Mitochondrial Dynamics and Apoptosis: A Painful Separation

Reporting in Molecular Cell, Sheridan et al. (2008) and Breckenridge et al. (2008) show that mitochondrial fragmentation is not required to induce cell death. Meanwhile, Yamaguchi et al. show that proapoptotic Bcl-2 family members promote cytochrome c mobilization through Opa1-mediated cristae remodeling. Therefore, the connection between mitochondrial structure and apoptosis is more complex than previously imagined

Differential Expression of Keratinocyte-Derived Extracellular Vesicle Mirnas Discriminate Exosomes From Apoptotic Bodies and Microvesicles

Extracellular vesicles (EVs) are mammalian cell-derived nano-scale structures enclosed by a lipid bilayer that were previously considered to be cell debris with little biological value. However, EVs are now recognized to possess biological function, acting as a packaging, transport and delivery mechanisms by which functional molecules (i.e., miRNAs) can be transferred to target cells over some distance. To examine the miRNA from keratinocyte-derived EVs, we isolated three distinct populations of EVs from both HaCaT and primary human keratinocytes (PKCs) and characterized their biophysical, biochemical and functional features by using microscopy, immunoblotting, nanoparticle tracking, and next generation sequencing. We identified 1,048; 906; and 704 miRNAs, respectively, in apoptotic bodies (APs), microvesicles (MVs) and exosomes (EXs) released from HaCaT, and 608; 506; and 622 miRNAs in APs, MVs and EXs released from PKCs. In which, there were 623 and 437 identified miRNAs common to three HaCaT-derived EVs and PKC-derived EVs, respectively. In addition, we found hundreds of exosomal miRNAs that were previously un-reported. Differences in the abundance levels of the identified EV miRNAs could discriminate between the three EV populations. These data contribute substantially to knowledge within the EV-identified miRNA database, especially with regard to keratinocyte-derived EV miRNA content

Rubidium and potassium levels are altered in Alzheimer's disease brain and blood but not in cerebrospinal fluid

Loss of intracellular compartmentalization of potassium is a biochemical feature of Alzheimer's disease indicating a loss of membrane integrity and mitochondrial dysfunction. We examined potassium and rubidium (a biological proxy for potassium) in brain tissue, blood fractions and cerebrospinal fluid from Alzheimer's disease and healthy control subjects to investigate the diagnostic potential of these two metal ions. We found that both potassium and rubidium levels were significantly decreased across all intracellular compartments in the Alzheimer's disease brain. Serum from over 1000 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), showed minor changes according to disease state. Potassium and rubidium levels in erythrocytes and cerebrospinal fluid were not significantly different according to disease state, and rubidium was slightly decreased in Alzheimer's disease patients compared to healthy controls. Our data provides evidence that contrasts the hypothesized disruption of the blood-brain barrier in Alzheimer's disease, with the systemic decrease in cortical potassium and rubidium levels suggesting influx of ions from the blood is minimal and that the observed changes are more likely indicative of an internal energy crisis within the brain. These findings may be the basis for potential diagnostic imaging studies using radioactive potassium and rubidium tracers

Next-generation sequencing of pancreatic cyst wall specimens obtained using micro-forceps for improving diagnostic accuracy

Background and study aims: Pancreatic cysts are common incidental findings, with an estimated prevalence of 13-15% in imaging done for other reasons. Diagnosis often relies on collection of cyst fluid, but tissue sampling using micro-forceps may allow for a more reliable diagnosis and higher yield of DNA for next-generation sequencing (NGS). The primary aim was to assess the performance of NGS in identifying mucinous cyst. The secondary aims were to assess DNA yield between the cyst fluid and cyst wall tissue, complication rate and performance of conventional investigations. Patients and methods: 24 patients referred for endoscopic ultrasound were recruited. Biopsies were taken using micro-forceps and the AmpliSeq Cancer Hotspot panel was used for NGS, a PCR assay targeting several hotspots within 50 genes, including GNAS, KRAS and VHL. Results: The concentration of DNA extracted from 24 cyst wall samples was significantly higher than in the 9/24 available matched cyst fluid samples. The sensitivity, specificity and diagnostic accuracy of NGS for diagnosing mucinous cyst was 93%, 50% and 84%, standard of care -66.6%, 50% and 63.1% and for standard of care with NGS was 100%, 50% and 89.4% respectively. Cyst wall biopsy was able to diagnose 19/24 cysts (4 high risk, 7 intraductal papillary mucinous neoplasm, 4 cysts of mucinous origin and 4 benign). Conclusions: NGS data correlates well with histology and may aid in diagnosis and risk stratification of pancreatic cysts. Cyst wall biopsy performs well in diagnosing cysts but was inadequate in 5/24 patients

Role of Condom Negotiation on Condom use among Women of Reproductive Age in three Districts in Tanzania.

ABSTRACT: BACKGROUND: HIV/AIDS remains being a disease of great public health concern worldwide. In regions such as sub-Saharan Africa (SSA) where women are disproportionately infected with HIV, women are reportedly less likely capable of negotiating condom use. However, while knowledge of condom use for HIV prevention is extensive among men and women in many countries including Tanzania, evidence is limited about the role of condom negotiation on condom use among women in rural Tanzania. METHODS: Data originate from a cross-sectional survey of random households conducted in 2011 in Rufiji, Kilombero and Ulanga districts in Tanzania. The survey assessed health-seeking behaviour among women and children using a structured interviewer-administered questionnaire. A total of 2,614 women who were sexually experienced and aged 15--49 years were extracted from the main database for the current analysis. Linkage between condom negotiation and condom use at the last sexual intercourse was assessed using multivariate logistic regression. RESULTS: Prevalence of condom use at the last sexual intercourse was 22.2% overall, ranging from12.2% among married women to 54.9% among unmarried (single) women. Majority of the women (73.4%) reported being confident to negotiate condom use, and these women were significantly more likely than those who were not confident to have used a condom at the last sexual intercourse (OR = 3.13, 95% CI 2.22-4.41). This effect was controlled for marital status, age, education, religion, number of sexual partners, household wealth and knowledge of HIV prevention by condom use. CONCLUSION: Confidence to negotiate condom use is a significant predictor of actual condom use among women in rural Tanzania. Women especially unmarried ones or those in multiple partnerships should be empowered with condom negotiation skills to enhance their sexual and reproductive health outcomes

Inhomogeneous Einstein-Rosen String Cosmology

Families of anisotropic and inhomogeneous string cosmologies containing non-trivial dilaton and axion fields are derived by applying the global symmetries of the string effective action to a generalized Einstein-Rosen metric. The models exhibit a two-dimensional group of Abelian isometries. In particular, two classes of exact solutions are found that represent inhomogeneous generalizations of the Bianchi type VI_h cosmology. The asymptotic behaviour of the solutions is investigated and further applications are briefly discussed.Comment: Minor extension of concluding section; 18 pages, to appear in Phys.Rev.

Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy:The BRAVO Trial

Objectives: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method. Background: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform. Methods: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro–B-type natriuretic peptide. Results: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro–B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms. Conclusions: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829

Overactivation of fear systems to neutral faces in schizophrenia

Background The amygdala plays a central role in detecting and responding to fear-related stimuli. A number of recent studies have reported decreased amygdala activation in schizophrenia to emotional stimuli (such as fearful faces) compared with matched neutral stimuli (such as neutral faces). We investigated whether the apparent decrease in amygdala activation in schizophrenia could actually derive from increased amygdala activation to the neutral comparator stimuli. Methods Nineteen patients with schizophrenia and 24 matched control participants viewed pictures of faces with either fearful or neutral facial expressions, and a baseline condition, during functional magnetic resonance imaging scanning. Results Patients with schizophrenia showed a relative decrease in amygdala activation to fearful faces compared with neutral faces. However, this difference resulted from an increase in amygdala activation to the neutral faces in patients with schizophrenia, not from a decreased response to the fearful faces. Conclusions Patients with schizophrenia show an increased response of the amygdala to neutral faces. This is sufficient to explain their apparent deficit in amygdala activation to fearful faces compared with neutral faces. The inappropriate activation of neural systems involved in fear to otherwise neutral stimuli may contribute to the development of psychotic symptoms in schizophrenia