <br/