Pneumocystis jirovecii genotype associated with increased death rate of HIV-infected patients with pneumonia.

Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days.

Assessing the epidemiology and pattern of care of colorectal cancer in Valais, Switzerland

Background: The Valais's cancer registry (RVsT) of the Observatoire valaisan de le santé (OVS) and the department of oncology of Valais's Hospital conducted a study on the epidemiology and pattern of care of colorectal cancer in Valais. Colorectal cancer is the third cause of death by cancer in Switzerland with about 1600 deaths per year. It is the third most frequent cancer for males and the second most frequent for females in Valais. The number of new colorectal cancer cases (average per year) increased between 1989 and 2009 for males as well as for females in Valais. The number of colorectal cancer death cases (average per year) slightly increased between 1989 and 2009 for males as well as for females in Valais. Age-standardized rates of incidence were stable for males and females in Valais and in Switzerland between 1989 and 2009, while age-standardized rates of mortality decreased for males and females in Valais and Switzerland. Results: 774 cases were recorded (59% males). Median age at diagnosis was 70 years old. Most of cancers were invasive (79%) and the main localization was the colon (71%). The most frequent mode of detection was a consultation for non emergency symptoms (75%), but almost 10% of patients consulted in emergency. 82% of patients were treated within 30 days from diagnosis. 90% of the patients were treated by surgery alone or with combined treatment. The first treatment was surgery, including endoscopic resection in 86% of the cases. The treatment was different according to the localization and the stage of the cancer. Survival rate was 95% at 30 days and 79% at one year. The survival was dependent on the stage and the age at diagnosis. Cox model shows an association between mortality and age (better survival for young people) and between mortality and stage (better survival for the lower stages). Methods: RVsT collects information on all cancer cases since 1989 for people registered in the communes of Valais. RVsT has an authorization to collect non anonymized data. All new incident cancers are coded according to the International Classification of Diseases for Oncology (ICD-O-3) and the stages are coded according to the TNM classification. We studied all cases of in situ and invasive colorectal cancers diagnosed between 2006 and 2009 and registered routinely at the RVsT. We checked for data completeness and if necessary sent questionnaires to avoid missing data. A distance of 15 cm has been chosen to delimitate the colon (sigmoid) and the rectal cancers. We made an active follow-up for vital status to have a valid survival analysis. We analyzed the characteristics of the tumors according to age, sex, localization and stage with stata 9 software. Kaplan-Meier curves were generated and Cox model were fitted to analyze survival. Conclusion: The characteristics of patients and tumors and the one year survival were similar to those observed in Switzerland and some European countries. Patterns of care were close to those recommended in guidelines. Routine data recorded in a cancer registry can be used, not only to provide general statistics, but also to help clinicians assess local practices.

Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death.

BACKGROUND: A major goal of antiretroviral therapy (ART) for HIV-1-infected persons is the recovery of CD4 T lymphocytes, resulting in thorough protection against opportunistic complications. Interruptions of ART are still frequent. The long-term effect on CD4 T-cell recovery and clinical events remains unknown. METHODS: Immunological and clinical endpoints were evaluated in 2491 participants of the Swiss HIV Cohort Study initiating ART during a mean follow-up of 7.1 years. Data were analysed in persons with treatment interruptions (n = 1271; group A), continuous ART, but intermittent HIV-1 RNA at least 1000 copies/ml (n = 469; group B) and continuous ART and HIV-1 RNA constantly less than 1000 copies/ml (n = 751; group C). Risk factors for low CD4 T-cell counts and clinical events were analysed using Cox proportional hazards models. RESULTS: In groups A-C, CD4 T lymphocytes increased to a median of 427, 525 and 645 cells/μl at 8 years. In group A, 63.0 and 37.2% reached above 350 and 500 CD4 T cells/μl, whereas in group B 76.3 and 55.8% and in group C 87.3 and 68.0% reached these thresholds (P < 0.001). CD4 T-cell recovery directly depended on the cumulative duration of treatment interruptions. In addition, participants of group A had more Centers for Disease Control and Prevention B/C events, resulting in an increased risk of death. Major risk factors for not reaching CD4 T cells above 500 cells/μl included lower baseline CD4 T-cell count, higher age and hepatitis C virus co-infection. CONCLUSION: In persons receiving continuous ART larger CD4 T-cell recovery and a reduced risk for opportunistic complications and death was observed. CD4 T-cell recovery was smaller in persons with treatment interruptions more than 6 months.

Cardiovascular Pathology. 004. Pathomorphological and CT-angiographical characteristics of coronary atherosclerotic plaques in cases of sudden cardiac death

Objective. The goal of this study was to present the pathological and radiological patterns of "vulnerable" atherosclerotic plaques in cases of sudden cardiac death. Method. This retrospective study was performed on forensic cases for which the cause of death was attributed to coronary artery disease. A complete autopsy was performed in all cases, along with either post-mortem CT-angiography, toxicological analyses and/or biochemistry. Results. 89 cases were selected (mean age 55±11.6 years; 75 men and 14 women). In 96.6% of cases a CT-angiography was performed. Acute coronary lesions were found in 60 cases (mean age 53±11.1 years), which included plaque erosion in 26 cases (mean age 47±8.3 years) and ruptures or intraplaque hemorrhage in 33 cases (mean age 58±10.4 years). Erosions were most frequently found in the left ascending artery (61.5 %), while only 36% of ruptures were observed in this artery. Chronic coronary pathology was described in 30 cases (mean age 58±10.4 years). CT-angiographies performed prior to the autopsy enabled an initial evaluation of coronary artery perfusion. Conclusion. In the face of decreasing clinical autopsy rates, postmortem studies on forensic autopsies, including modern radiological examinations, allow for a more thorough understanding of the clinical picture of disease which can result in sudden cardiac death.

Estimation du degré de couverture d'un registre pour les cancers notifiés au décès [Evaluation of the comprehensiveness of a cancer register from death certificates].

The comparison of cancer prevalence with cancer mortality can lead under some hypotheses to an estimate of registration rate. A method is proposed, where the cases with cancer as a cause of death are divided into 3 categories: (1) cases already known by the registry (2) unknown cases having occured before the registry creation date (3) unknown cases occuring during the registry operates. The estimate is then the number of cases in the first category divided by the total of those in categories 1 and 3 (these only are to be registered). An application is performed on the data of the Canton de Vaud. Survival rates of the Norvegian Cancer Registry are used for computing the number of unknown cases to be included in second and third category, respectively. The discussion focusses on the possible determinants of the obtained comprehensiveness rates for various cancer sites.

Caveolin expression changes in the neurovascular unit after juvenile traumatic brain injury: signs of blood-brain barrier healing?

Traumatic brain injury (TBI) is one of the major causes of death and disability in pediatrics, and results in a complex cascade of events including the disruption of the blood-brain barrier (BBB). A controlled-cortical impact on post-natal 17 day-old rats induced BBB disruption by IgG extravasation from 1 to 3 days after injury and returned to normal at day 7. In parallel, we characterized the expression of three caveolin isoforms, cav-1, cav-2 and cav-3. While cav-1 and cav-2 are expressed on endothelial cells, both cav-1 and cav-3 were found to be present on reactive astrocytes, in vivo and in vitro. Following TBI, cav-1 expression was increased in blood vessels at 1 and 7 days in the perilesional cortex. An increase of vascular cav-2 expression was observed 7 days after TBI. In contrast, astrocytic cav-3 expression decreased 3 and 7 days after TBI. Activation of eNOS (via its phosphorylation) was detected 1 day after TBI and phospho-eNOS was detected both in association with blood vessels and with astrocytes. The molecular changes involving caveolins occurring in endothelial cells following juvenile-TBI might participate, independently of eNOS activation, to a mechanism of BBB repair while, they might subserve other undefined roles in astrocytes.

A Swiss neighbourhood index of socioeconomic position: Development and Association with Mortality

Background Area-based measures of socioeconomic position (SEP) suitable for epidemiological research are lacking in Switzerland. The authors developed the Swiss neighbourhood index of SEP (Swiss-SEP). Methods Neighbourhoods of 50 households with overlapping boundaries were defined using Census 2000 and road network data. Median rent per square metre, proportion households headed by a person with primary education or less, proportion headed by a person in manual or unskilled occupation and the mean number of persons per room were analysed in principle component analysis. The authors compared the index with independent income data and examined associations with mortality from 2001 to 2008. Results 1.27 million overlapping neighbourhoods were defined. Education, occupation and housing variables had loadings of 0.578, 0.570 and 0.362, respectively, and median rent had a loading of −0.459. Mean yearly equivalised income of households increased from SFr42 000 to SFr72 000 between deciles of neighbourhoods with lowest and highest SEP. Comparing deciles of neighbourhoods with lowest to highest SEP, the age- and sex-adjusted HR was 1.38 (95% CI 1.36 to 1.41) for all-cause mortality, 1.83 (95% CI 1.71 to 1.95) for lung cancer, 1.48 (95% CI 1.44 to 1.51) for cardiovascular diseases, 2.42 (95% CI 1.94 to 3.01) for traffic accidents, 0.93 (95% CI 0.85 to 1.02) for breast cancer and 0.86 (95% CI 0.78 to 0.95) for suicide. Conclusions Developed using a novel approach to define neighbourhoods, the Swiss-SEP index was strongly associated with household income and some causes of death. It will be useful for clinical- and population-based studies, where individual-level socioeconomic data are often missing, and to investigate the effects on health of the socioeconomic characteristics of a place.

The glasses of the transept's rosette of the Cathedral of Tarragona: characterization, classification and decay.

The glasses of the rosette forming the main window of the transept of the Gothic Cathedral of Tarragona have been characterised by means of SEM/EDS, XRD, FTIR and electronic microprobe. The multivariate statistical treatment of these data allow to establish a classification of the samples forming groups having an historical significance and reflecting ancient restorations. Furthermore, the decay patterns and mechanisms have been determined and the weathering by-products characterised. It has been demonstrated a clear influence of the bioactivity in the decay of these glasses, which activity is partially controlled by the chemical composition of the glasses.

The glasses of the transept's rosette of the Cathedral of Tarragona: characterization, classification and decay.

The glasses of the rosette forming the main window of the transept of the Gothic Cathedral of Tarragona have been characterised by means of SEM/EDS, XRD, FTIR and electronic microprobe. The multivariate statistical treatment of these data allow to establish a classification of the samples forming groups having an historical significance and reflecting ancient restorations. Furthermore, the decay patterns and mechanisms have been determined and the weathering by-products characterised. It has been demonstrated a clear influence of the bioactivity in the decay of these glasses, which activity is partially controlled by the chemical composition of the glasses.

A first population-based cohort study of risk factors of stroke mortality in Africa

Background: We are not aware of any population-based cohort study of risk factors of stroke in the African region. We conducted a longitudinal study in the Seychelles (Indian Ocean, east of Kenya), a middle-income island state with majority of the population of African descent. Data in Africa are important for international comparison and for advocacy in the region. Methods: Three population-based examination surveys were performed in 1989, 1994 and 2004 (n_1081, 1067, and 1255, respectively). Baseline data were linked with cause-specific mortality from vital statistics up to May 2007. We considered stroke (any type) as a cause of death if the diagnosis was reported in any of the 4 fields for underlying and concomitant causes of death. Results. Among the 3317 different persons aged 25-64 at baseline, 291 died including 58 with stroke during follow up (mean: 10.2 years). The prevalence of high blood pressure (BP _140/90 mmHg) was 38%. In multivariate Cox regression, stroke mortality was increased by 18% and 35% for a 10-mmHg increase in systolic, respectively diastolic BP (p_0.001). The hazard ratios were 2.4 (95% CI: 1.7-3.3) for a 10-year age increase, 0.32 (0.15- 0.67) for a 1-mmol HDL-cholesterol increase, 2.2 (1.1- 4.2) for smoking _5 cigarettes vs. no smoking and 1.7 for diabetes (0.93-3.3; p_0.08). No significant association was found for sex, LDL-cholesterol, alcohol intake, and occupation. Conclusion. This first populationbased cohort study in the African region demonstrates high mortality rates from stroke in middle-aged adults and confirms the important role of high BP. This emphasizes the critical importance of reducing BP and other modifiable risk factors in this population.

Surgical interventions with fatal outcome: Utility of multi-phase postmortem CT angiography

Cases of fatal outcome after surgical intervention are autopsied to determine the cause of death and to investigate whether medical error caused or contributed to the death. For medico-legal purposes, it is imperative that autopsy findings are documented clearly. Modern imaging techniques such as multi-detector computed tomography (MDCT) and postmortem CT angiography, which is used for vascular system imaging, are useful tools for determining cause of death. The aim of this study was to determine the utility of postmortem CT angiography for the medico-legal death investigation. This study investigated 10 medico-legal cases with a fatal outcome after surgical intervention using multi-phase postmortem whole body CT angiography. A native CT scan was performed as well as three angiographic phases (arterial, venous, and dynamic) using a Virtangio((R)) perfusion device and the oily contrast agent, Angiofil((R)). The results of conventional autopsy were compared to those from the radiological investigations. We also investigated whether the radiological findings affected the final interpretation of cause-of-death. Causes of death were hemorrhagic shock, intracerebral hemorrhage, septic shock, and a combination of hemorrhage and blood aspiration. The diagnoses were made by conventional autopsy as well as by postmortem CT angiography. Hemorrhage played an important role in eight of ten cases. The radiological exam revealed the exact source of bleeding in seven of the eight cases, whereas conventional autopsy localized the source of bleeding only generally in five of the seven cases. In one case, neither conventional autopsy nor CT angiography identified the source of hemorrhage. We conclude that postmortem CT angiography is extremely useful for investigating deaths following surgical interventions. This technique helps document autopsy findings and allows a second examination if it is needed; specifically, it detects and visualizes the sources of hemorrhages in detail, which is often of particular interest in such cases.

Classification and fingerprinting of different berries based on biochemical profiling and antioxidant capacity

The objective of this work was to evaluate the biochemical composition of six berry types belonging to Fragaria, Rubus, Vaccinium and Ribes genus. Fruit samples were collected in triplicate (50 fruit each) from 18 different species or cultivars of the mentioned genera, during three years (2008 to 2010). Content of individual sugars, organic acids, flavonols, and phenolic acids were determined by high performance liquid chromatography (HPLC) analysis, while total phenolics (TPC) and total antioxidant capacity (TAC), by using spectrophotometry. Principal component analysis (PCA) and hierarchical cluster analysis (CA) were performed to evaluate the differences in fruit biochemical profile. The highest contents of bioactive components were found in Ribes nigrum and in Fragaria vesca, Rubus plicatus, and Vaccinium myrtillus. PCA and CA were able to partially discriminate between berries on the basis of their biochemical composition. Individual and total sugars, myricetin, ellagic acid, TPC and TAC showed the highest impact on biochemical composition of the berry fruits. CA separated blackberry, raspberry, and blueberry as isolate groups, while classification of strawberry, black and red currant in a specific group has not occurred. There is a large variability both between and within the different types of berries. Metabolite fingerprinting of the evaluated berries showed unique biochemical profiles and specific combination of bioactive compound contents.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Vorapaxar in the secondary prevention of atherothrombotic events.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.