Down-regulation of mechanisms involved in cell transport and maintenance of mucosal integrity in pigs infected with Lawsonia intracellularis

Lawsonia intracellularis is an obligate intracellular bacterium, responsible for the disease complex known as proliferative enteropathy (PE). L. intracellularis is associated with intestinal crypt epithelial cell proliferation but the mechanisms responsible are yet to be defined. Microarray analysis was used to investigate the host-pathogen interaction in experimentally infected pigs to identify pathways that may be involved. Ileal samples originating from twenty-eight weaner pigs experimentally challenged with a pure culture of L. intracellularis (strain LR189/5/83) were subjected to microarray analysis. Microarray transcriptional signatures were validated using immunohistochemistry and quantitative real time PCR of selected genes at various time points post challenge. At peak of infection (14 days post challenge) 86% of altered transcripts were down regulated, particularly those involved in maintenance of mucosal integrity and regulation of cell transport. Among the up-regulated transcripts, CD163 and CDK1 were novel findings and considered to be important, due to their respective roles in innate immunity and cellular proliferation. Overall, targeted cellular mechanisms included those that are important in epithelial restitution, migration and protection; maintenance of stable inter-epithelial cell relationships; cell transport of nutrients and electrolytes; innate immunity; and cell cycle

Changes in appetite, energy intake, body composition and circulating ghrelin constituents during an incremental trekking ascent to high altitude

Purpose Circulating acylated ghrelin concentrations are associated with altitude-induced anorexia in laboratory environments, but have never been measured at terrestrial altitude. This study examined time course changes in appetite, energy intake, body composition, and ghrelin constituents during a high-altitude trek. Methods Twelve participants [age: 28(4) years, BMI 23.0(2.1) kg m−2] completed a 14-day trek in the Himalayas. Energy intake, appetite perceptions, body composition, and circulating acylated, des-acylated, and total ghrelin concentrations were assessed at baseline (113 m, 12 days prior to departure) and at three fixed research camps during the trek (3619 m, day 7; 4600 m, day 10; 5140 m, day 12). Results Relative to baseline, energy intake was lower at 3619 m (P = 0.038) and 5140 m (P = 0.016) and tended to be lower at 4600 m (P = 0.056). Appetite perceptions were lower at 5140 m (P = 0.027) compared with baseline. Acylated ghrelin concentrations were lower at 3619 m (P = 0.046) and 4600 m (P = 0.038), and tended to be lower at 5140 m (P = 0.070), compared with baseline. Des-acylated ghrelin concentrations did not significantly change during the trek (P = 0.177). Total ghrelin concentrations decreased from baseline to 4600 m (P = 0.045). Skinfold thickness was lower at all points during the trek compared with baseline (P ≤ 0.001) and calf girth decreased incrementally during the trek (P = 0.010). Conclusions Changes in plasma acylated and total ghrelin concentrations may contribute to the suppression of appetite and energy intake at altitude, but differences in the time course of these responses suggest that additional factors are also involved. Interventions are required to maintain appetite and energy balance during trekking at terrestrial altitudes

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Self-help in Jewish Law

https://scholarship.law.bu.edu/books/1197/thumbnail.jp

Self-help in Jewish Law

https://scholarship.law.bu.edu/books/1197/thumbnail.jp

A Randomized, Double-Blind, Placebo-Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis

The interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD). Of the fILDs, Idiopathic pulmonary fibrosis is the most common. Pulmonary hypertension (PH) frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy. There is no proven treatment for patients with fILD-PH. We report results from the first cohort of a phase 2b/3 trial with pulsed inhaled nitric oxide (iNO) in patients with fILD-PH. Subjects in cohort 1 were randomized to iNO 30 μg/kg ideal body weight/h (iNO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on iNO30 followed by dose escalation to iNO45 then iNO75. Activity monitoring was used to assess changes in daily activity. Safety and efficacy were evaluated. Twenty-three patients were randomized to iNO30 and 18 to placebo. During blinded treatment, iNO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity. Placebo subjects showed an average drop of 26% in MVPA and a 12% drop in overall activity. The iNO group had an improvement in oxygen saturation. During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters. Inhaled nitric oxide at all doses (30, 45, and 75) was safe and well tolerated. Treatment with iNO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity. In the OLE, higher doses of iNO were also safe and well tolerated while showing maintenance in activity parameters

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

AbstractObjectivesThe aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH).BackgroundPrimary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized.MethodsEchocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone.ResultsDuring the mean follow-up period of 36.9 ± 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis.ConclusionsPericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation