Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells

In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl− and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl− secretion was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers. At high concentrations (0.5–1 mM), DCA acutely stimulated Cl− secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10–200 μM) inhibited responses to Ca2+ and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids – taurodeoxycholic acid, chenodeoxycholic acid and cholic acid – had similar antisecretory effects. DCA (50 μM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity

Peer assessment of outpatient consultation letters – feasibility and satisfaction

<p>Abstract</p> <p>Background</p> <p>Written correspondence is one of the most important forms of communication between health care providers, yet there is little feedback provided to specialists. The objective of this study was to determine the feasibility and satisfaction of a peer assessment program on consultation letters and to determine inter-rater reliability between family physicians and specialists.</p> <p>Methods</p> <p>A rating scale of nine 5-point Likert scale items including specific content, style items, education value of the letter and an overall rating was developed from a previous validated tool.</p> <p>Nine Internal Medicine specialists/subspecialists from two tertiary care centres submitted 10 letters with patient and physician identifiers removed. Two Internal Medicine specialists, and 2 family physicians from the other centre rated each letter (to protect writer anonymity). A satisfaction survey was sent to each writer and rater after collation of the results. A follow-up survey was sent 6–8 months later.</p> <p>Results</p> <p>There was a high degree of satisfaction with the process and feedback. The rating scale information was felt to be useful and appropriate for evaluating the quality of consultation letters by 6/7 writers. 5/7 seven writers felt that the feedback they received resulted in immediate changes to their letters. Six months later, 6/9 writers indicated they had maintained changes in their letters.</p> <p>Raters rank ordered letters similarly (Cronbach's alpha 0.57–0.84) but mean scores were highly variant. At site 1 there were significant differences in scoring brevity (p < 0.01) between family physician and specialist raters; whereas, at site 2 there were differences in scoring of history (p < 0.01), physical examination (p < 0.01) and educational value (p < 0.01) of the letter.</p> <p>Conclusion</p> <p>Most participants found peer assessment of letters feasible and beneficial and longstanding changes occurred in some individuals. Family physicians and specialists appear to have different expectations on some items. Further studies on reliability and validity, with a larger sample, are required before high stakes professional assessments include consultation letters.</p

Evaluating diverse electronic consultation programs with a common framework.

BackgroundElectronic consultation is an emerging mode of specialty care delivery that allows primary care providers and their patients to obtain specialist expertise without an in-person visit. While studies of individual programs have demonstrated benefits related to timely access to specialty care, electronic consultation programs have not achieved widespread use in the United States. The lack of common evaluation metrics across health systems and concerns related to the generalizability of existing evaluation efforts may be hampering further growth. We sought to identify gaps in knowledge related to the implementation of electronic consultation programs and develop a set of shared evaluation measures to promote further diffusion.MethodsUsing a case study approach, we apply the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) and the Quadruple Aim frameworks of evaluation to examine electronic consultation implementation across diverse delivery systems. Data are from 4 early adopter healthcare delivery systems (San Francisco Health Network, Mayo Clinic, Veterans Administration, Champlain Local Health Integration Network) that represent varied organizational structures, care for different patient populations, and have well-established multi-specialty electronic consultation programs. Data sources include published and unpublished quantitative data from each electronic consultation database and qualitative data from systems' end-users.ResultsOrganizational drivers of electronic consultation implementation were similar across the systems (challenges with timely and/or efficient access to specialty care), though unique system-level facilitators and barriers influenced reach, adoption and design. Effectiveness of implementation was consistent, with improved patient access to timely, perceived high-quality specialty expertise with few negative consequences, garnering high satisfaction among end-users. Data about patient-specific clinical outcomes are lacking, as are policies that provide guidance on the legal implications of electronic consultation and ideal remuneration strategies.ConclusionA core set of effectiveness and implementation metrics rooted in the Quadruple Aim may promote data-driven improvements and further diffusion of successful electronic consultation programs

Chronic regulation of colonic epithelial secretory function by activation of G protein-coupled receptors.

BACKGROUND: Enteric neurotransmitters that act at G protein-coupled receptors (GPCRs) are well known to acutely promote epithelial Cl(-) and fluid secretion. Here we examined if acute GPCR activation might have more long-term consequences for epithelial secretory function. METHODS: Cl(-) secretion was measured as changes in short-circuit current across voltage-clamped T(84) colonic epithelial cells. Protein expression was measured by western blotting and intracellular Ca(2+) levels by Fura-2 fluorescence. KEY RESULTS: While acute (15 min) treatment of T(84) cells with a cholinergic G(q) PCR agonist, carbachol (CCh), rapidly stimulated Cl(-) secretion, subsequent CCh-induced responses were attenuated in a biphasic manner. The first phase was transient and resolved within 6 h but this was followed by a chronic phase of attenuated responsiveness that was sustained up to 48 h. CCh-pretreatment did not chronically alter responses to another G(q)PCR agonist, histamine, or to thapsigargin or forskolin which elevate intracellular Ca(2+) and cAMP, respectively. This chronically acting antisecretory mechanism is not shared by neurotransmitters that activate G(s)PCRs. Conditioned medium from CCh-pretreated cells mimicked its chronic antisecretory actions, suggesting involvement of an epithelial-derived soluble factor but further experimentation ruled out the involvement of epidermal growth factor receptor ligands. Acute CCh exposure did not chronically alter surface expression of muscarinic M(3) receptors but inhibited intracellular Ca(2+) mobilization upon subsequent agonist challenge. CONCLUSIONS \u26 INFERENCES: These data reveal a novel, chronically acting, antisecretory mechanism that downregulates epithelial secretory capacity upon repeated G(q)PCR agonist exposure. This mechanism involves release of a soluble factor that uncouples receptor activation from downstream prosecretory signals

SGAS 143845.1+145407: A Big, Cool Starburst at Redshift 0.816

We present the discovery and a detailed multi-wavelength study of a strongly-lensed luminous infrared galaxy at z=0.816. Unlike most known lensed galaxies discovered at optical or near-infrared wavelengths this lensed source is red, r-Ks = 3.9 [AB], which the data presented here demonstrate is due to ongoing dusty star formation. The overall lensing magnification (a factor of 17) facilitates observations from the blue optical through to 500micron, fully capturing both the stellar photospheric emission as well as the re-processed thermal dust emission. We also present optical and near-IR spectroscopy. These extensive data show that this lensed galaxy is in many ways typical of IR-detected sources at z~1, with both a total luminosity and size in accordance with other (albeit much less detailed) measurements in samples of galaxies observed in deep fields with the Spitzer telescope. Its far-infrared spectral energy distribution is well-fit by local templates that are an order of magnitude less luminous than the lensed galaxy; local templates of comparable luminosity are too hot to fit. Its size (D~7kpc) is much larger than local luminous infrared galaxies, but in line with sizes observed for such galaxies at z~1. The star formation appears uniform across this spatial scale. In this source, the luminosity of which is typical of sources that dominate the cosmic infrared background, we find that star formation is spatially extended and well organised, quite unlike the compact merger-driven starbursts which are typical for sources of this luminosity at z~0.Comment: 18 pages, 10 figure

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon

Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6 alpha-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-alpha, IL-6, Il-1 beta, and IFN-alpha) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metab-olism of UDCA is necessary for the full expression of its protective effects against colonic inflammation

CANDELS Observations Of The Structural Properties Of Cluster Galaxies At Z=1.62

We discuss the structural and morphological properties of galaxies in a z = 1.62 proto-cluster using near-IR imaging data from Hubble Space Telescope Wide Field Camera 3 data of the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The cluster galaxies exhibit a clear color-morphology relation: galaxies with colors of quiescent stellar populations generally have morphologies consistent with spheroids, and galaxies with colors consistent with ongoing star formation have disk-like and irregular morphologies. The size distribution of the quiescent cluster galaxies shows a deficit of compact (less than or similar to 1 kpc), massive galaxies compared to CANDELS field galaxies at z = 1.6. As a result, the cluster quiescent galaxies have larger average effective sizes compared to field galaxies at fixed mass at greater than 90% significance. Combined with data from the literature, the size evolution of quiescent cluster galaxies is relatively slow from z similar or equal to 1.6 to the present, growing as (1 + z)(-0.6 +/- 0.1). If this result is generalizable, then it implies that physical processes associated with the denser cluster region seem to have caused accelerated size growth in quiescent galaxies prior to z = 1.6 and slower subsequent growth at z < 1.6 compared to galaxies in the lower density field. The quiescent cluster galaxies at z = 1.6 have higher ellipticities compared to lower redshift samples at fixed mass, and their surface-brightness profiles suggest that they contain extended stellar disks. We argue that the cluster galaxies require dissipationless (i.e., gas-poor or "dry") mergers to reorganize the disk material and to match the relations for ellipticity, stellar mass, size, and color of early-type galaxies in z < 1 clusters.NASA NAS5-26555HST GO-12060NASA through from the Space Telescope Science Institute GO-12060European Research CouncilRoyal SocietyTexas AM UniversityGeorge P. and Cynthia Woods Institute for Fundamental Physics and AstronomyAstronom

Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission.

To study transmission patterns of Pneumocystis carinii pneumonia (PCP) in persons with AIDS, we evaluated P. carinii isolates from patients in five U.S. cities for variation at two independent genetic loci, the mitochondrial large subunit rRNA and dihydropteroate synthase. Fourteen unique multilocus genotypes were observed in 191 isolates that were examined at both loci. Mixed infections, accounting for 17.8% of cases, were associated with primary PCP. Genotype frequency distribution patterns varied by patients' place of diagnosis but not by place of birth. Genetic variation at the two loci suggests three probable characteristics of transmission: that most cases of PCP do not result from infections acquired early in life, that infections are actively acquired from a relatively common source (humans or the environment), and that humans, while not necessarily involved in direct infection of other humans, are nevertheless important in the transmission cycle of P. carinii f. sp. hominis

Feasibility of trial procedures for a randomised controlled trial of a community based group exercise intervention for falls prevention for visually impaired older people: the VIOLET study

Background Visually impaired older people (VIOP) have a higher risk of falling than their sighted peers, and are likely to avoid physical activity. The aim was to adapt the existing Falls Management Exercise (FaME) programme for VIOP, delivered in the community, and to investigate the feasibility of conducting a definitive randomised controlled trial (RCT) of this adapted intervention. Methods Two-centre randomised mixed methods pilot trial and economic evaluation of the adapted group-based FaME programme for VIOP versus usual care. A one hour exercise programme ran weekly over 12 weeks at the study sites (Newcastle and Glasgow), delivered by third sector (voluntary and community) organisations. Participants were advised to exercise at home for an additional two hours over the week. Those randomised to the usual activities group received no intervention. Outcome measures were completed at baseline, 12 and 24 weeks. The potential primary outcome was the Short Form Falls Efficacy Scale – International (SFES-I). Participants’ adherence was assessed by reviewing attendance records and self-reported compliance to the home exercises. Adherence with the course content (fidelity) by instructors was assessed by a researcher. Adverse events were collected in a weekly phone call. Results Eighteen participants, drawn from community-living VIOP were screened; 68 met the inclusion criteria; 64 participants were randomised with 33 allocated to the intervention and 31 to the usual activities arm. 94% of participants provided data at the 12 week visit and 92% at 24 weeks. Adherence was high. The intervention was found to be safe with 76% attending nine or more classes. Median time for home exercise was 50 min per week. There was little or no evidence that fear of falling, balance and falls risk, physical activity, emotional, attitudinal or quality of life outcomes differed between trial arms at follow-up. Conclusions The intervention, FaME, was implemented successfully for VIOP and all progression criteria for a main trial were met. The lack of difference between groups on fear of falling was unsurprising given it was a pilot study but there may have been other contributory factors including suboptimal exercise dose and apparent low risk of falls in participants. These issues need addressing for a future trial

3D Collagen Alignment Limits Protrusions to Enhance Breast Cancer Cell Persistence

Patients with mammographically dense breast tissue have a greatly increased risk of developing breast cancer. Dense breast tissue contains more stromal collagen, which contributes to increased matrix stiffness and alters normal cellular responses. Stromal collagen within and surrounding mammary tumors is frequently aligned and reoriented perpendicular to the tumor boundary. We have shown that aligned collagen predicts poor outcome in breast cancer patients, and postulate this is because it facilitates invasion by providing tracks on which cells migrate out of the tumor. However, the mechanisms by which alignment may promote migration are not understood. Here, we investigated the contribution of matrix stiffness and alignment to cell migration speed and persistence. Mechanical measurements of the stiffness of collagen matrices with varying density and alignment were compared with the results of a 3D microchannel alignment assay to quantify cell migration. We further interpreted the experimental results using a computational model of cell migration. We find that collagen alignment confers an increase in stiffness, but does not increase the speed of migrating cells. Instead, alignment enhances the efficiency of migration by increasing directional persistence and restricting protrusions along aligned fibers, resulting in a greater distance traveled. These results suggest that matrix topography, rather than stiffness, is the dominant feature by which an aligned matrix can enhance invasion through 3D collagen matrices