tbuckley/cabot-search huggingface dataset:
T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex
Authors: Masakatsu Yamashita, Makoto Katsumata, Makio Iwashima, Motoko Kimura, Chiori Shimizu, Tohru Kamata, Tahiro Shin, Nobuo Seki, Seiichi Suzuki, Masaru Taniguchi, Toshinori Nakayama
Journal: The Journal of Experimental Medicine (2000)

The activation of downstream signaling pathways of both T cell receptor (TCR) and interleukin 4 receptor (IL-4R) is essential for T helper type 2 (Th2) cell development, which is central to understanding immune responses against helminthic parasites and in allergic and autoimmune diseases. However, little is known about how these two distinct signaling pathways cooperate with each other to induce Th2 cells. Here, we show that successful Th2 cell development depends on the effectiveness of TCR-induced activation of calcineurin. An inhibitor of calcineurin activation, FK506, inhibited the in vitro anti-TCR–induced Th2 cell generation in a dose-dependent manner. Furthermore, the development of Th2 cells was significantly impaired in naive T cells from dominant-negative calcineurin Aα transgenic mice, whereas that of Th1 cells was less affected. Efficient calcineurin activation in naive T cells upregulated Janus kinase (Jak)3 transcription and the amount of protein. The generation of Th2 cells induced in vitro by anti-TCR stimulation was inhibited significantly by the presence of Jak3 antisense oligonucleotides, suggesting that the Jak3 upregulation is an important event for the Th2 cell development. Interestingly, signal transducer and activator of transcription (STAT)5 became physically and functionally associated with the IL-4R in the anti-TCR–activated developing Th2 cells that received efficient calcineurin activation, and also in established cloned Th2 cells. In either cell population, the inhibition of STAT5 activation resulted in a diminished IL-4–induced proliferation. Moreover, our results suggest that IL-4–induced STAT5 activation is required for the expansion process of developing Th2 cells. Thus, Th2 cell development is controlled by TCR-mediated activation of the Ca2+/calcineurin pathway, at least in part, by modifying the functional structure of the IL-4R signaling complex.
Medicine in Europe: Complementary medicine in Europe
Authors: P. Fisher, A. Ward
Journal: BMJ (1994)

Complementary or unconventional treatments are used by many doctors and other therapists throughout Europe. The major forms are acupuncture, homoeopathy, manual therapy or manipulation, and phytotherapy or herbal medicine. The relative popularity of therapies differs between countries, but public demand is strong and growing. Regulation of practitioners varies widely: in most countries only registered health professionals may practice, but in the United Kingdom practice is virtually unregulated. Germany and some Scandinavian countries have intermediate systems. Legal reforms are in progress in the Netherlands and the United Kingdom. European institutions are starting to influence the development of complementary medicine. Harmonisation of training and regulation of practitioners is the challenge for the future.
An Experiment in Medical Education
Authors: Larry J. Goodman, Erich E. Brueschke, Roger C. Bone, William H. Rose, E. Jane Williams, Harold A. Paul
Journal: JAMA (1991)

In 1984, in addition to its standard traditional curriculum, Rush Medical College (Chicago, Ill) developed a Socratic problem-based method of teaching basic science material called the alternative curriculum. As part of an evaluation of this new curriculum, students in the two curricula were compared using three traditional measurements: (1) test scores from the National Board of Medical Examiners, Part I; (2) test scores from the National Board of Medical Examiners, Part II; and (3) performance on an oral examination. Alternative curriculum students did not differ significantly from their traditional curriculum classmates on National Board of Medical Examiners, Part I and Part II total scores, although their subset scores on Part I did tend to be lower, reaching significance in one subset area. Differences in performance favoring the traditional curriculum were primarily seen in the early years of the program. Alternative curriculum students in the class matriculated in 1987 scored significantly higher in three of five categories on the oral examination. (<i>JAMA</i>. 1991;265:2373-2376)
Surgeons warn about trusts' rationing of crucial operations
Authors: A. O'Dowd
Journal: BMJ (2011)

Surgeons have warned that primary care trusts in England are rationing surgical procedures to save money.

The Federation of Surgical Specialty Associations (FSSA) has written an open letter to the Guardian claiming that trusts are using lists of surgical procedures and interventions that are deemed to be of low clinical effectiveness or of “lower value” to limit access to procedures such as spinal, bariatric, dental, cancer, and ear, nose, and throat surgery, and hip replacements, “for which there is overwhelming evidence of benefit” (www.guardian.co.uk/society/2011/apr/18/open-letter-federation-surgical).

The letter does, however, admit that some procedures may be of low value and mentions that members are already working with the Department of Health “to determine what, if any, surgical procedures should be limited on the NHS.” …
Are There Differences Between Women’s and Men’s Antidepressant Responses?
Authors: Frederic M. Quitkin, Jonathan W. Stewart, Patrick J. McGrath, Bonnie P. Taylor, Mayra S. Tisminetzky, Eva Petkova, Ying Chen, Guoguang Ma, Donald F. Klein
Journal: American Journal of Psychiatry (2002)

The study examined a large data set to determine whether patients' sex affected the outcome of antidepressant treatment.Data for 1,746 patients aged 18-65 years who had been treated with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), fluoxetine, or placebo were examined in a retrospective analysis to determine whether men and women differed in their responses to antidepressants. To examine the effect of menopausal status in the absence of data on individual patients' menopausal status, results for female patients younger or older than age 50, 52, 54, and 56 were compared.Men and women both younger and older than age 50 had equivalent response rates to tricyclics and fluoxetine. Women had a statistically superior response to MAOIs. Placebo response was equivalent across all groups.Neither sex nor menopausal status may be relevant in antidepressant treatment of adult depressed patients up to 65 years of age. Although women had a statistically superior response to MAOIs, this difference may not be clinically relevant.
Release of different relaxing factors by cultured porcine endothelial cells.
Authors: C Boulanger, H Hendrickson, R R Lorenz, P M Vanhoutte
Journal: Circulation Research (1989)

Experiments were performed to determine the effect of ouabain on the release of relaxing factor(s) from cultured endothelial cells, and its action on the effect of the relaxing factor(s) on arterial smooth muscle. A column of porcine aortic endothelial cells grown on microcarrier beads in suspension culture was perfused with modified Krebs-Ringer bicarbonate solution. The release of relaxing factor(s) by the endothelial cells was detected under bioassay conditions by measuring the relaxing activity of the perfusate overflowing a ring of canine coronary artery (without endothelium) contracted with prostaglandin F2 alpha. Incubation of the endothelial cells with ouabain did not affect the relaxation of the bioassay ring under basal conditions or upon stimulation of the endothelial cells with ADP but impaired the relaxation induced by bradykinin or the calcium ionophore A23187. Incubation of the bioassay ring with ouabain reduced the relaxation under basal conditions as well as the relaxation induced by ADP but did not affect the relaxation observed upon stimulation with bradykinin and A23187 and the endothelium-independent relaxations induced by nitric oxide. These experiments suggest that cultured porcine aortic endothelial cells release two endothelium-derived relaxing factors; one is released under basal conditions and upon stimulation with adenosine diphosphate and the other (which presumably is nitric oxide) upon stimulation with bradykinin and the calcium ionophore A23187.
Association of Loop Diuretic Use With Higher Parathyroid Hormone Levels in Patients With Normal Renal Function
Authors: Kristin M. Corapi, Gearoid M. McMahon, Julia B. Wenger, Julian L. Seifter, Ishir Bhan
Journal: JAMA Internal Medicine (2014)

Elevations in parathyroid hormone (PTH) level have been associated with adverse clinical outcomes, including cardiovascular disease and mortality.1,2 Loop diuretics have been linked to increased PTH levels in patients with chronic kidney disease (CKD),3,4 but this association has not been investigated in the general population. We used data from the National Health and Nutrition Examination Survey (NHANES)5,6 to test the hypothesis that loop diuretic use associates with elevated PTH in adults with preserved renal function.
Small Doses of Prednisolone in the Management of Rheumatoid Arthritis
Authors: J. R. de Andrade, J. N. McCormick, A. G. S. Hill
Journal: Annals of the Rheumatic Diseases (1964)

Throughout its15-year history thetreatment of rheumatoid arthritis withcorticosteroids haspresented clinicians withasuccession ofdiffering aspects -first abrief flash ofhopethat mostoftheproblems ofthedisease hadbeensolved, thenasombre picture ofimpermanent benefit bought attoogreat acost in terms ofundesirable effects, andlast amorebalanced sceneoflimited objectives andgreatly reduced dangers. Thedoseofcortisone empirically chosen fortheearliest clinical trials (Hench, Kendall, Slocumb andPolley, 1949) wascommonly 100mg./ day,equivalent toabout20 mg.prednisolone. Prolongation oftreatment atthis level ofadministration soonrevealed theadverse effects which induced manyclinicians toabandontheuseof corticosteroids entirely andothers toaccept theless complete control ofthedisease butgreater safety offered bysmaller doses, and6years later Polley, Slocumb, Ward,andHench(1955) recommended
Molecular probes of phylogeny and biogeography in toads of the widespread genus Bufo.
Authors: L R Maxson
Journal: Molecular Biology and Evolution (1984)

Genetic relationships among 25 species of Central and South American Bufo and among representative North, Central, and South American, Asian, and African Bufo were probed, using the quantitative immunological technique of microcomplement fixation (MC'F) which indicated a clear separation of North, Central, and South American lineages of Bufo. The South American lineage likely diverged from the Central and North American lineages in the Eocene; the latter two lineages diverged later, probably in the mid-Oligocene. Some species groups of South American toads, defined on the basis of traditional morphological studies, are genetically quite similar within groups, whereas others are genetically divergent. The amount of albumin evolution does not appear to parallel the amount of karyotypic, morphological, ecological, or behavioral evolution documented. Comparisons suggest that the African lineages separated from the American and Asian lineages in the late Cretaceous, corresponding to the time of the final separation of Gondwanaland, the southern supercontinent including the modern continents of South America, Africa, Australia, Antarctica, and India. The Asian lineages diverged from the lineage giving rise to all of the American species in the early Paleocene.
The Effect of an Aldose Reductase Inhibiting Agent on Limited Joint Mobility in Diabetic Patients
Authors: R. Philip Eaton
Journal: JAMA (1985)

Improvement in range of motion and in strength of digital flexion and extension is reported in three diabetic subjects with the syndrome of limited joint mobility. Therapy was accomplished with sorbinil, an inhibitor of the enzyme aldose reductase, which inhibits the polyol pathway. We propose that reduction in collagen hydration secondary to reduced tissue content of polyols may participate in the clinical response.
Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin
Authors: Ira M. Jacobson, Patrick Marcellin, Stefan Zeuzem, Mark S. Sulkowski, Rafael Esteban, Fred Poordad, Savino Bruno, Margaret H. Burroughs, Lisa D. Pedicone, Navdeep Boparai, Weiping Deng, Mark J. DiNubile, Keith M. Gottesdiener, Clifford A. Brass, Janice K. Albrecht, Jean-Pierre Bronowicki
Journal: Hepatology (2012)

In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR.Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.
Bile reflux gastritis and intestinal metaplasia at the cardia
Authors: M F Dixon
Journal: Gut (2002)

<b>Background and aims:</b> Intestinal metaplasia (IM) at the cardia is likely to be a precursor of cardia cancer. Previous work has shown that it is associated with chronic inflammation attributable to either gastro-oesophageal reflux disease (GORD) or <i>Helicobacter pylori</i> infection. An alternative aetiological factor is bile reflux. Duodenogastric reflux brings about histological changes in the gastric mucosa that can be graded and used to calculate a bile reflux index (BRI). We used the BRI to assess whether reflux of bile plays a part in the development of cardia IM. <b>Methods:</b> Histological changes in simultaneous gastric antrum and cardia biopsies from 267 dyspeptic patients were independently graded by two pathologists. The association between cardia IM and age, sex, clinical group, <i>H pylori</i> status, increased BRI (&gt;14), and inflammation at the cardia were evaluated using logistic regression. <b>Results:</b> A total of 226 patients had adequate cardia and antral biopsies; 149 had GORD and 77 had non-ulcer dyspepsia. Cardia IM was present in 66 (29%) patients, of whom 28 (42%) had complete IM. Increasing age, male sex, chronic inflammation, and a high BRI emerged as significant independent associations with cardia IM. Clinical group and <i>H pylori</i> status were not independent risk factors. <b>Conclusions:</b> Histological evidence of bile reflux into the stomach is associated with cardia IM. This could have an important bearing on carcinogenesis at this site.
Time course of recovery of health status following an infective exacerbation of chronic bronchitis
Authors: S Spencer
Journal: Thorax (2003)

The magnitude and time course of effect of an acute exacerbation of chronic bronchitis (AECB) on health status are not known. Data from the GLOBE study, a randomised double blind trial of antibiotic therapy, were used to investigate these effects.438 patients with AECB received either gemifloxacin 320 mg once daily for 5 days (214 patients) or clarithromycin 500 mg twice daily for 7 days (224 patients) and were followed up for 26 weeks. St George's Respiratory Questionnaire (SGRQ) scores were obtained at baseline and after 4, 12, and 26 weeks.At presentation during an exacerbation SGRQ scores were worse (Total score difference 5.4 units, 95% CI 1.9 to 8.8, p=0.002) in patients who had a subsequent exacerbation during follow up. The greatest improvement in SGRQ score occurred within the first 4 weeks (mean 8.9 units, 95% CI 6.5 to 11.5, p<0.0001). Subsequently, scores improved more rapidly in patients with no further exacerbations. At 26 weeks the difference between the two groups was 9.6 units (95% CI 5.7 to 13.4, p<0.0001). In patients with no further exacerbations the SGRQ score improved between 4 and 12 weeks by a further 4.1 units (95% CI 2.2 to 5.9, p<0.0001).A single infective AECB has a sustained effect on health status. The recovery period is long even in patients who have no further exacerbations. A second episode within 6 months limits recovery markedly. Treatments that reduce exacerbation frequency could have a significant impact on health status.
Deficiency of the autologous mixed lymphocyte reaction in patients with classic hemophilia treated with commercial factor VIII concentrate. Correlation with T cell subset distribution, antibodies to lymphadenopathy-associated or human T lymphotropic virus, and analysis of the cellular basis of the deficiency.
Authors: J S Smolen, P Bettelheim, U Köller, S McDougal, W Graninger, T A Luger, W Knapp, K Lechner
Journal: Journal of Clinical Investigation (1985)

14 patients with hemophilia were studied for the distribution of T cell subsets, the presence of antibody to lymphadenopathy-associated or human T lymphotropic virus type III (LAV/HTLV-III), and their responsiveness in autologous mixed lymphocyte reactions. In addition, mitogen and alloantigen responsiveness and Interleukin-2 production were investigated. Seven patients were found to have low Leu 3a/Leu 2a (T4/T8) ratios; eight patients had antibody to LAV/HTLV-III; and an additional patient had acquired immunodeficiency syndrome. Responsiveness to mitogens and alloantigens as well as Interleukin-2 production were comparable with those of healthy individuals. However, patients with low ratio, many of whom had antibodies to LAV/HTLV-III, had a highly deficient autologous mixed lymphocyte reaction. This reduced response of T cells to autologous non-T cells could not be corrected by elimination of Leu 2a/T8 cells, which indicated that there was a preferential loss of the Leu 3a cell subset(s) which responded to autologous non-T cells. Thus, these patients have a deficiency of intercellular communication within their immune system.
S2 Multi-drug Resistant Tuberculosis (MDR-TB) treatment in the UK: a survey of injectable use and toxicity in practice
Authors: A. Sturdy, A. Goodman, R. J. Jose, A. Loyse, M. O'Donoghue, O. M. Kon, M. J. Dedicoat, T. Harrison, L. John, M. Lipman, G. Cooke
Journal: Thorax (2010)

<h3>Rationale</h3> Recent discoveries in human genetics have identified mitochondrial mutations which confer a high risk of sensorineural deafness in individuals exposed to aminoglycosides. Successful MDR-TB treatment often requires prolonged use of these agents. There are little data from the UK to inform the use of genetic tests within MDR-TB patients. We set out to survey MDR-TB practice in the UK with an emphasis on injectable drug use, ototoxicity and audiological monitoring practice. <h3>Methods</h3> Five centres took part in a retrospective study of patients initiating injectable treatment for MDR-TB between 1 January 2004 and 31 December 2009. Data were collected regarding patient characteristics, choice of injectable, methods and frequency of ototoxicity screening and incidence of drug-related complications. <h3>Results</h3> Treatment for 50 MDR-TB patients was reviewed. 29/50 (58%) patients received amikacin, 11/50 (22%) capreomycin, 4/50 (8%) streptomycin and 6/50 (12%) more than one injectable. Three centres used amikacin as their preferred injectable, two used capreomycin. Audiological screening for ototoxicity was variable. 21/50 (42%) patients received baseline screening within 2 weeks of starting an injectable. 16/50 (32%) patients went on to have monthly audiograms, with the majority screened more infrequently or if symptoms were reported. 12/50 (24%) patients received no screening at any point. Ototoxicity was defined as a 20 dB loss from baseline on audiogram at one test frequency, or a 10 dB loss at two adjacent frequencies, or in the absence of a baseline result, as two or more frequencies below 20 dB. If no audiograms were available, the definition was symptomatic. 14/50 (28%) of patients experienced ototoxicity, with 9/50 (18%) left with persistent hearing loss. Increased age (p=0.02), use of amikacin (p=0.02) and decreased renal function on therapy (p=0.01) were significantly associated with ototoxicity (see Abstract S2 Table 1). No centre routinely tests for mitochondrial DNA mutations. <h3>Conclusions</h3> There is local variation in both choice of injectable agent and in ototoxicity screening practices between the MDR treatment centres studied. The data suggest capreomycin might be associated with less ototoxicity when compared to amikacin. There are no UK guidelines to inform best practice and better evidence, including clinical and cost-effectiveness studies, is needed to inform the implementation of current technology including genetic testing.
Malignant tγ/δ lymphoproliferative disease with natural killer lytic activity
Authors: Roberto P. Falcão, Julio C. Voltarelli, Belinda P. Simões, Denise N. R. Pestana, Marco A. Zago, Mauro S. Figueiredo
Journal: American Journal of Hematology (1992)

Abstract A 17‐year‐old girl presented with a lymphoproliferative disease involving the bone marrow, peripheral blood, and liver associated with reactive hyperplasia of the spleen. Neoplastic cells were atypical medium‐sized lymphoblasts with convoluted nuclei and nucleoli without features of large granular lymphocytes (LGL). The phenotype was CD3 + CD4 ‐ CD8 ‐ , TCRα/β ‐ , TCRγ/δ + , δTCS1 ‐ . and CD16 + , and these cells exhibited spontaneous natural killer (NK) activity. DNA analysis showed rearrangement of the TCRγ gene but not of TCRβ or of lg μ genes. This unusual lymphoproliferative disease may represent the neoplastic expansion of a minor subset of normal Tγ/δ cells with NK activity. © 1992 Wiley‐Liss, Inc.