Profile of mortality of patients admitted to Weskoppies Psychiatric Hospital in South Africa over a 5-year period (2001-2005)

Objective: Mortality in the psychiatric population, both from natural and unnatural causes, is higher than in the general population and this is despite an improvement in the delivery of care and treatment of mental illness in recent years. The study was conducted to determine a profile of mortality and standardized mortality rates within our psychiatric hospital. Method: A retrospective clinical case audit was conducted of deaths that occurred at Weskoppies Hospital between 1st January 2001 and 31st December 2005. Direct standardised mortality rates were calculated (gender specific adjusted for age according to the South African population). Results: A total of 164 deaths were observed during this period. The gender-specific all cause mortality rates, standardised to the South African population, were 0.0177 (95% CI 0.0141, 0.0213) and 0.0163 (95% CI 0.0121, 0.0206) for males and females respectively. The all cause mortality rates for the South African male and female population were 0.0188 and 0.0170 respectively (not significantly different as it falls within the 95% confidence interval of the standardised rates). The predominant natural cause of mortality was infection. Ten of the deaths were due to unnatural causes, of these 7 were suicides. The mortality ratio for unnatural causes was 0.47. Conclusion: Mortality studies are important tools for determining quality of health care provisions to patients. Studies of this nature assist in making recommendations for optimal clinical practice and aid in developing preventative measures.Key words: Psychiatric; In-patient; Mortality; Mortality rati

Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53

Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O6-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg−1 protein, and there was a correlation between MGMT activity and the level of resistance to TMZ and fotemustine. MGMT inactivation by O6-benzylguanine sensitized all melanoma cell lines expressing MGMT to TMZ and fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O6-alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to TMZ without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and TMZ sensitivity was not found. Apoptosis in melanoma cells induced by TMZ and fotemustine was accompanied by double-strand break (DSB) formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For TMZ, DSBs correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to TMZ and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with TMZ. Overall, the findings are in line with the model that in melanoma cells TMZ-induced O6-methylguanine triggers the apoptotic (and necrotic) pathway through DSBs, whereas for chloroethylating agents apoptosis is triggered in a more complex manner

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ-  cognitively normal (CN) individuals and Aβ+  (CN and CI) individuals separately. RESULTS: In Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ-  individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal

Kefir consumption does not alter plasma lipid levels or cholesterol fractional synthesis rates relative to milk in hyperlipidemic men: a randomized controlled trial [ISRCTN10820810]

BACKGROUND: Fermented milk products have been shown to affect serum cholesterol concentrations in humans. Kefir, a fermented milk product, has been traditionally consumed for its potential health benefits but has to date not been studied for its hypocholesterolemic properties. METHODS: Thirteen healthy mildly hypercholesterolemic male subjects consumed a dairy supplement in randomized crossover trial for 2 periods of 4 wk each. Subjects were blinded to the dairy supplement consumed. Blood samples were collected at baseline and after 4 wk of supplementation for measurement of plasma total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglyceride concentrations, as well as fatty acid profile and cholesterol synthesis rate. Fecal samples were collected at baseline and after 2 and 4 wk of supplementation for determination of fecal short chain fatty acid level and bacterial content. RESULTS: Kefir had no effect on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglyceride concentrations nor on cholesterol fractional synthesis rates after 4 wk of supplementation. No significant change on plasma fatty acid levels was observed with diet. However, both kefir and milk increased (p < 0.05) fecal isobutyric, isovaleric and propionic acids as well as the total amount of fecal short chain fatty acids. Kefir supplementation resulted in increased fecal bacterial content in the majority of the subjects. CONCLUSIONS: Since kefir consumption did not result in lowered plasma lipid concentrations, the results of this study do not support consumption of kefir as a cholesterol-lowering agent

Genetically identical twin-pair difference models support the amyloid cascade hypothesis

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual-level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau-PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume), and cognitive data (composite memory). Associations between each modality were tested at the individual-level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual-level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual-level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β=0.68, p < 0.001), and moderately associated with within-pair differences in hippocampal volume (β=-0.37, p = 0.03) and memory functioning (β=-0.57, p < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β=-0.53, p < 0.001) and strongly associated with within-pair differences in memory functioning (β=-0.68, p < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated: 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs

MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome

BACKGROUND: Despite limited clinical efficacy, treatment with dacarbazine or temozolomide (TMZ) remains the standard therapy for metastatic melanoma. In glioblastoma, promoter methylation of the counteracting DNA repair enzyme O(6)-methylguanine-DNA-methyltransferase (MGMT) correlates with survival of patients exposed to TMZ in combination with radiotherapy. For melanoma, data are limited and controversial. METHODS: Biopsy samples from 122 patients with metastatic melanoma being treated with TMZ in two multicenter studies of the Dermatologic Cooperative Oncology Group were investigated for MGMT promoter methylation. We used the COBRA (combined bisulphite restriction analysis) technique to determine aberrant methylation of CpG islands in small amounts of genomic DNA isolated from paraffin-embedded tissue sections. To detect aberrant methylation, bisulphite-treated DNA was amplified by PCR, enzyme restricted, and visualised by gel electrophoresis. RESULTS: Correlation with clinical data from 117 evaluable patients in a best-response evaluation indicated no statistically significant association between MGMT promoter methylation status and response. A methylated MGMT promoter was observed in 34.8% of responders and 23.4% of non-responders (P=0.29). In addition, no survival advantage for patients with a methylated MGMT promoter was detectable (P=0.79). Interestingly, we found a significant correlation between MGMT methylation and tolerance of therapy. Patients with a methylated MGMT promoter had more severe adverse events, requiring more TMZ dose reductions or discontinuations (P=0.007; OR 2.7 (95% CI: 1.32-5.7)). Analysis of MGMT promoter methylation comparing primaries and different metastases over the clinical course revealed no statistical difference (P=0.49). CONCLUSIONS: In advanced melanoma MGMT promoter, methylation correlates with tolerance of therapy, but not with clinical outcome

Right ventricular peak systolic longitudinal strain is a sensitive marker for right ventricular deterioration in adult patients with tetralogy of Fallot

The aim of this study was to evaluate the feasibility of right ventricular (RV) longitudinal peak systolic strain (LPSS) assessment for the follow-up of adult patients with corrected tetralogy of Fallot (TOF). Adult patients (n = 18) with corrected TOF underwent echocardiography and CMR twice with a time interval of 4.2 ± 1.7 years. RV performance was derived from CMR, and included RV volumes and ejection fraction (EF). LPSS was calculated globally (GLPSS) and in the RV free wall (LPSS FW), with echocardiographic speckle-tracking strain-analysis. Baseline (G)LPSS values were compared between patients and healthy controls; the relation between (G)LPSS and CMR parameters was evaluated and the changes in (G)LPSS and CMR parameters during follow-up were compared. GLPSS and LPSS FW were significantly reduced in patients as compared to controls (−14.9 ± 0.7% vs. −21.6 ± 0.9% and −15.5 ± 0.9% vs. −22.7 ± 1.5%, P < 0.01). Moderate agreement between LPSS and CMR parameters was observed. RV EF remained unchanged during follow-up, whereas GLPSS and LPSS FW demonstrated a significant reduction. RVEF showed a 1% increase, whereas GLPSS decreased by 14%, and LPSS FW by 27%. RV LPSS is reduced in TOF patients as compared to controls; during follow-up RV EF remained unchanged whereas LPSS decreased suggesting that RV LPSS may be a sensitive marker to detect early deterioration in RV performance

Mitochondrial Genome Sequences Effectively Reveal the Phylogeny of Hylobates Gibbons

BACKGROUND: Uniquely among hominoids, gibbons exist as multiple geographically contiguous taxa exhibiting distinctive behavioral, morphological, and karyotypic characteristics. However, our understanding of the evolutionary relationships of the various gibbons, especially among Hylobates species, is still limited because previous studies used limited taxon sampling or short mitochondrial DNA (mtDNA) sequences. Here we use mtDNA genome sequences to reconstruct gibbon phylogenetic relationships and reveal the pattern and timing of divergence events in gibbon evolutionary history. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the mitochondrial genomes of 51 individuals representing 11 species belonging to three genera (Hylobates, Nomascus and Symphalangus) using the high-throughput 454 sequencing system with the parallel tagged sequencing approach. Three phylogenetic analyses (maximum likelihood, Bayesian analysis and neighbor-joining) depicted the gibbon phylogenetic relationships congruently and with strong support values. Most notably, we recover a well-supported phylogeny of the Hylobates gibbons. The estimation of divergence times using Bayesian analysis with relaxed clock model suggests a much more rapid speciation process in Hylobates than in Nomascus. CONCLUSIONS/SIGNIFICANCE: Use of more than 15 kb sequences of the mitochondrial genome provided more informative and robust data than previous studies of short mitochondrial segments (e.g., control region or cytochrome b) as shown by the reliable reconstruction of divergence patterns among Hylobates gibbons. Moreover, molecular dating of the mitogenomic divergence times implied that biogeographic change during the last five million years may be a factor promoting the speciation of Sundaland animals, including Hylobates species

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente