tbuckley/cabot-search huggingface dataset:
The in vitro generation and sustained culture of nude mouse cytolytic T-lymphocytes.
Authors: S Gillis, N A Union, P E Baker, K A Smith
Journal: The Journal of Experimental Medicine (1979)

In addition to allowing for the long-term culture of both murine and human cytolytic T lymphocytes, T-cell growth factor (TCGF) functions as the key proliferation-inducing second signal in both T-cell antigen sensitization and mitogenesis. The observation that thymocytes responded normally to T-cell mitogens in the presence of TCGF, prompted the investigation of the effect of TCGF on nude mouse lymphocyte responses in vitro. We found that spleen, lymph node, and bone marrow cells, isolated from nude mice, were incapable of producing TCGF yet responded normally to T-cell mitogen sensitization provided stimulation was conducted in the presence of TCGF. Nude mouse spleen cells were also capable of responding to alloantigen sensitization in mixed lymphocyte cultures (NLMC) conducted in the presence of TCGF. Thy-1 antigen-positive cells harvested from TCGF-supplemented nude mouse MLC effectively mediated the cytolysis of alloantigen-specific target cells as tested in standard 51Cr-release assays. Cytolytic nude mouse effector cells have remained in TCGF-dependent culture for over 3 mo during which they have continued to mediate significant levels of alloantigen-specific cytolytic reactivity. These results suggest that prothymocytes present in nude mice are capable of responding to immunologic stimuli by differentiating, in vitro, into cytolytic T lymphocytes and that furthermore, a major function of the thymus may be to effect the maturation of TCGF-producing cells.
Caerulein induced plasma amino acid decrease: a simple, sensitive, and specific test of pancreatic function.
Authors: L Gullo, R Pezzilli, M Ventrucci, L Barbara
Journal: Gut (1990)

We measured total plasma amino acid concentrations before and during pancreatic stimulation with secretin (1 clinical unit/kg/h) and caerulein (50 ng/kg/h) in 28 healthy volunteers, 60 patients with chronic pancreatitis (25 mild to moderate, 35 severe), and 22 patients with non-pancreatic digestive disease. In the healthy volunteers and patients with non-pancreatic digestive disease pancreatic stimulation caused a significant decrease (p less than 0.001) in plasma amino acid concentration, whereas in patients with chronic pancreatitis the decrease did not occur or was only slight. In six healthy volunteers and 24 patients with chronic pancreatitis (nine mild to moderate, 15 severe) repetition of the test using caerulein alone showed no significant differences from combined stimulation. Using the maximal per cent decrease in plasma amino acid concentration as an index of pancreatic function (lower normal limit 14%), 20 of the 25 patients with mild to moderate pancreatitis (80%) and 32 of the 35 with severe pancreatitis (91.4%) had values clearly below normal. The overall sensitivity of the test (86.7%) was significantly greater than that of the pancreolauryl test (64.2%) (p less than 0.02) and that of faecal chymotrypsin (66%) (p less than 0.05). None of the patients with non-pancreatic digestive disease had abnormal values. We conclude that the assessment of the decrease in the plasma amino acid concentration during pancreatic stimulation with secretin and caerulein is a simple, sensitive, and highly specific test of pancreatic function. The data obtained using caerulein stimulation alone suggest that the test can be further simplified, and made less costly, by eliminating the use of secretin.
A Cluster-Randomized, Controlled Trial of a Simplified Multifaceted Management Program for Individuals at High Cardiovascular Risk (SimCard Trial) in Rural Tibet, China, and Haryana, India
Authors: Maoyi Tian, Vamadevan S. Ajay, Danzeng Dunzhu, Safraj S. Hameed, Xian Li, Zhong Liu, Cong Li, Hao Chen, KaWing Cho, Ruilai Li, Xingshan Zhao, Devraj Jindal, Ishita Rawal, Mohammed K. Ali, Eric D. Peterson, Jiachao Ji, Ritvik Amarchand, Anand Krishnan, Nikhil Tandon, Li-Qun Xu, Yangfeng Wu, Dorairaj Prabhakaran, Lijing L. Yan
Journal: Circulation (2015)

In rural areas in China and India, the cardiovascular disease burden is high but economic and healthcare resources are limited. This study (the Simplified Cardiovascular Management Study [SimCard]) aims to develop and evaluate a simplified cardiovascular management program delivered by community health workers with the aid of a smartphone-based electronic decision support system.The SimCard study was a yearlong cluster-randomized, controlled trial conducted in 47 villages (27 in China and 20 in India). Recruited for the study were 2086 individuals with high cardiovascular risk (aged ≥40 years with self-reported history of coronary heart disease, stroke, diabetes mellitus, and/or measured systolic blood pressure ≥160 mm Hg). Participants in the intervention villages were managed by community health workers through an Android-powered app on a monthly basis focusing on 2 medication use and 2 lifestyle modifications. In comparison with the control group, the intervention group had a 25.5% (P<0.001) higher net increase in the primary outcome of the proportion of patient-reported antihypertensive medication use pre- and post-intervention. There were also significant differences in certain secondary outcomes: aspirin use (net difference: 17.1%; P<0.001) and systolic blood pressure (-2.7 mm Hg; P=0.04). However, no significant changes were observed in the lifestyle factors. The intervention was culturally tailored, and country-specific results revealed important differences between the regions.The results indicate that the simplified cardiovascular management program improved quality of primary care and clinical outcomes in resource-poor settings in China and India. Larger trials in more places are needed to ascertain the potential impacts on mortality and morbidity outcomes.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01503814.
Prevention of Diabetic Ketoacidosis
Authors: Stewart Wolf
Journal: JAMA (1980)

To the Editor.—  The article Prevention of Diabetic Ketoacidosis by Schade and Eaton (242:2455, 1979) in the TRENDS IN THERAPY section emphasizes the importance of stress in the pathogenesis of diabetic ketoacidosis. In describing the triggering of the anterior pituitary secretions responsible for the phenomenon, the only stresses the authors identify are infection, fever, and dehydration. They thereby ignore the role of emotional stress, which was carefully documented 30 years ago in a series of articles by Hinkle and associates. 1-5 In fact, Hinkle and his co-workers were able to observe the appearance of ketosis in a hospitalized patient during a serious emotional conflict, while insulin dosage, diet, and exercise were held constant. 1 Therefore, the preventive advice of Schade and Eaton should have included awareness of psychosocial stresses as well as the early signs of infection.
S27 The effects of statin therapy on inflammatory markers in patients with copd: a double blind randomised controlled trial
Authors: M John, AJ Knox, TM McKeever, G Meakin, H Bailey, JR Cockcroft, DJ Shale, TW Harrison, CE Bolton
Journal: Thorax (2013)

<h3>Background</h3> Systemic and airway inflammation are recognised in COPDand reducing inflammation has been postulated to alter disease course<sup>1</sup>. Statins have pleiotropic effects including anti-inflammatory properties<sup>2</sup>. A study in asthma showed that statins reduced sputum macrophage levels<sup>3</sup>. We hypothesised that statins would reduce systemic (hs-CRP) and airway (exhaled nitric oxide: FeNO, sputum neutrophils and macrophages) inflammation in patients with COPD. <h3>Methods</h3> Clinically stable patients with confirmed COPD were recruited and randomised to either simvastatin 20mg od (active) or placebo for 6 weeks in a double blinded parallel group randomised controlled trial. Circulating hs-CRP and fasting lipids were measured in all subjects' pre- and post- treatment. 5-flow FeNO and induced sputum were performed in consenting patients where possible pre- and post-treatment. Primary analysis compared the six week change in each inflammatory marker between active and placebo groups. <h3>Results</h3> Patients were matched for age, sex, smoking and lung function; active: n = 33, placebo: n = 37. Compliance was good and the active group achieved total cholesterol reduction: between arms mean (95% CI): -1.1 (-1.3, -0.8)mmol/L, p &lt; 0.001. Baseline median (IQR) hs-CRP was 3.09 (1.3–7.4)mg/l but there was no significant change after treatment between active and placebo: between arms mean (95% CI) 0.5(-3.2, 4.1)mg/l. Baseline sputum samples were obtained in n = 27 and 22/27 had neutrophilic sputum. Paired samples were obtained in 20 patients: active n = 8 and placebo n = 12 with no significant difference in change between treatment arms for sputum neutrophils or macrophages. FeNO was measured in 36 patients: active n = 17, placebo n = 19 with no significant difference in change between arms. <h3>Conclusions</h3> In this pilot RCT, despite significant lipid lowering, there was no demonstrable systemic or airway anti-inflammatory effect over 6 weeks with simvastatin 20mg od in patients with COPD. Baseline results showed a majority had neutrophilic sputum however only a small proportion had airway inflammation evaluation. Trial reference: NCT01151306 Supported by NIHR RfPB grant <h3>References</h3> Sin, DD, <i><i><i>et al</i></i></i>. <i>AJRCCM</i> 2004;170:760–765 Walsh, G. M <i>Expert Review of Respiratory Medicine</i> 2008;2(3):329–335 Hothersall, EJ, <i>et al.</i>, <i>Thorax</i> 2008;63(12):1070–5
Regulation of Elastinolytic Cysteine Proteinase Activity in Normal and Cathepsin K–Deficient Human Macrophages
Authors: Antonello Punturieri, Sergey Filippov, Edward Allen, Ingrid Caras, Richard Murray, Vivek Reddy, Stephen J. Weiss
Journal: The Journal of Experimental Medicine (2000)

Human macrophages mediate the dissolution of elastic lamina by mobilizing tissue-destructive cysteine proteinases. While macrophage-mediated elastin degradation has been linked to the expression of cathepsins L and S, these cells also express cathepsin K, a new member of the cysteine proteinase family whose elastinolytic potential exceeds that of all known elastases. To determine the relative role of cathepsin K in elastinolysis, monocytes were differentiated under conditions in which they recapitulated a gene expression profile similar to that observed at sites of tissue damage in vivo. After a 12-d culture period, monocyte-derived macrophages (MDMs) expressed cathepsin K in tandem with cathepsins L and S. Though cysteine proteinases are acidophilic and normally confined to the lysosomal network, MDMs secreted cathepsin K extracellularly in concert with cathepsins L and S. Simultaneously, MDMs increased the expression of vacuolar-type H+-ATPase components, acidified the pericellular milieu, and maintained extracellular cathepsin K in an active form. MDMs from a cathepsin K–deficient individual, however, retained the ability to express, process, and secrete cathepsins L and S, and displayed normal elastin-degrading activity. Thus, matrix-destructive MDMs exteriorize a complex mix of proteolytic cysteine proteinases, but maintain full elastinolytic potential in the absence of cathepsin K by mobilizing cathepsins L and S.
Crohn's disease: increased mortality 10 years after diagnosis in a Europe-wide population based cohort
Authors: F L Wolters
Journal: Gut (2005)

<b>Background:</b> No previous correlation between phenotype at diagnosis of Crohn's disease (CD) and mortality has been performed. We assessed the predictive value of phenotype at diagnosis on overall and disease related mortality in a European cohort of CD patients. <b>Methods:</b> Overall and disease related mortality were recorded 10 years after diagnosis in a prospectively assembled, uniformly diagnosed European population based inception cohort of 380 CD patients diagnosed between 1991 and 1993. Standardised mortality ratios (SMRs) were calculated for geographic and phenotypic subgroups at diagnosis. <b>Results:</b> Thirty seven deaths were observed in the entire cohort whereas 21.5 deaths were expected (SMR 1.85 (95% CI 1.30–2.55)). Mortality risk was significantly increased in both females (SMR 1.93 (95% CI 1.10–3.14)) and males (SMR 1.79 (95% CI 1.11–2.73)). Patients from northern European centres had a significant overall increased mortality risk (SMR 2.04 (95% CI 1.32–3.01)) whereas a tendency towards increased overall mortality risk was also observed in the south (SMR 1.55 (95% CI 0.80–2.70)). Mortality risk was increased in patients with colonic disease location and with inflammatory disease behaviour at diagnosis. Mortality risk was also increased in the age group above 40 years at diagnosis for both total and CD related causes. Excess mortality was mainly due to gastrointestinal causes that were related to CD. <b>Conclusions:</b> This European multinational population based study revealed an increased overall mortality risk in CD patients 10 years after diagnosis, and age above 40 years at diagnosis was found to be the sole factor associated with increased mortality risk.
Subcellular [Ca <sup>2+</sup> ] <sub>i</sub> Gradients During Excitation-Contraction Coupling in Newborn Rabbit Ventricular Myocytes
Authors: Peter S. Haddock, William A. Coetzee, Emily Cho, Lisa Porter, Hideki Katoh, Donald M. Bers, M. Saleet Jafri, Michael Artman
Journal: Circulation Research (1999)

Abstract —The central role of T-tubule and sarcoplasmic reticulum (SR) diadic junctions in excitation-contraction (EC) coupling in adult (AD) ventricular myocytes suggests that their absence in newborn (NB) cells may manifest as an altered EC coupling phenotype. We used confocal microscopy to compare fluo-3 [Ca 2+ ] i transients in the subsarcolemmal space and cell center of field-stimulated NB and AD rabbit ventricular myocytes. Peak systolic [Ca 2+ ] i occurred sooner and was higher in the subsarcolemmal space compared with the cell center in NB myocytes. In AD myocytes, [Ca 2+ ] i rose and declined with similar profiles at the cell center and subsarcolemmal space. Disabling the SR (10 μmol/L thapsigargin) slowed the rate of rise and decline of Ca 2+ in AD myocytes but did not alter Ca 2+ transient kinetics in NB myocytes. In contrast to adults, localized SR Ca 2+ release events (“Ca 2+ sparks”) occurred predominantly at the cell periphery of NB myocytes. Immunolabeling experiments demonstrated overlapping distributions of the Na + -Ca 2+ exchanger and ryanodine receptors (RyR2) in AD myocytes. In contrast, RyR2s were spatially separated from the sarcolemma in NB myocytes. Confocal sarcolemmal imaging of di-8-ANEPPS–treated myocytes confirmed an extensive T-tubule network in AD cells, and that T-tubules are absent in NB myocytes. A mathematical model of subcellular Ca 2+ dynamics predicts that Ca 2+ flux via the Na + -Ca 2+ exchanger during an action potential can account for the subsarcolemmal Ca 2+ gradients in NB myocytes. Spatial separation of sarcolemmal Ca 2+ entry from SR Ca 2+ release channels may minimize the role of SR Ca 2+ release during normal EC coupling in NB ventricular myocytes.
Diagnostic Performance of Noninvasive Fractional Flow Reserve Derived From Coronary Computed Tomography Angiography in Suspected Coronary Artery Disease
Authors: Bjarne L. Nørgaard, Jonathon Leipsic, Sara Gaur, Sujith Seneviratne, Brian S. Ko, Hiroshi Ito, Jesper M. Jensen, Laura Mauri, Bernard De Bruyne, Hiram Bezerra, Kazuhiro Osawa, Mohamed Marwan, Christoph Naber, Andrejs Erglis, Seung-Jung Park, Evald H. