Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.     

Predictive Association of Smoking with Depressive Symptoms: a Longitudinal Study of Adolescent Twins

Prevention Science - Longitudinal, genetically informative studies of the association between cigarette smoking and depressive symptoms among adolescents are limited. We examined the longitudinal...     

Evaluation of personality traits in panic disorder using Swedish universities Scales of Personality

Personality factors may interact with development and expressions of panic disorder (PD). This study sought to identify differences in personality traits between patients with PD and healthy individuals and explore the relationships between personality domains and various demographic and clinical variables of PD. Personality traits were evaluated in 193 patients and 314 matched healthy subjects using the Swedish universities Scales of Personality (SSP). All SSP traits, except for detachment and physical trait aggression, were significantly deviated in PD group, as compared to healthy subjects. The SSP factors of neuroticism and aggressiveness, but not extraversion, were significantly higher in PD group than in controls. More pronounced aberrations in personality traits were observed in PD with affective comorbidity. Only few demographic and clinical variables were associated with SSP scores in PD group. These results add to the evidence of maladaptive personality disposition in patients with PD, particularly high neuroticism and manifest somatic trait anxiety. Use of SSP proved to add clinically relevant information on personality traits in patients with PD.     

An isoquinoline alkaloid, berberine, can inhibit fungal alpha amylase: enzyme kinetic and molecular modeling studies

Aspergillus flavus is a commonly found fungal pathogen, which produces aflatoxins, highly toxic and hepatocarcinogenic natural compounds. Inhibition of fungal alpha amylase activity has been found to limit the ability of the fungus to produce aflatoxins. Berberine, an isoquinoline alkaloid commonly found in many medicinal plants, was identified to inhibit the growth of A. flavus. The amount of berberine required to inhibit the fungal mycelial growth was determined. The compound was also found to inhibit the alpha amylase from the A. flavus. The binding affinity of the compound toward alpha amylase and the enzyme inhibitory activity have been determined by enzyme kinetic studies and Isothermal Titration Calorimetric analysis. Molecular modeling and docking studies were carried out to understand the enzyme–ligand interactions.     

Predictors of the quality of cardiovascular prevention �C a multilevel cross-sectional study

Aim

To attempt to develop a model of predictors for quality of the process of cardiovascular prevention in patients at high risk of cardiovascular disease (CVD).

Methods

We formed a random sample of patients from a stratified sample of 36 family practice registers of patients at high risk of CVD without diabetes and without established CVD. Data were gathered by chart audit and questionnaires about patient and practice characteristics. We defined the process of care as a dependent variable by principle component analysis and tested the relationship of the process with several independent variables (family physicians’, patients’, and practice characteristics). To study the effects of independent variables (predictors) on the process of care we carried out multilevel regression analysis with the patients constituting the lower level and nested within the family physician/practice (the second level).

Results

Multilevel regression analysis included 645 patients from 36 practices (74.1% from the final sample). Patients’ characteristics that predicted the higher-quality process of CVD prevention were younger age (t = -4.94, 95% confidence interval [CI] -0.018 to -0.008) and lower socioeconomic status (t = -2.18, 95%CI -0.195 to -0.010). Practice characteristics that predicted the higher-quality process of CVD prevention were smaller practice size (t = 2.83, 95% CI 0.063 to 1.166), a good information system for CVD prevention (t = 3.15, 95% CI 0.030 to 0.282), and the organization of education on CVD prevention (t = 3.19, 95%CI 0.043 to 0.380).

Conclusion

This study shows that the quality of cardiovascular prevention could be measured as a composite outcome and future studies should further develop this approach and test the impact of several practice/patient characteristics on the quality of CVD prevention with the international data.Prevention of cardiovascular diseases (CVD) is an important task for family physicians. While patients with a low risk of CVD profit mostly from public health activities, high risk patients also need preventive activities provided by their family physicians (1,2). In the countries with a national program of CVD prevention (Slovenia is one of them), these activities and procedures can be highly standardized (3) and, therefore, should be easily measurable. The Slovenian national preventive program for CVD was launched in 2001 and requires preventive check-ups for the defined age groups of patients (women from 45 to 70 years and men from 35 to 65 years). Eighty percent of the target group in every practice needs to go through the program in 5 years, and a register of high risk patients is created in each practice and collected on the national level. The preventive activities consist of two parts: the first part includes a health check-up with determination of risk factors (information on life-style, clinical exam, laboratory tests of lipids and fasting blood glucose) and the second part includes the referral of patients at high risk to preventive workshops, for example for healthy weight reduction, smoking cessation, etc.Although there is some evidence on several isolated aspects of CVD prevention in Slovenia (4-6), a comprehensive and systematic approach for measuring its quality and actual outcomes is still not available. Therefore, we aimed to develop an integral statistically evaluated presentation of the process of cardiovascular prevention and determine the variables that influence it. Post-hoc analyses were performed on patients at a high risk for coronary diseases using Slovenian data from the international EPA-Cardio study, a cross-sectional study conducted in 9 European countries that had developed quality indicators for cardiovascular prevention on the international level (7) and evaluated the quality of cardiovascular prevention for high-risk patients (8).     

Neuromyelitis optica: changing concepts

Neuromyelitis optica (NMO; Devic's disease) and the NMO spectrum disorders are idiopathic inflammatory demyelinating disorders that affect the central nervous system and have a predilection for optic nerves and spinal cord. The identification of NMO-IgG as a disease-specific marker and aquaporin 4 as the target antigen has renewed interest in NMO. Based on current data, we suspect that autoantibodies arising from peripheral B cells bind to aquaporin 4 expressed on astrocyte foot processes on the abluminal surface of microvessels, activate complement and initiate inflammatory demyelination and necrosis. The development of animal models and further analysis of the association of NMO-IgG with disease severity and treatment response will elucidate the pathobiology of NMO.     

The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland

Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population.     

Tamoxifen-induced rapid death of MCF-7 breast cancer cells is mediated via extracellularly signal-regulated kinase signaling and can be abrogated by estrogen

Tamoxifen (Tam) is widely used in chemotherapy of breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor (ER)-dependent modulation of gene expression. In addition, recent reports have shown that Tam also has nongenomic effects. We previously reported induction of a rapid mitochondrial death program in breast cancer cells at pharmacological concentrations of Tam. Here we studied the upstream signaling events leading to mitochondrial disruption by Tam. We observed that 5 mum Tam rapidly induced sustained activation of ERK1/2 in ER-positive breast cancer cell lines (MCF-7 and T47D) and that PD98059 (inhibitor of ERK activation) was able to protect MCF-7 cells against Tam-induced death. These data suggest that activation of ERK has a primary role in the acute death response of the cells. In addition, inhibition of epidermal growth factor receptor (EGFR) opposed both Tam-induced ERK1/2 phosphorylation and cell death, which suggests that EGFR-associated mechanisms are involved in Tam-induced death. ERK1/2 phosphorylation was associated with a prolonged nuclear localization of ERK1/2 as determined by fluorescence microscopy with ERK2-green fluorescent protein construct. 17beta-Estradiol was shown to exert a different kind of temporal pattern of ERK nuclear localization in comparison with Tam. Moreover, 17beta-estradiol was found to oppose the rapid effects of Tam in MCF-7 and T47D cells but not in MDA-MB-231 cells, which implies a role for estrogen receptors in the protective effect of estrogen. The pure antiestrogen ICI182780 could not, however, prevent Tam-induced ERK1/2 phosphorylation, suggesting that the Tam-induced rapid cell death is primarily ER-independent or mediated by ICI182780 insensitive nongenomic mechanisms.