tbuckley/cabot-search huggingface dataset:
Amino acid sequence diversity within the family of antibodies bearing the major antiarsonate cross-reactive idiotype of the A strain mouse.
Authors: C A Slaughter, J D Capra
Journal: The Journal of Experimental Medicine (1983)

VH region amino acid sequences are described for five A/J anti-p-azophenylarsonate (anti-Ars) hybridoma antibodies for which the VL region sequences have previously been determined, thus completing the V domain sequences of these molecules. These antibodies all belong to the family designated Ars-A which bears the major anti-arsonate cross-reactive idiotype (CRI) of the A strain mouse. However, they differ in the degree to which they express the CRI in standard competition radioimmunoassays. Although the sequences are closely related, all are different from each other. Replacements are distributed throughout the VH region and occur in positions of the chain encoded by all three gene segments, VH, DH, and JH. It is likely that somatic diversification processes play a dominant role in producing the sequence variability in each of these segments. The number of differences from the sequence encoded by the germline is smallest for antibodies that express the CRI most strongly, suggesting that somatic diversification is responsible for loss of the CRI in members of the Ars-A antibody family. There is an unusual degree of clustering of differences in both CDR2 and CDR3 and many of the substitutions are located in "hot spots" of variation. The large number of differences between the chains prohibits the unambiguous identification of positions at which alterations play a major role in reducing the expression of the CRI. However, the data suggest that the loss of the CRI is associated with a definable repertoire of somatic changes at a restricted number of highly variable sites.
Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome.
Authors: D Louvel, M Delvaux, A Felez, J Fioramonti, L Bueno, Y Lazorthes, J Frexinos
Journal: Gut (1996)

AIM: The effects of oxytocin on colonic perception of intraluminal distension were evaluated in 26 patients with irritable bowel syndrome (IBS), using a flaccid bag placed in the descending colon and connected to a computerised barostat. METHOD: Symptomatic responses (first sensation and pain) were evaluated during isobaric distensions (4 mm Hg increments, five minute duration, five minute interval with return to zero pressure between each step), performed automatically by the barostat, during a continuous infusion of placebo or various doses of oxytocin (10, 20, 30, and 50 mU/min). RESULTS: The distension pressure (mean (SD)) required to induce a first abdominal sensation was 17.3 (5.5) mm Hg on placebo, 19.9 (5.8) on oxytocin 10 mU/min (NS), 22.3 (6.0) mm Hg on oxytocin 20 mU/min (p &lt; 0.01), 23.1 (6.6) mm Hg on oxytocin 30 mU/min (p &lt; 0.01), and 24.0 (7.1) mm Hg on oxytocin 50 mU/min (p &lt; 0.01). The distension pressure required to induce pain was 24.8 (6.3) mm Hg on placebo, 26.0 (5.8) on oxytocin 10 mU/min (NS), 33.3 (7.8) mm Hg on oxytocin 20 mU/min (p &lt; 0.01), 34.2 (7.6) mm Hg on oxytocin 30 mU/min (p &lt; 0.01), and 34.3 (7.9) mm Hg on oxytocin 50 mU/ min (p &lt; 0.01). Compliance curves were not different after placebo and oxytocin injection at the different doses. Naloxone did not inhibit the effect of oxytocin. Oxytocin also did not alter somatic perception, characterised by the RIII reflex at the level of the biceps femori. CONCLUSIONS: Oxytocin significantly increases thresholds for visceral perception in IBS patients at doses equal or to greater than 20 mU/min, possibly by acting at the level of visceral afferents.
The reliability measurements of lateral scapular slide test at three different degrees of shoulder joint abduction
Authors: A Shadmehr, H Bagheri, N N Ansari, H Sarafraz
Journal: British Journal of Sports Medicine (2008)

Background Lateral scapular slide test (LSST) quantitatively measures the distance between thoracic spine (T7) and inferior angle of scapula. Objective In this study, the intra-rater reliability, inter-rater reliability and diagnostic accuracy of LSST were measured using a caliper. Methods Three measurements of each test position were obtained bilaterally. Intraclass correlation coefficient (ICC) (2.1), 95% CI and 2 SEMs were calculated for intra-rater and inter-rater reliability of the absolute scapular distance. Sensitivity, specificity, positive and negative likelihood ratios were determined. Results 27 people with and 30 people without shoulder pain participated. The mean age (SD) for the participant was 47.7 (11.6) years and 33.5 (11.7) years, respectively. The ICCs for intra-rater reliability were high. A range of poor to good ICCs was found for inter-rater reliability. The 2 SEMs ranged from 4.6 to 7.9 mm for intra-rater reliability and from 6.8 to 13.4 mm for inter-rater reliability for people with shoulder pain. Positive and negative likelihood ratios from 0.94 to 1.22 and from 0.21 to 2.5, respectively, were demonstrated. Conclusion SST did not show a consistent high reliability. The diagnostic accuracy of the LSST was low, which questions the clinical importance of the tests outcomes.
TTC7A mutations disrupt intestinal epithelial apicobasal polarity
Authors: Amélie E. Bigorgne, Henner F. Farin, Roxane Lemoine, Nizar Mahlaoui, Nathalie Lambert, Marine Gil, Ansgar Schulz, Pierre Philippet, Patrick Schlesser, Tore G. Abrahamsen, Knut Oymar, E. Graham Davies, Christian Lycke Ellingsen, Emmanuelle Leteurtre, Brigitte Moreau-Massart, Dominique Berrebi, Christine Bole-Feysot, Patrick Nischke, Nicole Brousse, Alain Fischer, Hans Clevers, Geneviève de Saint Basile
Journal: Journal of Clinical Investigation (2013)

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.
Determinants of, and reference equation for, exhaled nitric oxide in the Chinese population
Authors: Fanny W.S. Ko, Ting F. Leung, Gary W.K. Wong, Jojo H.Y. Chu, Hing Y. Sy, David S.C. Hui
Journal: European Respiratory Journal (2012)

Measurement of fractional exhaled nitric oxide concentration ( F eNO ) has been proposed as a useful biomarker for monitoring and management of airway diseases. Limited information is available regarding reference levels of F eNO levels in Chinese adults. This study aimed to investigate the reference equation and determinants of F eNO in Chinese adults. 1093 (577 males) healthy nonsmoking subjects aged 18–90 years were recruited. F eNO was measured online using a chemiluminescence analyser. Other assessments included spirometry, skin prick tests, total serum IgE levels and eosinophil count in peripheral blood. The geometric mean F eNO was 32.6 (95% reference interval (RI) 31.4–33.7) ppb for all subjects. F eNO values were higher in males than females (geometric mean (95% RI) 38.3 (36.5–40.2) ppb versus 27.1 (25.8–28.5) ppb, p&lt;0.0001), and in atopic than nonatopic subjects (34.6 (33.0–36.3) ppb versus 29.8 (28.3–31.4) ppb, p&lt;0.0001). F eNO correlated with age (r 2 = 0.23), height (r 2 = 0.20), IgE level (r 2 = 0.18) and percentage eosinophil count (r 2 = 0.18) (all p&lt;0.0001), but not with spirometric parameters. Based on multiple regression modelling, the reference equation of F eNO value was: log( F eNO ) = 0.781 + 0.104(sex) + 0.004(age) + 0.084(atopy) + 0.003(height in cm), where for sex 1 = male and 0 = female, age is measured in years, for atopy 1 = atopic and 0 = nonatopic, and height is measured in cm. The F eNO of Chinese adults is higher than that of the Caucasian population, and is affected by age, sex, height and atopic status. This study provides useful references for the interpretation of F eNO .
Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients
Authors: Azeem Saleem, Julian C. Matthews, Malcolm Ranson, Sophie Callies, Valérie André, Michael Lahn, Claire Dickinson, Christian Prenant, Gavin Brown, Adam McMahon, Denis Talbot, Terry Jones, Patricia M. Price
Journal: Theranostics (2011)

Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.
Impaired CD28-mediated Interleukin 2 Production and Proliferation in Stress Kinase SAPK/ERK1 Kinase (SEK1)/Mitogen-activated Protein Kinase Kinase 4 (MKK4)-deficient T Lymphocytes
Authors: Hiroshi Nishina, Martin Bachmann, Antonio J. Oliveira-dos-Santos, Ivona Kozieradzki, Klaus D. Fischer, Bernhard Odermatt, Andrew Wakeham, Arda Shahinian, Hiroaki Takimoto, Alan Bernstein, Tak W. Mak, James R. Woodgett, Pamela S. Ohashi, Josef M. Penninger
Journal: The Journal of Experimental Medicine (1997)

The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH2 terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1−/− recombination-activating gene (RAG)2−/− chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross-linking. SEK1−/− peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1−/−RAG2−/− chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca2+ ionophore stimulation, which mimics TCR–CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1−/− mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1−/− thymocytes failed to induce SAPK/JNK in response to PMA/Ca2+ ionophore, SEK1−/−RAG2−/− thymocytes proliferated and made IL-2 after PMA/Ca2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1+/+RAG2−/− thymocytes, implying that CD28 costimulation and PMA/Ca2+ ionophore–triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL-2 production and T cell proliferation.
Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial
Authors: Iman Satti, Joel Meyer, Stephanie A Harris, Zita-Rose Manjaly Thomas, Kristin Griffiths, Richard D Antrobus, Rosalind Rowland, Raquel Lopez Ramon, Mary Smith, Sharon Sheehan, Henry Bettinson, Helen McShane
Journal: The Lancet Infectious Diseases (2014)

Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A METHODS: In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769.Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine.Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens.The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.
Using the Transcription Factor Inhibitor of DNA Binding 1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth
Authors: Albert S. Mellick, Prue N. Plummer, Daniel J. Nolan, Dingcheng Gao, Kathryn Bambino, Mary Hahn, Raul Catena, Vivian Turner, Kevin McDonnell, Robert Benezra, Robert Brink, Alexander Swarbrick, Vivek Mittal
Journal: Cancer Research (2010)

Abstract Tumor angiogenesis is essential for malignant growth and metastasis. Bone marrow (BM)–derived endothelial progenitor cells (EPC) contribute to angiogenesis-mediated tumor growth. EPC ablation can reduce tumor growth; however, the lack of a marker that can track EPCs from the BM to tumor neovasculature has impeded progress in understanding the molecular mechanisms underlying EPC biology. Here, we report the use of transgenic mouse and lentiviral models to monitor the BM-derived compartment of the tumor stroma; this approach exploits the selectivity of the transcription factor inhibitor of DNA binding 1 (Id1) for EPCs to track EPCs in the BM, blood, and tumor stroma, as well as mature EPCs. Acute ablation of BM-derived EPCs using Id1-directed delivery of a suicide gene reduced circulating EPCs and yielded significant defects in angiogenesis-mediated tumor growth. Additionally, use of the Id1 proximal promoter to express microRNA-30–based short hairpin RNA inhibited the expression of critical EPC-intrinsic factors, confirming that signaling through vascular endothelial growth factor receptor 2 is required for EPC-mediated tumor biology. By exploiting the selectivity of Id1 gene expression in EPCs, our results establish a strategy to track and target EPCs in vivo, clarifying the significant role that EPCs play in BM-mediated tumor angiogenesis. Cancer Res; 70(18); 7273–82. ©2010 AACR.
Reliability and predictive value of the national institute of diabetes and digestive and kidney diseases liver transplantation database nomenclature and grading system for cellular rejection of liver allografts
Authors: A DEMETRIS
Journal: Hepatology (1995)

Pathologists participating in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Database (LTD) created a histopathological grading system for acute liver allograft rejection, and tested it first for inter- and intra-rater reliability among a group of five pathologists experienced in liver and transplantation pathology. Specimens from post-transplantation biopsies from 48 patients with rejection, hepatitis, or other diagnosis(es) were reviewed. There was moderate to good (kappa = 0.40 to 0.55) inter-rater and good (kappa = 0.55 to 0.58) intrarater agreement for the diagnosis and exact grading of mild, moderate, or severe acute rejection, which improved when a short clinical history was provided. Thus, the scheme was reproducible, and few of the disagreements among the pathologists would have affected treatment decisions. Secondly, the ability of the grading system to predict an unfavorable short- or long-term outcome from the initial histopathological diagnosis of cellular rejection was tested on groups of 168 and 133 patients, respectively, from the three LTD clinical centers, who were followed up for at least 6 months after the first onset of rejection. This analysis showed that a higher histopathological grade of acute rejection on first biopsy diagnosis was significantly associated (P < or = .006) with both an unfavorable short-term outcome, defined by failure of the episode to resolve within 21 days or the need for aggressive immunosuppressive treatment, and a long-term outcome defined by death or retransplantation from rejection within 6 months of onset. Lastly, an analysis was performed to determine whether subjective rejection grading by the pathologist or certain "objective" histopathological features identified by logistic regression modeling were more accurate in predicting an unfavorable outcome.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of retirement on major chronic conditions and fatigue: French GAZEL occupational cohort study
Authors: H. Westerlund, J. Vahtera, J. E. Ferrie, A. Singh-Manoux, J. Pentti, M. Melchior, C. Leineweber, M. Jokela, J. Siegrist, M. Goldberg, M. Zins, M. Kivimaki
Journal: BMJ (2010)

<b>Objectives</b> To determine, using longitudinal analyses, if retirement is followed by a change in the risk of incident chronic diseases, depressive symptoms, and fatigue. <b>Design </b>Prospective study with repeat measures from 7 years before to 7 years after retirement. <b>Setting</b> Large French occupational cohort (the GAZEL study), 1989-2007. <b>Participants </b>11 246 men and 2858 women. <b>Main outcome measures</b> Respiratory disease, diabetes, coronary heart disease and stroke, mental fatigue, and physical fatigue, measured annually by self report over the 15 year observation period; depressive symptoms measured at four time points. <b>Results</b> The average number of repeat measurements per participant was 12.1. Repeated measures logistic regression with generalised estimating equations showed that the cumulative prevalence of self reported respiratory disease, diabetes, and coronary heart disease and stroke increased with age, with no break in the trend around retirement. In contrast, retirement was associated with a substantial decrease in the prevalence of both mental fatigue (odds ratio for fatigue one year after versus one year before retirement 0.19, 95% confidence interval 0.18 to 0.21) and physical fatigue (0.27, 0.26 to 0.30). A major decrease was also observed in depressive symptoms (0.60, 0.53 to 0.67). The decrease in fatigue around retirement was more pronounced among people with a chronic disease before retirement. <b>Conclusions</b> Longitudinal modelling of repeat data showed that retirement did not change the risk of major chronic diseases but was associated with a substantial reduction in mental and physical fatigue and depressive symptoms, particularly among people with chronic diseases.
Some biomarkers of acute kidney injury are increased in pre-renal acute injury
Authors: Maryam Nejat, John W. Pickering, Prasad Devarajan, Joseph V. Bonventre, Charles L. Edelstein, Robert J. Walker, Zoltán H. Endre
Journal: Kidney International (2012)

Pre-renal acute kidney injury (AKI) is assumed to represent a physiological response to underperfusion. Its diagnosis is retrospective after a transient rise in plasma creatinine, usually associated with evidence of altered tubular transport, particularly that of sodium. In order to test whether pre-renal AKI is reversible because injury is less severe than that of sustained AKI, we measured urinary biomarkers of injury (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyl transpeptidase, IL-18, and kidney injury molecule-1 (KIM-1)) at 0, 12, and 24 h following ICU admission. A total of 529 patients were stratified into groups having no AKI, AKI with recovery by 24 h, recovery by 48 h, or the composite of AKI greater than 48 h or dialysis. Pre-renal AKI was identified in 61 patients as acute injury with recovery within 48 h and a fractional sodium excretion <1%. Biomarker concentrations significantly and progressively increased with the duration of AKI. After restricting the AKI recovery within the 48 h cohort to pre-renal AKI, this increase remained significant. The median concentration of KIM-1, cystatin C, and IL-18 were significantly greater in pre-renal AKI compared with no-AKI, while NGAL and γ-glutamyl transpeptidase concentrations were not significant. The median concentration of at least one biomarker was increased in all but three patients with pre-renal AKI. Thus, the reason why some but not all biomarkers were increased requires further study. The results suggest that pre-renal AKI represents a milder form of injury.