tbuckley/cabot-search huggingface dataset:
Experimental acute pancreatitis in PAP/HIP knock-out mice
Authors: M. Gironella, E. Folch-Puy, A. LeGoffic, S. Garcia, L. Christa, A. Smith, L. Tebar, S. P Hunt, R. Bayne, A. J H Smith, J.-C. Dagorn, D. Closa, J. L Iovanna
Journal: Gut (2007)

PAP/HIP was first reported as an additional pancreatic secretory protein expressed during the acute phase of pancreatitis. It was shown in vitro to be anti-apoptotic and anti-inflammatory. This study aims to look at whether PAP/HIP plays the same role in vivo.A model of caerulein-induced pancreatitis was used to compare the outcome of pancreatitis in PAP/HIP(-/-) and wild-type mice.PAP/HIP(-/-) mice showed the normal phenotype at birth and normal postnatal development. Caerulein-induced pancreatic necrosis was, however, less severe in PAP/HIP(-/-) mice than in wild-type mice, as judged by lower amylasemia and lipasemia levels and smaller areas of necrosis. On the contrary, pancreas from PAP/HIP(-/-) mice was more sensitive to apoptosis, in agreement with the anti-apoptotic effect of PAP/HIP in vitro. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP(-/-) mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression. This result, in apparent contradiction with the limited necrosis observed in these mice, is, however, in agreement with the anti-inflammatory function previously reported in vitro for PAP/HIP. This is supported by the observation that activation of the STAT3/SOCS3 pathway was strongly decreased in the pancreas of PAP/HIP(-/-) mice and by the reversion of the apoptotic and inflammatory phenotypes upon administration of recombinant PAP/HIP to PAP/HIP(-/-) mice.The anti-apoptotic and anti-inflammatory functions described in vitro for PAP/HIP have physiological relevance in the pancreas in vivo during caerulein-induced pancreatitis.
Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+ cytotoxic T lymphocytes by free antigenic peptide: a self-veto mechanism?
Authors: H Takahashi, Y Nakagawa, G R Leggatt, Y Ishida, T Saito, K Yokomuro, J A Berzofsky
Journal: The Journal of Experimental Medicine (1996)

Free peptide has been found to inhibit cytotoxic T lymphocyte (CTL) activity, and veto cells bearing peptide-major histocompatibility complex (MHC) complexes have been found to inactivate CTL, but the two phenomena have not been connected. Here we show that a common mechanism may apply to both. CD8+ CTL lines or clones specific for a determinant of the human immunodeficiency virus (HIV) 1 IIIB envelope protein gp160, P18IIIB, are inhibited by as little as 10 min exposure to the minimal 10-mer peptide, I-10, within P18IIIB, free in solution, in contrast to peptide already bound to antigen-presenting cells (APC), which does not inhibit. Several lines of evidence suggest that the peptide must be processed and presented by H-2Dd on the CTL itself to the specific T cell receptor (TCR) to be inhibitory. The inhibition was not killing, in that CTL did not kill 51Cr-labeled sister CTL in the presence of free peptide, and in mixing experiments with CTL lines of different specificities restricted by the same MHC molecule, Dd, the presence of free peptide recognized by one CTL line did not inhibit the activity of the other CTL line that could present the peptide. Also, partial recovery of activity could be elicited by restimulation with cell-bound peptide, supporting the conclusion that neither fratricide nor suicide (apoptosis) was involved. The classic veto phenomenon was ruled out by failure of peptide-bearing CTL to inactivate others. Using pairs of CTL lines of differing specificity but similar MHC restriction, each pulsed with the peptide for which the other is specific, we showed that the minimal requirement is simultaneous engagement of the TCR and class I MHC molecules of the same cell. This could occur in single cells or pairs of cells presenting peptide to each other. Thus, mechanistically, the inhibition is analogous to veto, and might be called self-veto. As a clue to a possible mechanism, we found that free I-10 peptide induced apparent downregulation of expression of specific TCR as well as interleukin 2 receptor, CD69, lymphocyte function-associated antigen 1, and CD8. This self-veto effect also has implications for in vivo immunization and mechanisms of viral escape from CTL immunity.
Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients
Authors: Edoardo Savarino, Roberto Carbone, Elisa Marabotto, Manuele Furnari, Luca Sconfienza, Massimo Ghio, Patrizia Zentilin, Vincenzo Savarino
Journal: European Respiratory Journal (2013)

The aim of the study was to characterise gastro-oesophageal reflux (GOR) in idiopathic pulmonary fibrosis (IPF). 40 consecutive IPF patients underwent pulmonary high-resolution computed tomography (HRCT) scan and impedance-pH monitoring while off antisecretory therapy. The presence of pulmonary fibrosis was assessed using validated HRCT scores. Reflux features included distal oesophageal acid exposure, number of acid/weakly acidic reflux episodes and their proximal migration. 40 consecutive patients with interstitial lung disease other than IPF (non-IPF patients) and 50 healthy volunteers were also enrolled. IPF patients had significantly higher (p&lt;0.01) oesophageal acid exposure (median (interquartile range (IQR)) 9.25 (4.7–15.4)% versus 3.3 (1.4–7.4)% versus 0.7 (0.2–4.2)%, number of acid (median (IQR) 45 (23–55) versus 32 (19–44) versus 18 (10–31)), weakly acidic (median (IQR) 34 (19–43) versus 21 (11–33) versus 18 (15–28)) and proximal reflux (median (IQR) 51 (26.5–65.5) versus 20 (9.5–34.5) versus 9 (5–20)) events compared to non-IPF patients and healthy volunteers, respectively. Pulmonary fibrosis HRCT scores correlated well with reflux episodes in both the distal (r 2 =0.567) and proximal (r 2 =0.6323) oesophagus. Patients with IPF had more bile acids and pepsin (p&lt;0.03) in bronchoalveolar lavage fluid (BALF) (62% and 67%, respectively) and saliva (61% and 68%, respectively) than non-IPF patients (25% and 25% in BALF, and 33% and 36%, respectively, in saliva) and controls (0% and 0% in BALF and saliva, respectively). Acid GOR is common in IPF, but weakly acidic GOR may also occur. Patients with IPF had a risk of pulmonary aspiration of gastric contents. Outcome studies with intense antireflux therapy are needed.
Identification of Functional Human Splenic Memory B Cells by Expression of CD148 and CD27
Authors: Stuart G. Tangye, Yong-Jun Liu, Gregorio Aversa, Joseph H. Phillips, Jan E. de Vries
Journal: The Journal of Experimental Medicine (1998)

Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distinguished from naive follicular B cells by a distinct cell surface phenotype and by the presence of somatic mutations in their Ig V region genes. Although differences exist between human naive and memory B cells, no cell surface molecules have been identified that positively identify all memory B cells. In this study, we have examined the expression of the receptor-type protein tyrosine phosphatase CD148 on human B cells. CD148+ B cells present in human spleen exhibited characteristics typical of memory B cells. These included an activated phenotype, localization to the marginal zone, the expression of somatically mutated Ig V region genes, and the preferential differentiation into plasma cells. In contrast, CD148− B cells appeared to be naive B cells due to localization to the mantle zone, the expression of surface antigens typical of unstimulated B cells, and the expression of unmutated Ig V region genes. Interestingly, CD148+ B cells also coexpressed CD27, whereas CD148− B cells were CD27−. These results identify CD148 and CD27 as markers which positively identify memory B cells present in human spleen. Thus, assessing expression of these molecules may be a convenient way to monitor the development of memory B cell responses in immunocompromised individuals or in vaccine trials.
Enhanced Basal Activity of a Cardiac Ca <sup>2+</sup> Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death
Authors: Dawei Jiang, Bailong Xiao, Lin Zhang, S.R. Wayne Chen
Journal: Circulation Research (2002)

Mutations in the human cardiac Ca 2+ release channel (ryanodine receptor, RyR2) gene have recently been shown to cause effort-induced ventricular arrhythmias. However, the consequences of these disease-causing mutations in RyR2 channel function are unknown. In the present study, we characterized the properties of mutation R4496C of mouse RyR2, which is equivalent to a disease-causing human RyR2 mutation R4497C, by heterologous expression of the mutant in HEK293 cells. [ 3 H]ryanodine binding studies revealed that the R4496C mutation resulted in an increase in RyR2 channel activity in particular at low Ca 2+ concentrations. This increased basal channel activity remained sensitive to modulation by caffeine, ATP, Mg 2+ , and ruthenium red. In addition, the R4496C mutation enhanced the sensitivity of RyR2 to activation by Ca 2+ and by caffeine. Single-channel analysis showed that single R4496C mutant channels exhibited considerable channel openings at low Ca 2+ concentrations. HEK293 cells transfected with mutant R4496C displayed spontaneous Ca 2+ oscillations more frequently than cells transfected with wild-type RyR2. Substitution of a negatively charged glutamate for the positively charged R4496 (R4496E) further enhanced the basal channel activity, whereas replacement of R4496 by a positively charged lysine (R4496K) had no significant effect on the basal activity. These observations indicate that the charge and polarity at residue 4496 plays an essential role in RyR2 channel gating. Enhanced basal activity of RyR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia.
Value of clinical factors in selecting postmenopausal women with rheumatoid arthritis for bone densitometry
Authors: J M Nolla
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> Criteria to decide which patients with rheumatoid arthritis (RA) should be examined by dual energy <i>x</i> ray absorptiometry (DXA) are currently not available. The rheumatologists from Amsterdam have proposed preliminary criteria based on clinical risk factors (age, disease activity, and functional status). These criteria are preliminary and not widely accepted but might be helpful in practice. The value of the proposal in a group of Spanish postmenopausal women with RA is analysed. <h3>METHODS</h3> DXA (lumbar spine and femoral neck) was performed in 128 patients recruited from a clinical setting, and the proposed criteria were applied. T and Z scores were established for a Spanish reference population. <h3>RESULTS</h3> The mean (SD) age of the patients was 61.3 (10.7) and mean duration of the postmenopausal period 14.5 (10.1) years. Mean duration of RA was 13.7 (7.7) years. Mean C reactive protein was 22 (21) mg/l; mean erythrocyte sedimentation rate 26 (18) mm/1st h; and mean Health Assessment Questionnaire score 1.25 (0.79). Ninety (70%) patients fulfilled the proposed criteria. Their sensitivity for the diagnosis of osteoporosis (T score ⩽−2.5 SD) was 86% and their specificity, 43%. Positive predictive value was 54% and negative predictive value, 79%. <h3>CONCLUSIONS</h3> The proposed criteria seem a good screening method for the selection of those patients with RA whose bone mineral density should be assessed as the sensitivity and negative predictive value are acceptable.
Regional differences in dosage compensation on the chicken Z chromosome
Authors: Esther Melamed, Arthur P Arnold
Journal: Genome biology (2007)

Abstract Background Most Z chromosome genes in birds are expressed at a higher level in ZZ males than in ZW females, and thus are relatively ineffectively dosage compensated. Some Z genes are compensated, however, by an unknown mechanism. Previous studies identified a non-coding RNA in the male hypermethylated (MHM) region, associated with sex-specific histone acetylation, which has been proposed to be involved in dosage compensation. Results Using microarray mRNA expression analysis, we find that dosage compensated and non-compensated genes occur across the Z chromosome, but a cluster of compensated genes are found in the MHM region of chicken chromosome Zp, whereas Zq is enriched in non-compensated genes. The degree of dosage compensation among Z genes is predicted better by the level of expression of Z genes in males than in females, probably because of better compensation of genes with lower levels of expression. Compensated genes have different functional properties than non-compensated genes, suggesting that dosage compensation has evolved gene-by-gene according to selective pressures on each gene. The group of genes comprising the MHM region also resides on a primitive mammalian (platypus) sex chromosome and, thus, may represent an ancestral precursor to avian ZZ/ZW and monotreme XX/XY sex chromosome systems. Conclusion The aggregation of dosage compensated genes near the MHM locus may reflect a local sex- and chromosome-specific mechanism of dosage compensation, perhaps mediated by the MHM non-coding RNA.
Notch–RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization
Authors: Haixia Xu, Jimmy Zhu, Sinead Smith, Julia Foldi, Baohong Zhao, Allen Y Chung, Hasina Outtz, Jan Kitajewski, Chao Shi, Silvio Weber, Paul Saftig, Yueming Li, Keiko Ozato, Carl P Blobel, Lionel B Ivashkiv, Xiaoyu Hu
Journal: Nature Immunology (2012)
Glutamate Synapses in Human Cognitive Disorders
Authors: Lenora Volk, Shu-Ling Chiu, Kamal Sharma, Richard L. Huganir
Journal: Annual Review of Neuroscience (2015)

Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.
Effects of Home-Based Pulmonary Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease
Authors: François Maltais
Journal: Annals of Internal Medicine (2008)

Background: Home-based rehabilitation is a promising approach to improve access to pulmonary rehabilitation. Objective: To assess whether self-monitored, home-based rehabilitation is as effective as outpatient, hospital-based rehabilitation in patients with chronic obstructive pulmonary disease (COPD). Design: Randomized, multicenter, noninferiority trial. Setting: 10 academic and community medical centers in Canada. Patients: 252 patients with moderate to severe COPD. Intervention: After a 4-week education program, patients took part in home-based rehabilitation or outpatient, hospital-based rehabilitation for 8 weeks. They were followed for 40 weeks to complete the 1-year study. Measurements: The primary outcome was the change in Chronic Respiratory Questionnaire dyspnea subscale score at 1 year. The primary analysis took a modified intention-to-treat approach by using all patients who provided data at the specified follow-up time, regardless of their level of adherence. The analysis used regression modeling that adjusted for the effects of center, sex, and baseline level. All differences were computed as home intervention minus outpatient intervention. Results: Both interventions produced similar improvements in the Chronic Respiratory Questionnaire dyspnea subscale at 1 year: improvement in dyspnea of 0.62 (95% CI, 0.43 to 0.80) units in the home intervention (n = 107) and 0.46 (CI, 0.28 to 0.64) units in the outpatient intervention (n = 109). The difference between the 2 treatments at 1 year was small and clinically unimportant. The 95% CI of the difference did not exceed the prespecified noninferiority margin of 0.5: difference in dyspnea score of 0.16 (CI, −0.08 to 0.40). Most adverse events were related to COPD exacerbations. No serious adverse event was considered to be related to the study intervention. Limitation: The contribution of the educational program to the improvement in health status and exercise tolerance cannot be ascertained. Conclusion: Home rehabilitation is a useful, equivalent alternative to outpatient rehabilitation in patients with COPD.
Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial
Authors: John McIntyre, Sue Robertson, Elizabeth Norris, Richard Appleton, William P Whitehouse, Barbara Phillips, Tim Martland, Kathleen Berry, Jacqueline Collier, Stephanie Smith, Imti Choonara
Journal: The Lancet (2005)
Early identification of atopy in the prediction of persistent asthma in children
Authors: Peter D Sly, Attilio L Boner, Bengt Björksten, Andy Bush, Adnan Custovic, Philippe A Eigenmann, James E Gern, Jorrit Gerritsen, Eckard Hamelmann, Peter J Helms, Robert F Lemanske, Fernando Martinez, Soren Pedersen, Harald Renz, Hugh Sampson, Erika von Mutius, Ulrich Wahn, Patrick G Holt
Journal: The Lancet (2008)
Pulmonary infection due to Mycobacterium szulgai, case report and review of the literature
Authors: E Tortoli, G Besozzi, C Lacchini, V Penati, MT Simonetti, S Emler
Journal: European Respiratory Journal (1998)

We describe the case of a patient with a chronic pulmonary infection due to a mycobacterium tentatively identified as Mycobacterium flavescens, but finally shown to be Mycobacterium szulgai; this is the first M. szulgai infection reported in Italy. The patient responded to treatment with multiple antituberculosis drugs only after two cycles of 10 and 6 months, respectively. The literature concerning previous case reports in which M. szulgai is involved is revised and the difficulty concerning the identification of this rare mycobacterium, along with its in vitro and in vivo susceptibility, are discussed.
Factors determining the quality of screening colonoscopy: a prospective study on adenoma detection rates, from 12 134 examinations (Berlin colonoscopy project 3, BECOP-3)
Authors: Andreas Adler, Karl Wegscheider, David Lieberman, Alireza Aminalai, Jens Aschenbeck, Rolf Drossel, Michael Mayr, Michael Mroß, Mathias Scheel, Andreas Schröder, Katharina Gerber, Gabriela Stange, Stephanie Roll, Ulrich Gauger, Bertram Wiedenmann, Lutz Altenhofen, Thomas Rosch
Journal: Gut (2012)

<h3>Background</h3> Screening colonoscopy (SC) outcome quality is best determined by the adenoma detection rate (ADR). The substantial variability in the ADRs between endoscopists may reflect different skills, experience and/or equipment. <h3>Objective</h3> To analyse the potential factors that may influence ADR variance, including case volume. <h3>Design</h3> 12 134 consecutive SCs (mean age 64.5 years, 47% men) from 21 Berlin private-practice colonoscopists were prospectively studied during 18 months. The data were analysed using a two-level mixed linear model to adequately address the characteristics of patients and colonoscopists. The ADR was regressed after considering the following factors: sex, age, bowel cleanliness, NSAID intake, annual SC case volume, lifetime experience, instrument withdrawal times, instrument generations used, and the number of annual continuing medical education (CME) meetings attended by the physician. The case volume was also retrospectively analysed from the 2007 national SC registry data (312 903 colonoscopies and 1004 colonoscopists). <h3>Results</h3> The patient factors that correlated with the ADR were sex, age (p&lt;0.001) and low quality of bowel preparation (p=0.005). The factors that were related to the colonoscopists were the number of CME meetings attended (p=0.012) and instrument generation (p=0.001); these factors accounted for approximately 40% of the interphysician variability. Within a narrow range (6–11 min), the withdrawal time was not correlated with the ADR. Annual screening case volume did not correlate with the ADR, and this finding was confirmed by the German registry data. <h3>Conclusions</h3> The outcome quality of screening colonoscopies is mainly influenced by individual colonoscopist factors (ie, CME activities) and instrument quality. <h3>Clinical trial registration number</h3> Clinical Trial Gov Registration number: NCT00860665.
IGIV-10% Infused Intravenously And Subcutaneously To Subjects With Primary Immunodeficiency Diseases - Comparison Of Pharmacokinetic Properties
Authors: H. Leibl, W. Engl, I. Melamed, M. Stein, R.L. Wasserman, M. Berger, R.I. Schiff
Journal: Journal of Allergy and Clinical Immunology (2009)
Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival
Authors: Emmanuel L. Gautier, Stoyan Ivanov, Jesse W. Williams, Stanley Ching-Cheng Huang, Genevieve Marcelin, Keke Fairfax, Peter L. Wang, Jeremy S. Francis, Paola Leone, David B. Wilson, Maxim N. Artyomov, Edward J. Pearce, Gwendalyn J. Randolph
Journal: The Journal of Experimental Medicine (2014)

The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6flox/flox mice to tackle this issue. In Lyz2-Cre x Gata6flox/flox mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages.