tbuckley/cabot-search huggingface dataset:
T cell tolerance studied at the level of antigenic determinants. I. Latent reactivity to lysozyme peptides that lack suppressogenic epitopes can be revealed in lysozyme-tolerant mice.
Authors: A Oki, E Sercarz
Journal: The Journal of Experimental Medicine (1985)

Whether T cell tolerance represents direct inactivation of antigen-specific T cells via recognition of antigen plus major histocompatibility complex, or via T suppressor (Ts) cells, or a combination of these mechanisms, remains to be clarified. This problem was investigated using a novel approach based on the finding in several systems that T helper/proliferative (Th/Tp) cell-inducing antigenic determinants are dissociable from Ts cell-inducing determinants. Thus, peptide probes containing known sites that stimulate T proliferative activity, as well as peptides from distinct sites assumed to bear Ts-inducing determinants, were used in studying hen (chicken) eggwhite lysozyme (HEL)-tolerant mice. The clear prediction from clonal deletion model is that Th/Tp response potential to short peptides in the tolerant mouse would not exist, while regulatory suppression models predict the coexistence of antigen-reactive cells and antigen-specific regulatory cells that prevent their expression. Adult mice, treated with 2 mg HEL in saline, were tolerant to HEL in complete Freund's adjuvant (CFA). Latent T cell proliferative responses could be revealed to determinants within two HEL peptide probes, which lacked the amino-terminal region of the molecule. This responsiveness suggested two conclusions: first, Ts cells directed against the amino terminus of lysozyme exist in the tolerant genetic responder B10.A; second, these Ts regulate the activity of functional antigen-reactive T cells directed against epitopes elsewhere on the molecule, but only in the presence of the complete molecule, HEL. Examination of neonatally induced tolerance did not reveal any latent responsiveness, supporting the hypothesis that clonal deletion or anergy is the relevant mechanism in this situation. Possible reservations in these explanations of the two tolerant states, plus analysis of the more complex "split tolerance" resulting from 20 mg HEL in saline treatment in adults, are discussed. The approach of dissociation of proliferation-inducing determinants from suppression-inducing determinants clarifies our understanding of the tolerant state and holds promise for more definitive exploration of mechanisms of T cell tolerance.
Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events
Authors: N. Petrosillo, M.F. Proietti, L. Cecchini, M. Masala, C. Franchi, M. Venditti, S. Esposito, E. Nicastri, P. Chinello
Journal: Clinical Microbiology and Infection (2005)
Diagnostic implications of telomerase activity in pleural effusions
Authors: E. Garcia-Pachon, I. Padilla-Navas
Journal: European Respiratory Journal (2004)

We thank D-J. Slebos and colleagues for their comments relating to our paper on the imbalance between haem oxygenase (HO)-1 and inducible nitric oxide synthase (iNOS) in the lungs of severe chronic obstructive pulmonary disease (COPD) patients [1].Our data showed that expression of HO-1 was decreased in alveolar macrophages in severe COPD, whereas iNOS expression in type-2 pneumocytes was increased.It is of great interest to see that the results provided by Slebos and colleagues confirm the part of our findings related to HO-1 expression in alveolar macrophages.Since the origin of macrophages retrieved by bronchoalveolar lavage is undetermined, the findings of Slebos and colleagues might indicate that the altered expression of HO-1 in COPD is not limited to the alveolar compartment, but extends to macrophages from the bronchial lumen.We believe that the presence of current smokers among our patients was a negligible confounding factor for the different expression of HO-1 in severe COPD as compared with control smokers without impairment of lung function [1].In fact, it was shown in our previous paper [2] that upregulation of HO-1 in alveolar macrophages of subjects with smoking history was irrespective of the fact they were current or ex-smokers.The data provided by Slebos and colleagues support the interpretation that HO-1 expression is not influenced directly by cigarette smoke.We are aware of the potential bias in studies performed on surgically resected specimens, due to the presence of cancer itself or to the selection of the worst part of the lungs in
An idiotype-specific helper population that bears immunoglobulin, Ia, and Lyt-1 determinants.
Authors: D H Sherr, M E Dorf
Journal: The Journal of Experimental Medicine (1984)

A helper cell population with phenotypic characteristics of both B and T cells is described. This helper population, called BH, is present in normal unprimed C57BL/6 mice and preferentially helps the expression of NPb idiotype-bearing plaque-forming B cells in the absence of T helper cells. Its surface phenotype is Lyt-1.2+, Ig+, Lyb-3+, Thy-1.2-, Lyt-2.2-. The helper activity of the BH population is IgH restricted and BH cells selectively bind NPb idiotypic determinants. Collectively the data demonstrate that this unique subpopulation can regulate the response of antibody-secreting B cells through specific recognition of idiotypic determinants.
High Frequency of <i>BMPR2</i> Exonic Deletions/Duplications in Familial Pulmonary Arterial Hypertension
Authors: Joy D. Cogan, Michael W. Pauciulo, Amy P. Batchman, Melissa A. Prince, Ivan M. Robbins, Lora K. Hedges, Krista C. Stanton, Lisa A. Wheeler, John A. Phillips, James E. Loyd, William C. Nichols
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Previous studies have shown that approximately 55% of patients with familial pulmonary arterial hypertension (FPAH) have BMPR2 coding sequence mutations. However, direct sequencing does not detect other types of heterozygous mutations, such as exonic deletions/duplications.To estimate the frequency of BMPR2 exonic deletions/duplications in FPAH.BMPR2 mRNA from lymphoblastoid cell lines of 30 families with PAH and 14 patients with idiopathic PAH (IPAH) was subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing. Sequencing of genomic DNA was used to identify point mutations in splice donor/acceptor sites. Multiplex ligation-dependent probe amplification (MLPA) was used to detect exonic deletions/duplications with verification by real-time PCR.Eleven (37%) patients with FPAH had abnormally sized RT-PCR products. Four of the 11 patients were found to have splice-site mutations resulting in aberrant splicing, and exonic deletions/duplications were detected in the remaining seven patients. MLPA identified three deletions/duplications that were not detectable by RT-PCR. Coding sequence point mutations were identified in 11 of 30 (37%) patients. Mutations were identified in 21 of 30 (70%) patients with FPAH, with 10 of 21 mutations (48%) being exonic deletions/duplications. Two of 14 (14%) patients with IPAH exhibited BMPR2 point mutations, whereas none showed exonic deletions/duplications.Our study indicates that BMPR2 exonic deletions/duplications in patients with FPAH account for a significant proportion of mutations (48%) that until now have not been screened for. Because the complementary approach used in this study is rapid and cost effective, screening for BMPR2 deletions/duplications by MLPA and real-time PCR should accompany direct sequencing in all PAH testing.
The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer
Authors: G.J. Weiss, R. Rosell, F. Fossella, M. Perry, R. Stahel, F. Barata, B. Nguyen, S. Paul, P. McAndrews, N. Hanna, K. Kelly, P.A. Bunn
Journal: Annals of Oncology (2007)
Elevated Blood Interleukin-6 Levels in Hyperketonemic Type 1 Diabetic Patients and Secretion by Acetoacetate-Treated Cultured U937 Monocytes
Authors: Sushil K. Jain, Krishnaswamy Kannan, Gideon Lim, Janice Matthews-Greer, Robert McVie, Joseph A. Bocchini
Journal: Diabetes Care (2003)

OBJECTIVE—Diabetic patients have elevated blood levels of interleukin-6 (IL-6), which is known to increase inflammation and the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the circulating levels of IL-6 in type 1 diabetic patients as well as the secretion of IL-6 in vitro in a cell culture model using U937 monocytes. RESEARCH DESIGN AND METHODS—Fasting blood was obtained from type 1 diabetic patients and healthy siblings. To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], β-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37°C for 24 h. IL-6 was determined by the sandwich enzyme-linked immunosorbent assay method, and intracellular reactive oxygen species (ROS) generation was detected using dihydroethidium dye. RESULTS—The blood level of IL-6 was higher in hyperketonemic (HK) diabetic patients than in normoketonemic (NK) diabetic patients (P &amp;lt; 0.05) and normal control subjects (P &amp;lt; 0.05). There was a significant correlation between ketosis and IL-6 levels (r = 0.36, P &amp;lt; 0.04, n = 34) in the blood of diabetic patients. Cell culture studies found that exogenous addition of the ketone body AA, but not BHB, increases IL-6 secretion and ROS generation in U937 cells. N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes. CONCLUSIONS—This study demonstrates that hyperketonemia increases IL-6 levels in the blood of type 1 diabetic patients and that NAC can inhibit IL-6 secretion by U937 monocytic cells cultured in a ketotic medium.
Lack of effect of 4 weeks of oral H1 antagonist on bronchial responsiveness
Authors: RE Ruffin, KM Latimer
Journal: European Respiratory Journal (1991)

Ten patients with stable chronic asthma completed a randomized double-blind placebo controlled crossover study examining the effect of 120mg terfenadine twice daily for 4 weeks on bronchial responsiveness. Bronchial responsiveness was measured by methacholine inhalation tests performed by the tidal breathing technique at 0, 2 and 4 weeks of active and placebo treatment periods separated by a one week washout period. There were no significant differences in mean baseline forced expired volume in 1 sec (FEV1) for placebo and terfenadine treatments (p greater than 0.05) and there were no differences between geometric mean provocative concentrations of methacholine to cause a 20% fall in FEV1 (PC20M) at 2 and 4 weeks of terfenadine (0.89 and 0.99 mg.ml.1) from placebo (0.94 and 0.84 mg.ml.1) (p greater than 0.05). Examination of individual PC20M values during terfenadine treatment showed that 5 patients had PC20M's outside their 95% confidence interval; 2 increased both 2 and 4 week values, 1 increased one value and 2 decreased one value each. It is concluded that terfenadine does not produce clinically significant changes in stable asthmatics.
New Approaches to Hemodialysis
Authors: Andreas Pierratos
Journal: Annual Review of Medicine (2004)

Treatment of end-stage renal disease with dialysis is characterized by high mortality rate, low quality of life, and high cost. Recent randomized controlled studies showed that increasing the dialysis dose above the currently recommended levels in thrice-weekly hemodialysis does not decrease the patient mortality rate. Short daily hemodialysis or daily home nocturnal hemodialysis are promising alternatives. Both improve quality of life and control blood pressure and anemia; nocturnal hemodialysis additionally controls serum phosphates without phosphate binders, allows a free diet, and corrects sleep apnea. Although the direct cost of daily hemodialysis is higher than that of conventional hemodialysis, the cost of total care, especially when delivered at home, seems to be lower. Further confirmation of these results is important. Restructuring of the dialysis reimbursement system is necessary to make the use of daily hemodialysis possible. Hemofiltration techniques, sorbents, and the renal tubular assist device may also help change the current grim statistics.
Validation of a Prognostic Model and the Impact of Mutations in Patients With Lower-Risk Myelodysplastic Syndromes
Authors: Rafael Bejar, Kristen E. Stevenson, Bennett A. Caughey, Omar Abdel-Wahab, David P. Steensma, Naomi Galili, Azra Raza, Hagop Kantarjian, Ross L. Levine, Donna Neuberg, Guillermo Garcia-Manero, Benjamin L. Ebert
Journal: Journal of Clinical Oncology (2012)

A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS.We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A.The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52).Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.
Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.
Authors: J W Schrader, G M Edelman
Journal: The Journal of Experimental Medicine (1976)

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.
Reliable prediction of clinical outcome in patients with chronic HCV infection and compensated advanced hepatic fibrosis: a validated model using objective and readily available clinical parameters
Authors: Adriaan J van der Meer, Bettina E Hansen, Giovanna Fattovich, Jordan J Feld, Heiner Wedemeyer, Jean-François Dufour, Frank Lammert, Andres Duarte-Rojo, Michael P Manns, Donatella Ieluzzi, Stefan Zeuzem, W Peter Hofmann, Robert J de Knegt, Bart J Veldt, Harry L A Janssen
Journal: Gut (2014)

<h3>Objective</h3> Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking. <h3>Design</h3> Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis. <h3>Results</h3> In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7–11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p&lt;0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p&lt;0.001) and log<sub>10</sub> aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4–9.0) years. Among patients with estimated 5-year mortality risks &lt;5%, 5–10% and &gt;10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort). <h3>Conclusions</h3> Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters.
Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data
Authors: C Camma
Journal: Gut (2002)

<b>Background and aims:</b> Retreatment with a combination of α interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. <b>Methods:</b> To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000–1200 mg/daily depending on body weight) was given for 24–60 (mean 39.5) weeks. <b>Results:</b> Biochemical end of treatment and sustained responses were observed in 271/581 (46.6%; 95% confidence interval (CI) 42.6–50.7%) and in 109/581 (18.7%; 95% CI 15.6–22.0%) cases, respectively. Two hundred and six of 532 patients (38.7%; 95% CI 34.6–42.9%) had an end of treatment complete response to retreatment while a complete sustained response occurred in 88 of 559 (15.7%; 95% CI 12.8–18.8%). Fifty four of 581 patients (9.2%; 95% CI 7.0–11.7%) stopped retreatment due to adverse effects. By logistic regression, complete sustained response was predicted independently by age &lt;45 years (p=0.04), by normal pretreatment γ-glutamyltransferase levels (p=0.01), and by a second course total IFN dose of at least 432 mega units (p=0.008). <b>Conclusions:</b> The overall low probability of effectiveness argues against indiscriminate retreatment of all IFN monotherapy non-responders with IFN/ribavirin. Patients less than 45 years old with normal γ-glutamyltransferase levels who were retreated with high dose long course combination therapy had a complete sustained response rate of 30%.
Association of IL-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers
Authors: L Joos, L McIntyre, J Ruan, J E Connett, N R Anthonisen, T D Weir, P D Paré, A J Sandford
Journal: Thorax (2001)

<h3>BACKGROUND</h3> There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The <i>IL1RN</i>gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1β (<i>IL1B</i>) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the <i>IL1RN</i>polymorphism. <h3>METHODS</h3> We investigated whether polymorphisms in the<i>IL1B</i> and <i>IL1RN</i>genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. <h3>RESULTS</h3> None of the genotypes was associated with the rate of decline of lung function. However, the distribution of <i>IL1B/IL1RN</i>haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). <h3>CONCLUSION</h3> These results suggest that <i>IL1B/IL1RN</i> haplotypes play a role in the rate of decline in lung function in smokers.
Diabetes-induced endothelial dysfunction in streptozotocin-treated rats
Authors: F X Dai, A Diederich, J Skopec, D Diederich
Journal: Journal of the American Society of Nephrology (1993)

The vasoactive responses of renal arteries from diabetic and control rats were compared in vitro in arteriograph assemblies. Diabetes was established by an iv injection of streptozotocin (55 mg/kg) in Wistar-Kyoto rats. Endothelium-dependent relaxations mediated by nitric oxide (EDNO) were impaired in arteries from the diabetic rats; the impairment in endothelial function increased with duration of the diabetic state. After 6 and 16 wk, the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine preconstriction were 3.2 and 25 microM for arteries from diabetic rats and 0.4 microM in control arteries, representing 8- and 62-fold decreases in sensitivity to the endothelium-dependent vasodilator in the diabetic arteries. After 6 wk of diabetes, renal arteries also became 20-fold less sensitive to relaxation induced by histamine, another agonist that induces EDNO-mediated relaxations. The inhibition of EDNO production with L-NG-nitroarginine produced greater impairments in acetylcholine relaxations in arteries from diabetic rats than from control rats. Relaxations in response to acetylcholine were impaired in arteries from diabetic rats because of increased production of factors that opposed the vasorelaxant effects of EDNO, rather than from decreased production of EDNO. Pretreatment of the diabetic arteries with the hydroxyl radical scavenger dimethylthiourea normalized relaxations in response to acetylcholine. The blockade of prostaglandin H2-thromboxane A2 receptors with SQ 29548 also improved relaxations in response to acetylcholine in diabetic arteries. These data indicate that endothelial dysfunction in the renal arteries of diabetic rats may be mediated by the increased production of free radicals and of prostaglandin endoperoxides, which oppose the vasorelaxant effects of EDNO.