Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Abstract Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship

Stigmatizing attitudes and low levels of knowledge but high willingness to participate in HIV management: A community-based survey of pharmacies in Pune, India

<p>Abstract</p> <p>Background</p> <p>The World Health Organization (WHO) recommends that the role of pharmacists in low-income settings be expanded to address the increasing complexity of HIV antiretroviral (ARV) and co-infection drug regimens. However, in many such settings including in India, many pharmacists and pharmacy workers are often neither well trained nor aware of the intricacies of HIV treatment. The aims of our study were; to determine the availability of ARVs, provision of ARVs, knowledge about ARVs, attitudes towards HIV-infected persons and self-perceived need for training among community-based pharmacies in an urban area of India.</p> <p>Methods</p> <p>We performed a survey of randomly selected, community-based pharmacies located in Pune, India, in 2004-2005 to determine the availability of ARVs at these pharmacies, how they were providing ARVs and their self-perceived need for training. We also assessed knowledge, attitudes and perceptions on HIV and ARVs and factors associated with stocking ARVs.</p> <p>Results</p> <p>Of 207 pharmacies included in the survey, 200 (96.6%) were single, private establishments. Seventy-three (35.3%) pharmacies stocked ARVs and 38 (18.4%) ordered ARVs upon request. The reported median number of ARV pills that patients bought at one time was 30, a two week supply of ARVs (range: 3-240 pills). Six (2.9%) pharmacy respondents reported selling non-allopathic medicines (i.e. Ayurvedic, homeopathy) for HIV. Ninety (44.2%) pharmacy respondents knew that ARVs cannot cure HIV, with those stocking ARVs being more likely to respond correctly (60.3% vs. 34.8%, p = 0.001). Respondents of pharmacies which stocked ARVs were also more likely to believe it was a professional obligation to provide medications to HIV-infected persons (91.8% vs. 78.8%, p = 0.007) but they were also more likely to believe that HIV-infected persons are unable to adhere to their medicines (79.5% vs. 40.9%, p < 0.01). Knowledge of the most common side effects of nevirapine, abnormal liver enzyme profile and skin rash, was reported correctly by 8 (3.9%) and 23 (11.1%) respondents, respectively. Seven (3.4%) respondents reported that they had received special training on HIV, 3 (1.5%) reported receipt of special training on ART and 167 (80.7%) reported that they believed that pharmacy staff should get special training on ART.</p> <p>Conclusion</p> <p>There is a high willingness to participate in HIV management among community-based pharmacies but there is a tremendous need for training on HIV therapies. Furthermore, stigmatizing attitudes towards HIV-infected persons persist and interventions to reduce stigma are needed, particularly among those that stock ARVs.</p

Crack kinking at the tip of a mode I crack in an orthotropic solid

The competition between crack penetration and crack kinking is addressed for a mode I macroscopic crack in an orthotropic elastic solid. Cohesive zones of finite peak strength and finite toughness are placed directly ahead of and orthogonal to the plane of the parent crack. The cohesive zone ahead of the crack tip is tensile in nature and leads to crack penetration, whereas the inclined zones slide without opening under a combined shear and normal traction, and give crack kinking. Thereby, the competition between continued crack growth by penetration ahead of the crack tip versus kinking is determined as a function of the relative strength and relative toughness of the cohesive zones. This competition is plotted in the form of a failure mechanism map, with the role of material orthotropy emphasized. Synergistic toughening is observed, whereby the parent crack tip is shielded by the activation of both the tensile and shear (kinking) cohesive zones, and the macroscopic toughness is elevated. The study is used to assess the degree to which various classes of composite have the tendency to undergo kinking

The cloud aerosol interaction and precipitation enhancement experiment (CAIPEEX): Overview and preliminary results

While the demand for enhancing rainfall through cloud seeding is strong and persistent in the country, considerable uncertainty exists on the success of such an endeavour at a given location. To understand the pathways of aerosol-cloud interaction through which this might be achieved, a national experiment named Cloud Aerosol Interaction and Precipitation Enhancement EXperiment (CAIPEEX) in two phases, was carried out. The rationale of CAIPEEX, the strategy for conducting the experiment, data quality and potential for path-breaking science are described in this article. Pending completion of quality control and calibration of the CAIPEEX phase-II data, here we present some initial results of CAIPEEX phase-I aimed at documenting the prevailing microphysical characteristics of aerosols and clouds and associated environmental conditions over different regions of the country and under different monsoon conditions with the help of an instrumented research aircraft. First-time simultaneous observations of aerosol, cloud condensation nuclei (CCN) and cloud droplet number concentration (CDNC) over the Ganges Valley during monsoon season show very high concentrations (&gt; 1000 cm-3) of CCN at elevated layers. Observations of elevated layers with high aerosol concentration over the Gangetic valley extending up to 6 km and relatively less aerosol concentration in the boundary layer are also documented. We also present evidence of strong cloud- aerosol interaction in the moist environments with an increase in the cloud droplet effective radius. Our observations also show that pollution increases CDNC and the warm rain depth, and delays its initiation. The critical effective radius for warm rain initiation is found to be between 10 and 12 μm in the polluted clouds and it is between 12 and 14 μm in cleaner monsoon clouds

Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs

Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD

Transcriptional Profiling of Chondrodysplasia Growth Plate Cartilage Reveals Adaptive ER-Stress Networks That Allow Survival but Disrupt Hypertrophy

Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology