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Population declines of amphibian species in many parts of the world are associated with a lethal fungal pathogen, Batrachochytrium dendrobatidis. Using laboratory challenge assays, we describe the inhibition of B. dendrobatidis by members of eight genera of bacteria isolated from the skin of two amphibian species that exhibit parental care behavior (Plethodon cinereus and Hemidactylium scutatum). We found that members of three genera of bacteria isolated from the skins of the salamander P. cinereus and members of seven genera isolated from the salamander H. scutatum inhibited the growth of B. dendrobatidis. Understanding how B.dendrobatidis interacts with an ecological community of cutaneous flora may be important in explaining and preventing amphibian population declines.

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The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXR␣/␤-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXR␣ and LXR␤ in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.The liver X receptors (LXR␣ and LXR␤) 4 are ligand-dependent transcription factors belonging to the nuclear hormone receptor superfamily (1). Although the two transcription factors are encoded by separate genes, LXR␣ and LXR␤ share 78% similarity within the ligand-binding domains (2). LXR␤ (NR1H2) is ubiquitously expressed, whereas LXR␣ (NR1H3) has a more restricted distribution with the highest expression observed in the liver, adipose tissue, intestine, kidney, and macrophages (3). LXRs regulate multiple genes involved in lipid metabolism, including those involved in sterol transport (4, 5) and fatty acid biosynthesis (6 -8). More recently, LXRs have been found to play a role in the regulation of glucose metabolism (9, 10), immunity, and cellular responses to various environmental stresses (11)(12)(13)(14).To function as a transcription factor, LXR must heterodimerize with retinoid X receptor (RXRs) and then bind to LXR-response elements in target genes. The LXR-response elements consist of two direct hexanucleotide repeats separated by four nucleotides (DR4 element) (3). The binding of LXR or RXR ligands results in a conformational change in the heterodimer and recruitment of nuclear receptor coactivators such as steroid receptor coactivator-1 (SRC-1), resulting in the activation of gene transcription (16). Several compounds have been identified that are potent LXR agonists, including various oxysterols (17, 18). Position-specific monooxidation of the sterol side chain leads to high affinity binding and activation of LXR (19). Analysis of...

Background & Aims: pH impedance monitoring detects acid and non-acid reflux events, but little is known about which parameters predict outcomes of different management strategies. We evaluated a cohort of medically and surgically managed patients following pH-impedance monitoring to identify factors that predict symptom improvement after therapy. Methods: In a prospective study, we followed 187 subjects undergoing pH impedance testing from January 2005 through August 2010 at Washington University in St. Louis (mean age, 53.8±0.9 years; 70.6% female). Symptom questionnaires assessed dominant symptom intensity (DSI) and global symptom severity (GSS) at baseline and on follow up. Data collected from pH impedance studies included acid exposure time (AET), reflux exposure time (RET, duration of impedance drop 5 cm above lower esophageal sphincter, reported as percentage of time similar to AET), symptom reflux correlation (symptom index and symptom association probability, SAP), and total numbers of reflux events. Univariate and multivariate analyses were performed to determine factors associated with changes in DSI and GSS after therapy. Results: Of study subjects, 49.7% were tested on proton pump inhibitor (PPI) therapy and 68.4% were managed medically. After 39.9±1.3 months follow up, DSI and GSS scores decreased significantly (P<.05). On univariate analysis, abnormal AET predicted decreased DSI and GSS scores (P≤.049 for each comparison); RET and SAP from impedance-detected reflux events (P≤.03) were also predictive. On multivariate analysis, abnormal AET consistently predicted symptomatic outcome; other predictors included impedance-detected SAP, older age, and testing performed off PPI therapy. Abnormal RET, acid symptom index or SAP, and numbers of reflux events did not independently predict decrease in DSI or GSS scores. Conclusion: Performing pH impedance monitoring off PPI therapy best predicts response to anti-reflux therapy. Key parameters with predictive value include increased AET, and correlation between symptoms and reflux events detected by impedance.

At time of publication, litigation between the manufacturer of VSL#3 and Dr. De Simone/ExeGi Pharma over intellectual property claims was ongoing.

Background Mean nocturnal baseline impedance (MNBI), a novel pH-impedance metric, may be a surrogate marker of reflux burden. Aim To assess the predictive value of MNBI on symptomatic outcomes after antireflux therapy. Methods In this prospective observational cohort study, pH-impedance studies performed over a 5-year period were reviewed. Baseline impedance was extracted from 6 channels at three stable nocturnal 10-min time periods, and averaged to yield MNBI. Distal and proximal esophageal MNBI values were calculated by averaging MNBI values at 3, 5, 7, and 9 cm, and 15 and 17 cm, respectively. Symptomatic outcomes were measured as changes in global symptom severity (GSS, rated on 100-mm visual analog scales) on prospective follow-up after medical or surgical antireflux therapy. Univariate and multivariate analyses assessed the predictive value of MNBI on symptomatic outcomes. Results Of 266 patients, 135 (50.8%) were tested off PPI therapy and formed the study cohort (52.1±1.1 yrs, 63.7% F). The 59 with elevated acid exposure time (AET) had lower composite and distal MNBI values than those with physiologic AET (p<0.0001), but similar proximal MNBI (p=0.62). Linear AET negatively correlated with distal MNBI, both individually and collectively (Pearson's r=−0.5, p<0.001), but not proximal MNBI (Pearson's r=0, p=0.72). After prospective follow-up (94 patients followed for 3.1±0.2 yrs), univariate and multivariate regression models showed that distal MNBI, but not proximal MNBI, was independently predictive of linear GSS improvement. Conclusions Distal esophageal MNBI negatively correlates with AET and, when assessed off PPI therapy, is independently predictive of symptomatic improvement following antireflux therapy.

Esophageal symptoms are common and may indicate the presence of gastroesophageal reflux disease (GERD), structural processes, motor dysfunction, behavioral conditions, or functional disorders. Esophageal physiologic tests are often performed when initial endoscopic evaluation is unrevealing, especially when symptoms persist despite empiric management. Commonly used esophageal physiologic tests include esophageal manometry, ambulatory reflux monitoring, and barium esophagram. Functional lumen imaging probe (FLIP) has recently been approved for the evaluation of esophageal pressure and dimensions using volumetric distension of a catheter-mounted balloon and as an adjunctive test for the evaluation of symptoms suggestive of motor dysfunction. Targeted utilization of esophageal physiologic tests can lead to definitive diagnosis of esophageal disorders but can also help rule out organic disorders while making a diagnosis of functional esophageal disorders. Esophageal physiologic tests can evaluate obstructive symptoms (dysphagia and regurgitation), typical and atypical GERD symptoms, and behavioral symptoms (belching and rumination). Certain parameters from esophageal physiologic tests can help guide the management of GERD and predict outcomes. In this ACG clinical guideline, we used the Grading of Recommendations Assessment, Development and Evaluation process to describe performance characteristics and clinical value of esophageal physiologic tests and provide recommendations for their utilization in routine clinical practice.