tbuckley/cabot-search huggingface dataset:
Evaluation of chloride/bicarbonate. Exchange in the human colon in vivo.
Authors: G R Davis, S G Morawski, C A Santa Ana, J S Fordtran
Journal: Journal of Clinical Investigation (1983)

During perfusion of a plasma-like solution, colonic absorption rate of chloride was much higher than the secretion rate of bicarbonate (34 vs. 3.5 meq/h, respectively). This might suggest that anion exchange (Cl/HCO3) accounts for only a small fraction of total chloride absorption. However, if the colon absorbs as well as secretes bicarbonate, this reasoning would underestimate the magnitude of the anion exchange. To see if the colon absorbs bicarbonate, we perfused a chloride-free solution (which would eliminate bicarbonate secretion via (Cl/HCO3 exchange) and found that the colon absorbed bicarbonate at a rate of 5.1 meq/h. Calculation of electrochemical gradients and measurement of luminal fluid PCO2 indicated that this bicarbonate absorption was mediated passively in response to electrical gradients, rather than via reversed Cl/HCO3 exchange or acid secretion. The combined results of the plasma-like and chloride-free perfusion experiments suggest Cl/HCO3 exchange at a rate of 8.6 meq/h (the sum of bicarbonate movements, 3.5 and 5.1 meq/h, observed in the two experiments). To obtain a second estimate under different experimental conditions, a choline chloride-choline bicarbonate (sodium-free) solution was perfused; with this solution, chloride and bicarbonate absorption dependent on active sodium transport should be eliminated or markedly reduced, and the magnitude of Cl/HCO3 exchange should be revealed. This experiment suggested a Cl/HCO3 exchange rate of 9.3 meq/h, similar to the first estimate. As chloride was absorbed at a rate of 34 meq/h during perfusion of the plasma-like solution, the Cl/HCO3 exchange provides for approximately one-fourth of total chloride absorption.
Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade
Authors: Karsten A. Pilones, Noriko Kawashima, Anne Marie Yang, James S. Babb, Silvia C. Formenti, Sandra Demaria
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Immunoregulatory and suppressive mechanisms represent major obstacles to the success of immunotherapy in cancer patients. We have shown that the combination of radiotherapy to the primary tumor and CTL-associated protein 4 (CTLA-4) blockade induces antitumor immunity, inhibiting metastases and extending the survival of mice bearing the poorly immunogenic and highly metastatic 4T1 mammary carcinoma. Similarly to patients with metastatic cancer, however, mice were seldom cured. Here we tested the hypothesis that invariant natural killer T (iNKT) cells, a subset with unique regulatory functions, can regulate the response to radiotherapy and CTLA-4 blockade. Experimental Design: The growth of 4T1 primary tumors and lung metastases was compared in wild-type and iNKT cell–deficient (iNKT-/-) mice. Treatment was started on day 13 when the primary tumors were palpable. Mice received radiotherapy to the primary tumor in two doses of 12 Gy in combination or not with 9H10 monoclonal antibody against CTLA-4. Response to treatment was assessed by measuring primary tumor growth delay/regression, survival, and number of lung metastases. Results: The response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator α-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10. Conclusions: iNKT cells play a major role in regulating the response to treatment with local radiotherapy and CTLA-4 blockade.
Predictors of variceal bleeding: an analysis of clinical, endoscopic, and haemodynamic variables, with special reference to intravariceal pressure.
Authors: S K Sarin, K R Sundaram, R K Ahuja
Journal: Gut (1989)

To assist in the prediction of variceal bleeding we examined 12 clinical, endoscopic and haemodynamic variables in 126 patients with portal hypertension (72 bleeders and 54 non-bleeders). Multiple regression and discriminant analysis were utilised for 101 patients. Stepwise regression among the 12 variables explained only 54% of the variability existing between bleeders and non-bleeders. Six of the 12 variables accounted for 51% of the total bleeder/non-bleeder variability. A predicting equation was evolved [Yp = -0.60 + 0.19 X1 (colour of varices) + 0.16 X2 (cherry red spots) + 0.03 X3 (red wale, markings) + 0.01 X4 (haematocystic spots) + 0.15 X5 (Conn9s grading of variceal size) + 0.03 X6 (intravariceal pressure)]. Of the six variables used, variceal size indicated 35%, and intravariceal pressure accounted for 12%, of the explained variability between bleeders and non-bleeders. The presence of the three red colour signs and the colour of the varices accounted for only 3% and 1% respectively of the total explained variation. Using the discriminant function analysis, we were able to correctly identify 85% of the bleeders and 81% of the non-bleeders. Additional studies are required to detect the variables responsible for the unexplained variability (46%) between bleeders and non-bleeders.
Dose dependent effect of thrombomodulin in a murine model of allergen-induced asthma
Authors: Takehiro Takagi, Kentaro Fujiwara, Masahiro Onishi, Masahiro Naito, Hajime Fujimoto, Tetsu Kobayashi, Hiroyasu Kobayashi, Corina D'Alessandro-Gabazza, Esteban Gabazza, Osamu Taguchi
Journal: European Respiratory Journal (2012)

Background:  Thrombomodulin (TM), the thrombin receptor on the endothelial cell surface, plays an important role in coagulation and inflammation by inactivating thrombin and activating protein C. Previously we reported that recombinant human TM (rhTM) is protective against murine asthma. However, the effect of different concentrations of rhTM on asthmatic inflammation remains unclear.   Objective:  To evaluate the dose-dependent effect of inhaled rhTM on airway inflammation and hyperresponsiveness in a murine asthma model.   Methods:  Bronchial asthma was induced by sensitization and challenge with ovalbumin (OVA). Mice treated with saline were used as control. The effect of inhaled low dose to high dose rhTM was assessed by administering it prior to OVA exposure. Airway inflammation was evaluated by measuring the number of inflammatory cells and the levels of cytokines in bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness was measured using a plethysmograph. Particle size distribution of each different rhTM was measured by Spraytec.   Results:  The number of eosinophils in BALF and airway hyperresponsiveness was decreased by rhTM in a dose-dependent manner compared to saline treated mice. rhTM concentration of 3.75μg/ml was associated with the lowest number of BALF eosinophils and airway hyperresponsiveness, and with the smallest particle size.   Conclusion:  These results suggest that the effect of rhTM in murine asthma is dose- and particle size-dependent.
Ankyrin Repeat Domain 1, <i>ANKRD1</i>, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer
Authors: Lyndee L. Scurr, Alexander D. Guminski, Yoke-Eng Chiew, Rosemary L. Balleine, Raghwa Sharma, Ying Lei, Kylie Pryor, Gerard V. Wain, Alison Brand, Karen Byth, Catherine Kennedy, Helen Rizos, Paul R. Harnett, Anna deFazio
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics. Experimental Design: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma. Results: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity &amp;gt;2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P = 0.013). Conclusions: These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.
Use of bilevel positive airway pressure ventilatory support for pathological flail chest complicating multiple myeloma
Authors: J Abisheganaden, CB Chee, YT Wang
Journal: European Respiratory Journal (1998)

Multiple myeloma is a common disease that universally involves the skeletal system. Although rib involvement may occur, the development of pathological flail chest is rare. We describe the treatment and course of this condition in an elderly female, and the use of the bilevel positive airway pressure (BiPAP) ventilatory system in providing pneumatic stabilization, while definitive chemotherapy was given to heal the pathological fractures. Our experience with this patient suggests that, despite its dramatic clinical manifestation, the association of flail chest with multiple myeloma may not predict a poor prognosis. We have also found that pneumatic stabilization can be achieved by using the bilevel positive airway pressure ventilatory support through a tracheostomy.
Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker
Authors: Stevo Julius, Shawna D. Nesbitt, Brent M. Egan, Michael A. Weber, Eric L. Michelson, Niko Kaciroti, Henry R. Black, Richard H. Grimm, Franz H. Messerli, Suzanne Oparil, M. Anthony Schork
Journal: New England Journal of Medicine (2006)

Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension.
Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia
Authors: Johann Steiner, Martin Walter, Wenzel Glanz, Zoltán Sarnyai, Hans-Gert Bernstein, Stefan Vielhaber, Andrea Kästner, Martin Skalej, Wolfgang Jordan, Kolja Schiltz, Christine Klingbeil, Klaus-Peter Wandinger, Bernhard Bogerts, Winfried Stoecker
Journal: JAMA Psychiatry (2013)

Evidence for symptomatic convergence of schizophrenia and N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders.To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis.Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined.Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n = 121), MD (n = 70), or BLPD (n = 38).The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups.Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R.Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.
Health service managers play down fears over primary care trust reorganisation
Authors: Adrian O'Dowd
Journal: BMJ (2005)

Health service managers have played down fears that reorganisation of primary care trusts will result in some of them operating well below current levels of efficiency for 18 months. But they have criticised the process and timescales involved.

Senior managers from primary care trusts; strategic health authorities; and the NHS Confederation, the representative body for NHS organisations, gave evidence to the parliamentary Health Select Committee last week as part of its inquiry into proposed changes to primary care trusts.

The witnesses said that much of the government's drive to merge primary care trusts …
Pilot Comparison of Extended-Release and Standard Preparations of Divalproex Sodium in Patients With Bipolar and Schizoaffective Disorders
Authors: Franca Centorrino, James P. Kelleher, Judith M. Berry, Paola Salvatore, Marion Eakin, Kate V. Fogarty, Veronica Fellman, Ross J. Baldessarini
Journal: American Journal of Psychiatry (2003)

The authors compared the new extended-release and standard preparations of divalproex sodium.Twelve patients with DSM-IV bipolar disorder or schizoaffective disorder who were clinically stable while taking the standard form of divalproex participated in the study. These patients were given a single daily dose of the extended-release preparation of divalproex in an open 6-week trial. Clinical symptoms and adverse effects were rated weekly. Doses were adjusted to maintain steady serum valproate concentrations.The medication change was associated with negligible changes in clinical status and tolerability. To maintain serum drug levels, however, 21% higher doses of the extended-release preparation were required.Use of extended-release divalproex once a day was as well tolerated as the standard preparation, with no change in efficacy within 6 weeks, but the daily dose needed to maintain stable serum valproic acid concentration was 21% higher.
Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease.
Authors: P Jolliet, J B Thorens, J C Chevrolet
Journal: Thorax (1995)

Pulmonary vascular reactivity tests were performed in a young woman with mixed connective tissue disease and severe pulmonary hypertension. Vasoreactivity was documented in response to intravenous prostacyclin (PGI2), oral nifedipine, and inhaled nitric oxide, with quantitative differences. Nitric oxide produced a moderate lowering of pulmonary arterial pressure and resistance without any deleterious systemic effect. The use of nitric oxide in testing for pulmonary vasoreactivity merits further evaluation.
Fasting Plasma Leptin, Tumor Necrosis Factor-α Receptor 2, and Monocyte Chemoattracting Protein 1 Concentration in a Population of Glucose-Tolerant and Glucose-Intolerant Women
Authors: Lorenzo Piemonti, Giliola Calori, Alessia Mercalli, Guido Lattuada, Paolo Monti, Maria Paola Garancini, Federica Costantino, Giacomo Ruotolo, Livio Luzi, Gianluca Perseghin
Journal: Diabetes Care (2003)

OBJECTIVE—Leptin and tumor necrosis factor (TNF)-α are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS—In this study, fasting plasma leptin, soluble TNF-α receptor 2 (TNF-α-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS—At baseline, leptin and TNF-α-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P &amp;lt; 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P &amp;lt; 0.02). CONCLUSIONS—In middle-aged women, MCP-1/CCL2, leptin, and TNF-α-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-α-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.
T cell development in B cell-deficient mice. V. Stopping anti-mu treatment results in Igh-restricted expansion of the T suppressor cell repertoire concomitant with the development of normal immunoglobulin levels.
Authors: K T Hayglass, B Benacerraf, M S Sy
Journal: The Journal of Experimental Medicine (1986)

B cell-deficient (anti-mu-treated) mice have proven to be a valuable tool with which to examine the influence of Ig idiotypic determinants upon the development of the Ts repertoire. We have previously reported that ABA-specific Ts repertoires matured in normal and Ig-deficient environments differ from one another in their composition, and consequently, their functionally expressed Igh restrictions. The present report characterizes the impact of natural development of mature B cell activity upon the composition of the Ts repertoire. After stopping anti-mu treatment of C.AL-20 mice, ABA-specific Ts repertoires undergo a defined expansion shown by their acquisition of an additional Ts network that displays Igh restrictions characteristic of normal C.AL-20 mice. This Igh-1d-restricted repertoire can be readily shown within 2 wk of major increases in surface Ig spleen cells and total serum Ig levels in these mice. At the same time, the original Ts restriction specificity (Igh-1a-restricted) generated in the Ig-deficient environment of anti-mu. C.AL-20 mice, is not lost for at least 20 wk. The resulting dual Ts repertoire, characterized by expression of parallel, idiotypically restricted Ts networks, is demonstrable for at least 13 wk. These findings favor an important role for Ig determinants in determining the makeup of the T cell repertoire, and ultimately, the composition of immunologic networks as a whole.
Fast Protein Evolution and Germ Line Expression of a Drosophila Parental Gene and Its Young Retroposed Paralog
Authors: E. Betran
Journal: Molecular Biology and Evolution (2006)

This is the first detailed study of the evolution, phylogenetic distribution, and transcription of one young retroposed gene, CG13732, and its parental gene CG15645, whose functions are unknown. CG13732 is a recognizable retroposed copy of CG15645 retaining the signals of this process. We name the parental gene Cervantes and the retrogene Quijote. To determine when this duplication occurred and the phylogenetic distribution of Quijote, we employed polymerase chain reaction, Southern blotting, and the available information on sequenced Drosophila genomes. Interestingly, these analyses revealed that Quijote is present only in 4 species of Drosophila (Drosophila melanogaster, Drosophila simulans, Drosophila sechellia, and Drosophila mauritiana) and that retroposed copies of Cervantes have also originated in the lineages leading to Drosophila yakuba and Drosophila erecta independently in the 3 instances. We name the new retrogene in the D. yakuba lineage Rocinante and the new retrogene in the D. erecta lineage Sancho. In this work, we present data on Quijote and its parental gene Cervantes. Polymorphism analysis of the derived gene and divergence data for both parental and derived genes were used to determine that both genes likely produce functional proteins and that they are changing at a fast rate (KA/KS ∼ 0.38). The negative value of H of Fay and Wu in the non-African sample reveals an excess of derived variants at high frequency. This could be explained either by positive selection in the region or by demographic effects. The comparative expression pattern shows that both genes express in the same adult tissues (male and female germ line) in D. melanogaster. Quijote is also expressed in male and female in D. simulans, D. sechellia, and D. mauritiana. We argue that the fast rate of evolution of these genes could be related to their putative germ line function and are further studying the independent recruitment of Cervantes-derived retrogenes in multiple lineages.
Type I Interferons Keep Activated T Cells Alive
Authors: Philippa Marrack, John Kappler, Tom Mitchell
Journal: The Journal of Experimental Medicine (1999)

Antigen injection into animals causes antigen-specific T cells to become activated and, rapidly thereafter, die. This antigen-induced death is inhibited by inflammation. To find out how inflammation has this effect, various cytokines were tested for their ability to interfere with the rapid death of activated T cells. T cells were activated in vivo, isolated, and cultured with the test reagents. Two groups of cytokines were active, members of the interleukin 2 family and the interferons (IFNs) α and β. This activity of IFN-α/β has not been described previously. It was due to direct effects of the IFNs on the T cells and was not mediated by induction of a second cytokine such as interleukin 15. IFN-γ did not slow the death of activated T cells, and therefore the activity of IFN-α/β was not mediated only by activation of Stat 1, a protein that is affected by both classes of IFN. IFN-α/β did not raise the levels of Bcl-2 or Bcl-XL in T cells. Therefore, their activity was distinct from that of members of the interleukin 2 family or CD28 engagement. Since IFN-α/β are very efficiently generated in response to viral and bacterial infections, these molecules may be among the signals that the immune system uses to prevent activated T cell death during infections.