Role of Cytolethal Distending Toxin in Altered Stool Form and Bowel Phenotypes in a Rat Model of Post-infectious Irritable Bowel Syndrome.

Background/aimsCampylobacter jejuni infection is a leading cause of acute gastroenteritis, which is a trigger for post-infectious irritable bowel syndrome (PI-IBS). Cytolethal distending toxin (CDT) is expressed by enteric pathogens that cause PI-IBS. We used a rat model of PI-IBS to investigate the role of CDT in long-term altered stool form and bowel phenotypes.MethodsAdult Sprague-Dawley rats were gavaged with wildtype C. jejuni (C+), a C. jejunicdtB knockout (CDT-) or saline vehicle (controls). Four months after gavage, stool from 3 consecutive days was assessed for stool form and percent wet weight. Rectal tissue was analyzed for intraepithelial lymphocytes, and small intestinal tissue was stained with anti-c-kit for deep muscular plexus interstitial cells of Cajal (DMP-ICC).ResultsAll 3 groups showed similar colonization and clearance parameters. Average 3-day stool dry weights were similar in all 3 groups, but day-to-day variability in stool form and stool dry weight were significantly different in the C+ group vs both controls (P < 0.01) and the CDT- roup (P < 0.01), but were not different in the CDT- vs controls. Similarly, rectal lymphocytes were significantly higher after C. jejuni (C+) infection vs both controls (P < 0.01) and CDT-exposed rats (P < 0.05). The counts in the latter 2 groups were not significantly different. Finally, c-kit staining revealed that DMP-ICC were reduced only in rats exposed to wildtype C. jejuni.ConclusionsIn this rat model of PI-IBS, CDT appears to play a role in the development of chronic altered bowel patterns, mild chronic rectal inflammation and reduction in DMP-ICC

Using the COPM with Veterans Who Have Sustained a Stroke

The authors collaborated with Mary Matthews-Brownell, OTR/L at the American Lake Veterans Affairs (VA). Our research question was, “What evidence is there to support best practices for veteran re-engagement in meaningful activities to promote overall quality of life for veterans who have sustained a stroke?” In response to Mary’s specific interest in the research supporting the use of the Canadian Occupational Performance Measure (COPM) and her desire to have concrete data to support her intervention outcomes, we chose to host an in-service on the use of the COPM for the occupational therapists at the VA. To monitor the impact of the in-service and use of the COPM in practice, we gave three surveys. The first survey was given before the in-service to measure the therapists’ knowledge of the COPM and its use with clients. The second survey was given immediately after the in-service to rate confidence in implementing the use of the COPM. The final survey was given five weeks post-implementation to gauge perception in the COPM’s usefulness in developing goals and measuring client performance and satisfaction. We recommend continued use of the COPM as a way to identify client interests and promote engagement in meaningful activities for veterans who have sustained a stroke

The Origin and Kinematics of Cold Gas in Galactic Winds: Insight from Numerical Simulations

We study the origin of Na I absorbing gas in ultraluminous infrared galaxies motivated by the recent observations by Martin of extremely superthermal linewidths in this cool gas. We model the effects of repeated supernova explosions driving supershells in the central regions of molecular disks with M_d=10^10 M_\sun, using cylindrically symmetric gas dynamical simulations run with ZEUS-3D. The shocked swept-up shells quickly cool and fragment by Rayleigh-Taylor instability as they accelerate out of the dense, stratified disks. The numerical resolution of the cooling and compression at the shock fronts determines the peak shell density, and so the speed of Rayleigh-Taylor fragmentation. We identify cooled shells and shell fragments as Na I absorbing gas and study its kinematics. We find that simulations with a numerical resolution of \le 0.2 pc produce multiple Rayleigh-Taylor fragmented shells in a given line of sight. We suggest that the observed wide Na I absorption lines, = 320 \pm 120 km s^-1 are produced by these multiple fragmented shells traveling at different velocities. We also suggest that some shell fragments can be accelerated above the observed average terminal velocity of 750 km s^-1 by the same energy-driven wind with an instantaneous starburst of \sim 10^9 M_\sun. The bulk of mass is traveling with the observed average shell velocity 330 \pm 100 km s^-1. Our results show that an energy-driven bubble causing Rayleigh-Taylor instabilities can explain the kinematics of cool gas seen in the Na I observations without invoking additional physics relying primarily on momentum conservation, such as entrainment of gas by Kelvin-Helmholtz instabilities, ram pressure driving of cold clouds by a hot wind, or radiation pressure acting on dust. (abridged)Comment: 65 pages, 22 figures, accepted by Astrophys. J. Changes during refereeing focused on context and comparison to observation

msbB deletion confers acute sensitivity to CO2 in Salmonella enterica serovar Typhimurium that can be suppressed by a loss-of-function mutation in zwf

<p>Abstract</p> <p>Background</p> <p>Pathogens tolerate stress conditions that include low pH, oxidative stress, high salt and high temperature in order to survive inside and outside their hosts. Lipopolysaccharide (LPS), which forms the outer-leaflet of the outer membrane in Gram-negative bacteria, acts as a permeability barrier. The lipid A moiety of LPS anchors it to the outer membrane bilayer. The MsbB enzyme myristoylates the lipid A precursor and loss of this enzyme, in <it>Salmonella</it>, is correlated with reduced virulence and severe growth defects that can both be compensated with extragenic suppressor mutations.</p> <p>Results</p> <p>We report here that <it>msbB </it>(or <it>msbB somA</it>) <it>Salmonella </it>are highly sensitive to physiological CO₂(5%), resulting in a 3-log reduction in plating efficiency. Under these conditions, <it>msbB Salmonella </it>form long filaments, bulge and lyse. These bacteria are also sensitive to acidic pH and high osmolarity. Although CO₂acidifies LB broth media, buffering LB to pH 7.5 did not restore growth of <it>msbB </it>mutants in CO₂, indicating that the CO₂-induced growth defects are not due to the effect of CO₂on the pH of the media. A transposon insertion in the glucose metabolism gene <it>zwf </it>compensates for the CO₂sensitivity of <it>msbB Salmonella</it>. The <it>msbB zwf </it>mutants grow on agar, or in broth, in the presence of 5% CO₂. In addition, <it>msbB zwf </it>strains show improved growth in low pH or high osmolarity media compared to the single <it>msbB </it>mutant.</p> <p>Conclusion</p> <p>These results demonstrate that <it>msbB </it>confers acute sensitivity to CO₂, acidic pH, and high osmolarity. Disruption of <it>zwf </it>in <it>msbB </it>mutants restores growth in 5% CO₂and results in improved growth in acidic media or in media with high osmolarity. These results add to a growing list of phenotypes caused by <it>msbB </it>and mutations that suppress specific growth defects.</p

Functional Folate Receptor Alpha Is Elevated in the Blood of Ovarian Cancer Patients

Background Despite low incidence, ovarian cancer is the fifth leading cause of cancer deaths and it has the highest mortality rate of all gynecologic malignancies among US women. The mortality rate would be reduced with an early detection marker. The folate receptor alpha (FRα) is one logical choice for a biomarker because of its prevalent overexpression in ovarian cancer and its exclusive expression in only a few normal tissues. In prior work, it was observed that patients with ovarian cancer had elevated serum levels of a protein that bound to a FRα-specific monoclonal antibody relative to healthy individuals. However, it was not shown that the protein detected was intact functional FRα. In the current study, the goal was to determine whether ovarian cancer patients (n = 30) had elevated serum levels of a fully functional intact FRα compared to matched healthy controls (n = 30). Methodology/Principal Findings FRα levels in serum were analyzed by two methods, immunoblotting analysis and a radiolabeled folic acid-based microfiltration binding assay. Using the immunoassay, we observed that levels of FRα were higher in serum of ovarian cancer patients as compared to controls. Similar results were also observed using the microfiltration binding assay, which showed that the circulating FRα is functional. Importantly, we also found that the levels of FRα were comparable between early and advanced stage patients. Conclusions Our results demonstrate that ovarian cancer patients have elevated levels of functional intact FRα. These findings support the potential use of circulating FRα as a biomarker of early ovarian cancer

Barriers to family history collection among Spanish-speaking primary care patients: a BRIDGE qualitative study

Objects: Family history is an important tool for assessing disease risk, and tailoring recommendations for screening and genetic services referral. This study explored barriers to family history collection with Spanish-speaking patients. Methods: This qualitative study was conducted in two US healthcare systems. We conducted semi-structured interviews with medical assistants, physicians, and interpreters with experience collecting family history for Spanish-speaking patients. Results: The most common patient-level barrier was the perception that some Spanish-speaking patients had limited knowledge of family history. Interpersonal communication barriers related to dialectical differences and decisions about using formal interpreters vs. Spanish-speaking staff. Organizational barriers included time pressures related to using interpreters, and ad hoc workflow adaptations for Spanish-speaking patients that might leave gaps in family history collection. Conclusions: This study identified multi-level barriers to family history collection with Spanish-speaking patients in primary care. Findings suggest that a key priority to enhance communication would be to standardize processes for working with interpreters. Innovation: To improve communication with and care provided to Spanish-speaking patients, there is a need to increase healthcare provider awareness about implicit bias, to address ad hoc workflow adjustments within practice settings, to evaluate the need for professional interpreter services, and to improve digital tools to facilitate family history collection

Medium-Term Complications Associated With Coronary Artery Aneurysms After Kawasaki Disease: A Study From the International Kawasaki Disease Registry.

Background Coronary artery aneurysms (CAAs) may occur after Kawasaki disease (KD) and lead to important morbidity and mortality. As CAA in patients with KD are rare and heterogeneous lesions, prognostication and risk stratification are difficult. We sought to derive the cumulative risk and associated factors for cardiovascular complications in patients with CAAs after KD. Methods and Results A 34-institution international registry of 1651 patients with KD who had CAAs (maximum CA

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology