tbuckley/cabot-search huggingface dataset:
The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation.
Authors: F D Howard, P Moingeon, U Moebius, D J McConkey, B Yandava, T E Gennert, E L Reinherz
Journal: The Journal of Experimental Medicine (1992)

CD2-mediated T lymphocyte activation requires surface expression of CD3-Ti, the T cell receptor (TCR) for antigen major histocompatibility complex protein. Given the importance of CD3 zeta in TCR signaling, we have directly examined the ability of the CD3 zeta cytoplasmic domain to couple CD2 to intracellular signal transduction pathways. A cDNA encoding a chimeric protein consisting of the human CD3 zeta cytoplasmic domain (amino acid residues 31-142) fused to the CD8 alpha extracellular and transmembrane domains (amino acid residues 1-187) was transfected into a CD2+CD3-CD8- variant of the human T cell line Jurkat. The resulting transfectants expressed the CD8 alpha/CD3 zeta chimeric receptor at the cell surface in the absence of other TCR subunits. Stimulation of these transfectants with anti-T11(2) + anti-T11(3) monoclonal antibodies (mAbs) initiated both a prompt cytosolic free calcium ([Ca2+]i) rise and protein tyrosine kinase activation. Stimulation with either intact anti-T11(2) + anti-T11(3) mAbs or purified F(ab')2 fragments resulted in interleukin 2 (IL-2) secretion. In contrast, control cell lines transfected with a cDNA encoding wild-type CD8 alpha, and thus lacking surface expression of the CD3 zeta cytoplasmic domain, failed to show any [Ca2+]i rise, protein tyrosine kinase activation, or IL-2 secretion after identical stimulation. These data directly establish the CD3 zeta cytoplasmic domain as a necessary and sufficient component of the CD3-Ti complex involved in T lymphocyte activation through CD2. Moreover, they show that CD2 signaling can function in the absence of Fc receptors.
Association of Single Measurements of Dipstick Proteinuria, Estimated Glomerular Filtration Rate, and Hematocrit with 25-Year Incidence of End-Stage Renal Disease in the Multiple Risk Factor Intervention Trial
Authors: Areef Ishani, Greg A. Grandits, Richard H. Grimm, Kenneth H. Svendsen, Allan J. Collins, Ronald J. Prineas, James D. Neaton
Journal: Journal of the American Society of Nephrology (2006)

The incidence of ESRD is increasing rapidly. Limited information exists regarding early markers for the development of ESRD. This study aimed to determine over 25 yr the risk for ESRD associated with proteinuria, estimated GFR (eGFR), and hematocrit in men who did not have identified kidney disease and were randomly assigned into the Multiple Risk Factor Intervention Study (MRFIT). A total of 12,866 men who were at high risk for heart disease were enrolled (1973 to 1975) and followed through 1999. Renal replacement therapy was ascertained by matching identifiers with the United States Renal Data System's data; vital status was from the National Death Index. Men who initiated renal replacement therapy or died as a result of kidney disease were deemed to have developed ESRD. Dipstick urine for proteinuria, eGFR, and hematocrit were related to development of ESRD. During 25 yr, 213 (1.7%) men developed ESRD. Predictors of ESRD were dipstick proteinuria of 1+ or > or =2+ (hazard ratio [HR] 3.1 [95% confidence interval (CI) 1.8 to 5.4] and 15.7 [95% CI 10.3 to 23.9] respectively) and an eGFR of <60 ml/min per 1.73 m(2) (HR 2.4; 95% CI 1.5 to 3.8). Correlation between eGFR and serum creatinine was 0.9; the risk for ESRD with a 1-SD difference of each was identical (HR 1.21). Bivariate analysis demonstrated a 41-fold increase in ESRD risk in those with an eGFR <60 ml/min per 1.73 m(2) and > or =2+ proteinuria (95% CI 15.2 to 71.1). There was no association between hematocrit and ESRD. Other baseline measures that independently predicted ESRD included age, cigarette smoking, BP, low HDL cholesterol, and fasting glucose. Among middle-aged men who were at high risk for cardiovascular disease but had no clinical evidence of cardiovascular disease or significant kidney disease, dipstick proteinuria and an eGFR value <60 ml/min per 1.73 m(2) were strong predictors of long-term development of ESRD. It remains unknown whether intervention for proteinuria or early identification of those with chronic kidney disease reduces the risk for ESRD.
Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study
Authors: Dean Ornish, Jue Lin, June M Chan, Elissa Epel, Colleen Kemp, Gerdi Weidner, Ruth Marlin, Steven J Frenda, Mark Jesus M Magbanua, Jennifer Daubenmier, Ivette Estay, Nancy K Hills, Nita Chainani-Wu, Peter R Carroll, Elizabeth H Blackburn
Journal: The Lancet Oncology (2013)
Step-up combination versus switching of non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a retrospective observational study
Authors: M Schoels, T Kapral, T Stamm, J S Smolen, D Aletaha
Journal: Annals of the Rheumatic Diseases (2007)

In rheumatoid arthritis (RA), treatment with disease-modifying antirheumatic drugs (DMARDs) frequently needs to be changed because of insufficient effectiveness.To compare the clinical outcomes of two potential strategies for patients experiencing DMARD discontinuations related to ineffectiveness: switching to another DMARD or step-up combination therapy of the present DMARD with a new one.In a large observational database of 4585 DMARD courses in 1214 patients with RA, all patients who had experienced a change in treatment regimen were identified, and retention, effectiveness and safety of these subsequent treatment courses between the two strategies (switching vs step-up combination). All analyses were stratified according to the type of the new DMARD into methotrexate (MTX), sulphasalazine (SSZ) or leflunomide (LEF); all other DMARDs were excluded.Kaplan-Meier analysis for MTX courses showed no significant difference in overall retention rates between the strategies of adding MTX and switching to MTX (p = 0.49 by log rank test). Likewise, switching or adding did not result in significantly different retention rates for SSZ and LEF (p = 0.61 and 0.74, respectively). This similarity between strategies remained after adjusting for several confounding variables. The frequencies of treatment terminations related to ineffectiveness or toxicity were likewise similar between the two strategies for the MTX, SSZ and LEF groups. This was also confirmed by the similarity of erythrocyte sedimentation rates that were reached at the end of the two therapeutic strategies for all three drugs, in adjusted analysis.Given all limitations of observational studies, the present data indicate that in situations of ineffective DMARD treatments, step-up combination therapy using traditional DMARDs, such as MTX, SSZ or LEF, bears no clear clinical advantage over switching to the new DMARD. Our results do not implicate any predication about step-up design including biologicals, where the benefit of combination therapy has been suggested convincingly.
The Effectiveness and Ethical Justification of Psychiatric Outpatient Commitment
Authors: Guido R. Zanni, Paul F. Stavis
Journal: The American Journal of Bioethics (2007)

Studies link involuntary outpatient commitment with improved patient outcomes, fueling debate on its ethical justification. This study compares inpatient utilization for committed outpatients in the 1990s with those who were not under outpatient civil commitment orders. Findings reveal committed outpatients had higher utilization of inpatient services and restraint episodes prior to their commitment compared with a control group. Committed outpatients also were more likely to have been on discharge status at the time of admission, have been admitted involuntarily under emergency legal procedures, and have had a greater number of admissions and hospital days prior to their commitment. Following commitment, patients had fewer hospitalizations, shorter lengths of stay, fewer seclusion episodes and hours, and fewer restraint episodes and hours. Findings are discussed within the context of parens patriae and therapeutic jurisprudence, and support medical and public policy justifications for ethical uses of outpatient civil commitment laws for seriously mentally ill patients.
Effect of cimetidine on the amounts of histamine in the gastric mucosa of patients with gastric or duodenal ulcers.
Authors: W K Man, J H Saunders, C Ingoldby, J Spencer
Journal: Gut (1981)

