Spironolactone and colitis: Increased mortality in rodents and in humans

Background: Crohn's disease causes intestinal inflammation leading to intestinal fibrosis. Spironolactone is an antifibrotic medication commonly used in heart failure to reduce mortality. We examined whether spironolactone is antifibrotic in the context of intestinal inflammation. Methods: In vitro, spironolactone repressed fibrogenesis in transforming growth factor beta (TGF‐β)‐stimulated human colonic myofibroblasts. However, spironolactone therapy significantly increased mortality in two rodent models of inflammation‐induced intestinal fibrosis, suggesting spironolactone could be harmful during intestinal inflammation. Since inflammatory bowel disease (IBD) patients rarely receive spironolactone therapy, we examined whether spironolactone use was associated with mortality in a common cause of inflammatory colitis, Clostridium difficile infection (CDI). Results: Spironolactone use during CDI infection was associated with increased mortality in a retrospective cohort of 4008 inpatients (15.9% vs. 9.1%, n = 390 deaths, P < 0.0001). In patients without liver disease, the adjusted odds ratio (OR) for inpatient mortality associated with 80 mg spironolactone was 1.99 (95% confidence interval [CI]: 1.51–2.63) In contrast to the main effect of spironolactone mortality, multivariate modeling revealed a protective interaction between liver disease and spironolactone dose. The adjusted OR for mortality after CDI was 1.96 (95% CI: 1.50–2.55) for patients without liver disease on spironolactone vs. 1.28 (95% CI: 0.82–2.00) for patients with liver disease on spironolactone when compared to a reference group without liver disease or spironolactone use. Conclusions: We propose that discontinuation of spironolactone in patients without liver disease during CDI could reduce hospital mortality by 2‐fold, potentially reducing mortality from CDI by 35,000 patients annually across Europe and the U.S. (Inflamm Bowel Dis 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92045/1/21929_ftp.pd

Rab11 and Actin Cytoskeleton Participate in Giardia lamblia Encystation, Guiding the Specific Vesicles to the Cyst Wall

The encystation process is crucial for survival and transmission of Giardia lamblia to new hosts. During this process, vesicular trafficking and the cytoskeleton play important roles. In eukaryotic cells, intracellular transport is regulated by proteins, including Rab-GTPases and SNAREs, which regulate vesicle formation along with recognition of and binding to the target membrane. Cytoskeletal structures are also involved in these processes. In this study, we demonstrate the participation of Rab11 in the transport of encystation-specific vesicles (ESVs). Additionally, we demonstrate that disruption of actin microfilaments affects ESVs transport. The modification of actin dynamics was also correlated with a reduction in rab11 and cwp1 expression. Furthermore, down-regulation of rab11 mRNA by a specific hammerhead ribozyme caused nonspecific localization of CWP1. We thus provide new information about the molecular machinery that regulates Giardia lamblia encystation. Given our findings, Rab11 and actin may be useful targets to block Giardia encystation

Enabling reliability assessments of pre-commercial perovskite photovoltaics with lessons learned from industrial standards

Photovoltaic modules are expected to operate in the field for more than 25 years, so reliability assessment is critical for the commercialization of new photovoltaic technologies. In early development stages, understanding and addressing the device degradation mechanisms are the priorities. However, any technology targeting large-scale deployment must eventually pass industry-standard qualification tests and undergo reliability testing to validate the module lifetime. In this Perspective, we review the methodologies to assess the reliability of established photovoltaics technologies and to develop standardized qualification tests. We present the stress factors and stress levels for degradation mechanisms currently identified in pre-commercial perovskite devices, along with engineering concepts for mitigation of those degradation modes. Recommendations for complete and transparent reporting of stability tests are given, to facilitate future inter-laboratory comparisons and to further the understanding of field-relevant degradation mechanisms, which will benefit the development of accelerated stress tests