Predictability of an Atmospheric Blocking Event that Occurred on 15 December 2005

Atmospheric blocking occurred over the Rocky Mountains at 1200 UTC 15 December 2005. The operational medium-range ensemble forecasts of the Canadian Meteorological Center (CMC), the Japan Meteorological Agency (JMA), and the National Centers for Environmental Prediction (NCEP), as initialized at 1200 UTC 10 December 2005, showed remarkable differences regarding this event. All of the NCEP members failed to predict the correct location of the blocking, whereas almost all of the JMA members and most of the CMC members were successful in predicting the correct location. The present study investigated the factors that caused NCEP to incorrectly predict the blocking location, based on an ensemble-based sensitivity analysis and the JMA global spectral model (GSM) multianalysis ensemble forecasts with NCEP, regionally amplified NCEP, and globally amplified NCEP analyses.A sensitive area for the blocking formation was detected over the central North Pacific. In this area, the NCEP control analysis experienced problems in the handling of a cutoff cyclone, and the NCEP initial perturbations were ineffective in reducing uncertainties in the NCEP control analysis. The JMA GSM multianalysis ensemble forecasts revealed that regional amplification of initial perturbations over the sensitive area could lead to further improvements in forecasts over the blocking region without degradation of forecasts over the Northern Hemisphere (NH), whereas the global amplification of initial perturbations could lead to improved forecasts over the blocking region and degraded forecasts over the NH. This finding may suggest that excessive amplification of initial perturbations over nonsensitive areas is undesirable, and that case-dependent rescaling of initial perturbations may be of value compared with climatology-based rescaling, which is widely used in current operational ensemble prediction systems

Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality

OBJECTIVES: To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies. DESIGN: Cross-sectional study of screened patients. SETTING: 10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011. PARTICIPANTS: The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications.PRIMARY OUTCOME MEASURES: Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality.RESULTS: Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE.CONCLUSIONS: A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based

The promoter and the enhancer region of the KLK 3 (prostate specific antigen) gene is frequently mutated in breast tumours and in breast carcinoma cell lines

KLK3 or prostate specific antigen (PSA) is a serine protease, which is an established tumour marker of prostatic adenocarcinoma. PSA is now used widely for the diagnosis and monitoring of patients with prostate cancer. Recent studies have demonstrated that about 70% of breast cancers produce PSA. In this study, we examined the molecular mechanism underlying the expression of the PSA gene in breast cancer and breast cancer cell lines. We analysed nine breast tumours categorized on the basis of high- or low-PSA expression in tumour cytosols and four breast cancer cell lines. To determine abnormalities associated with PSA expression in breast tumours, genomic DNA was extracted and all five exons of the PSA gene were polymerase chain reaction (PCR) amplified and sequenced on both strands. PCR amplification was also performed for the promoter and enhancer elements of the PSA gene. No mutations were observed in the coding portion of the gene. A polymorphism was observed in exon 2 from three breast tumours. However, sequencing of the promoter and the enhancer elements of the PSA gene reveals several point mutations. Within a 5.8-kb promoter/enhancer region of the PSA gene, we detected 16 different mutational hotspots (appearing more than once in the nine tumours). Among these hotspots, two appeared in seven out of nine tumours. Most importantly, the androgen response element (ARE I) in the proximal promoter was found mutated in four tumours and in the breast carcinoma cell line MCF-7. Mutations associated with the ARE I have been shown previously to result in an 80% decrease in PSA gene expression. The mutations in the core enhancer and promoter region probably contribute to the aberrant expression of the PSA gene in breast tumours, possibly by altering the regulation of the gene by steroid hormones. © 1999 Cancer Research Campaig

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED(50 )values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED(50 )of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma

What Are Effective Program Characteristics of Self-Management Interventions in Patients With Heart Failure? An Individual Patient Data Meta-analysis

To identify those characteristics of self-management interventions in patients with heart failure (HF) that are effective in influencing health-related quality of life, mortality, and hospitalizations

Anti-Fas mAb-induced apoptosis and cytolysis of airway tissue eosinophils aggravates rather than resolves established inflammation

BACKGROUND: Fas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation. This view is based on observations in vitro and in airway lumen with unknown translatability to airway tissues in vivo. In fact, apoptotic eosinophils have not been detected in human diseased airway tissues whereas cytolytic eosinophils abound and constitute a major mode of degranulation of these cells. Also, Fas receptor stimulation may bypass the apoptotic pathway and directly evoke cytolysis of non-apoptotic cells. We thus hypothesized that effects of anti-Fas mAb in vivo may include both apoptosis and cytolysis of eosinophils and, hence, that established eosinophilic inflammation may not resolve by this treatment. METHODS: Weeklong daily allergen challenges of sensitized mice were followed by airway administration of anti-Fas mAb. BAL was performed and airway-pulmonary tissues were examined using light and electron microscopy. Lung tissue analysis for CC-chemokines, apoptosis, mucus production and plasma exudation (fibrinogen) were performed. RESULTS: Anti-Fas mAb evoked apoptosis of 28% and cytolysis of 4% of eosinophils present in allergen-challenged airway tissues. Furthermore, a majority of the apoptotic eosinophils remained unengulfed and eventually exhibited secondary necrosis. A striking histopathology far beyond the allergic inflammation developed and included degranulated eosinophils, neutrophilia, epithelial derangement, plasma exudation, mucus-plasma plugs, and inducement of 6 CC-chemokines. In animals without eosinophilia anti-Fas evoked no inflammatory response. CONCLUSION: An efficient inducer of eosinophil apoptosis in airway tissues in vivo, anti-Fas mAb evoked unprecedented asthma-like inflammation in mouse allergic airways. This outcome may partly reflect the ability of anti-Fas to evoke direct cytolysis of non-apoptotic eosinophils in airway tissues. Additionally, since most apoptotic tissue eosinophils progressed into the pro-inflammatory cellular fate of secondary necrosis this may also explain the aggravated inflammation. Our data indicate that Fas receptor mediated eosinophil apoptosis in airway tissues in vivo may cause severe disease exacerbation due to direct cytolysis and secondary necrosis of eosinophils