Measurements were made of the amounts of histamine extracted from patients with peptic ulcer disease and control subjects suffering from various gastrointestinal diseases. Patients with duodenal ulcer, gastric ulcer, or recurrent duodenal ulcer after proximal gastric vagotomy often had less gastric mucosal histamine than did normal controls. Cimetidine therapy increased the amounts of the histamine to above control levels, presumably by suppression of output. It is concluded that endogenous amounts of histamine reflect the pathogenic states in the gastric mucosa of patients with peptic ulcer diseases. Cimetidine, as does vagotomy, increases the amount of gastric mucosal histamine. These findings suggest that the increase in mucosal histamine with cimetidine is not due to activation of histamine methyl transferase, but rather to suppression of histamine output into the gastric juice.
A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer
Authors: A. Schneeweiss, F. Marmé, A. Ruiz, A.G. Manikhas, A. Bottini, M. Wolf, H.-P. Sinn, K. Mansouri, L. Kennedy, T. Bauknecht
Journal: Annals of Oncology (2010)
THE MECHANISMS BY WHICH MACROPHAGES PHAGOCYTE ENCAPSULATED BACTERIA IN THE ABSENCE OF ANTIBODY
Authors: William D. Sawyer, Mary Ruth Smith, W. Barry Wood
Journal: The Journal of Experimental Medicine (1954)

EVIDENCE HAS BEEN PRESENTED: (1) that macrophages from experimentally produced inflammatory exudates are capable of phagocyting fully encapsulated Type I pneumococci and group A Friedländer's bacilli in the absence of antibody, (2) that the principal mechanisms involved are those of surface phagocytosis, and (3) that the majority of pneumococci ingested by macrophages in antibody-free preparations are ultimately destroyed. The relationship of these phenomena to the mechanism of recovery in pneumococcal and Friedländer's bacillus infections has been briefly discussed.
THE REQUIREMENT OF MORE THAN ONE ANTIGENIC DETERMINANT FOR IMMUNOGENICITY
Authors: K. Rajewsky, V. Schirrmacher, S. Nase, N. K. Jerne
Journal: The Journal of Experimental Medicine (1969)

Rabbits primarily stimulated with a BSA (bovine serum albumin)-sulfanilic acid complex will produce a good secondary response to the sulfanilic acid hapten if the carrier used in the secondary stimulus is again BSA, and not if the secondary carrier is HGG (human gamma globulin). In the latter situation, a good secondary response is obtained, however, if the rabbits are pretreated a few weeks earlier with free HGG. We conclude that the immune stimulus involves the recognition of carrier determinants unrelated to the hapten. As the receptors for recognition of unrelated determinants are probably situated on different cells, we suggest that the immune stimulus leading to antibody formation requires the interaction of two antigen-bridged cells.
Macrophage Elastase (Matrix Metalloproteinase-12) Suppresses Growth of Lung Metastases
Authors: A. McGarry Houghton, Jay L. Grisolano, Mary L. Baumann, Dale K. Kobayashi, R. Dean Hautamaki, Leslie C. Nehring, Lynn A. Cornelius, Steven D. Shapiro
Journal: Cancer Research (2006)

Abstract Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in macrophage elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely macrophage derived in this model, being expressed by tumor-associated macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic&amp;gt;angiogenic tumor microenvironment that retards lung tumor growth independent of the production of angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics. (Cancer Res 2006; 66(12): 6149-55)
G894T Polymorphism in the Endothelial Nitric Oxide Synthase Gene Is Associated With an Enhanced Vascular Responsiveness to Phenylephrine
Authors: Ivan Philip, Gaetan Plantefeve, Sandrine Vuillaumier-Barrot, Eric Vicaut, Claude LeMarie, Daniel Henrion, Odette Poirier, Bernard I. Levy, Jean Marie Desmonts, Geneviève Durand, Joelle Benessiano
Journal: Circulation (1999)

Background —Differences in vascular reactivity to phenylephrine (PE) responsiveness have been largely evidenced in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Because nitric oxide (NO) strongly affects modulation of the vascular tone in response to vasopressor agents, we hypothesized that the G894T polymorphism of the endothelial NO synthase gene ( eNOS ) could be related to changes in the pressor response to PE. Methods and Results —The protocol was performed in 68 patients undergoing coronary artery bypass grafting (n=33) or valve surgery (n=35) in whom mean arterial pressure decreased below 65 mm Hg during normothermic CPB. Under constant and nonpulsatile pump flow conditions (2 to 2.4 L · min −1 · m −2 ), a PE dose-response curve was generated by the cumulative injection of individual doses of PE (25 to 500 μg). The G894T polymorphism of the eNOS gene was determined, and 3 groups were defined according to genotype (TT, GT, and GG). Groups were similar with regard to perioperative characteristics. The PE dose-dependent response was significantly higher in the allele 894T carriers (TT and GT) than in the homozygote GG group ( P =0.02), independently of possible confounding variables. Conclusions —These results evidenced an enhanced responsiveness to α-adrenergic stimulation in patients with the 894T allele in the eNOS gene.
HbS/βdel-thalassemia associated with high levels of hemoglobins A2 and F in a Turkish family
Authors: G. O. Tadmouri, L. Yüksel, A. N. Başak
Journal: American Journal of Hematology (1998)

β-thalassemia and sickle cell disease (SCD) are common disorders in Turkey. Compound heterozygosity for these two disorders (βS/β-thalassemia) is encountered frequently. In this report we present hematological and molecular data of two Turkish siblings with βS/βdel-thalassemia caused by a 290 base pair (bp) deletion and associated with increased levels of hemoglobin A2 (HbA2) and hemoglobin F (HbF). Clinical analysis of the two patients showed a mild course of the disease. Haplotypic factors involved in increasing the levels of HbF were analyzed. The two patients showed no changes from the normal sequences at the XmnI site of Gγ-globin promoter and the (AT)xTy microsatellite 5′ to the β-globin mRNA cap site. The removal of the region between positions −125 to +78 relative to the β-globin gene mRNA cap site by the 290 bp deletion is thought to allow the β-locus control region to interact with the promoters of the δ- and γ-globin genes, leading to increased HbA2 and HbF levels. Am. J. Hematol. 59:83–86, 1998. © 1998 Wiley-Liss, Inc.
Phosphoinositide signalling and cardiac arrhythmias
Authors: E. A. Woodcock, P. M. Kistler, Y.-K. Ju
Journal: Cardiovascular Research (2008)

Arrhythmias arise from a complex interaction between structural changes in the myocardium and changes in cellular electrophysiology. Electrophysiological balance requires precise control of sarcolemmal ion channels and exchangers, many of which are regulated by phospholipid, phosphatidylinositol(4,5)bisphosphate. Phosphatidylinositol(4,5)bisphosphate is the immediate precursor of inositol(1,4,5)trisphosphate, a regulator of intracellular Ca2+ signalling and, therefore, a potential contributor to arrhythmogenesis by altering Ca2+ homeostasis. The aim of the present review is to outline current evidence that this signalling pathway can be a player in the initiation or maintenance of arrhythmias.
Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury
Authors: Liping Wu, Neriman Gokden, Philip R. Mayeux
Journal: Journal of the American Society of Nephrology (2007)

Acute kidney injury (AKI) remains a frequent and serious complication of human sepsis that contributes significantly to mortality. For better understanding of the development of AKI during sepsis, the cecal ligation and puncture (CLP) murine model of sepsis was studied using intravital video microscopy (IVVM) of the kidney. IVVM with FITC-dextran was used to determine the percentage of capillaries with continuous, intermittent or no flow at 0 (sham), 10, 16, and 22 h after CLP. There was a dramatic fall in capillary perfusion as early as 10 h after CLP that persisted through 22 h. The percentage of vessels with continuous flow at 16 h decreased from 73 +/- 2% in shams to 16 +/- 2% (P < 0.05), whereas the percentage of vessels with no flow increased from 4 +/- 1% in shams to 42 +/- 2% (P < 0.05). The capillary perfusion defect preceded the rise in serum creatinine. IVVM with dihydrorhodamine-123 was used to quantify in real time reactive nitrogen species (RNS) generation by renal tubules, and the inducible nitric oxide synthase inhibitor L-iminoethyl-lysine (mg/kg) was used to examine the role of inducible nitric oxide synthase inhibitor on capillary dysfunction and RNS generation. Tubular generation of RNS was significantly elevated at 10 h after CLP and was associated with tubules that were bordered by capillaries with reduced perfusion. L-iminoethyl-lysine significantly reversed the capillary perfusion defect, blocked RNS generation, and reduced AKI. These data show that capillary dysfunction and RNS generation contribute to tubular injury and suggest that RNS should be considered a potential therapeutic target in the treatment of sepsis-induced AKI.
Mucus clearance devices in bronchiectasis: Indian experience
Authors: Mandar Kubal, Kavita Mody
Journal: European Respiratory Journal (2013)

Introduction: Mucus accumulation contributes to recurrent respiratory infections in bronchiectasis.

Aim: To study the impact of mucus clearance device (Lung FluteTM) in addition to breathing exercises and postural drainage in patients of bronchiectasis.

Methods: 50 patients of post infective bronchiectasis were divided into two groups of 25. Group A was taught deep breathing exercises and postural drainage, while group B was told to use mucus clearance device (Lung Flute) in addition. Infective exacerbations, additional clinic visits, need for antibiotics, severity of episode and loss of working days were evaluated at the end of 6 months.

Results: The group B had on an average fewer infective exacerbations (1 vs 3) than group A. Parallel to the same, there were few additional visits to the clinic by group B patients (1 vs 3). Group B patients lost on an average fewer days at work (2 days) versus group A (8 days). Group B patients also had no serious respiratory infection requiring hospitalization as compared to group A (average 1 hospitalization). Group A patients had a casual attitude towards deep breathing exercises and postural drainage. Many missed their daily exercise schedule. Similar defaults were observed in Group B patients, but they were surprisingly compliant with the mucus clearance device. Average cost of device (35 - 50 US$) was very nominal compared to the cost of hospitalization due to infection (200 - 300 US$).

Conclusion: Patient acceptance of mucus clearance devices is good. Patients tend to use these technical devices regularly and with seriousness as compared to breathing exercises and postural drainage. Physicians and physiotherapists should encourage use of such devices in addition to routine therapy.
Effect of Warfarin on Survival in Small Cell Carcinoma of the Lung
Authors: Leo R. Zacharski
Journal: JAMA (1981)

In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.
A training culture in surgery
Authors: D. H Hargreaves
Journal: BMJ (1996)

The coincidence of the Calman reforms on the training of junior doctors with the reduction in their hours means that the quality and quantity of training must be improved."Train the trainer" courses are one obvious way of enhancing consultants' teaching skills.An improved capacity to train does not, however, always lead to changed practices.Trained consultants have more confidence about training, but colleagues lacking this preparation may be sceptical of, feel threatened by, or become resistant to new ideas or practices.So trained consultants may keep newly acquired skills to themselves or even revert to former attitudes and practices.Junior doctors value on the job training very highly.Yet research has shown that their experience of training is often bleak, and the relation between training and service delivery is seen as unsatisfactory.'By contrast, in * Step 1: trainee observes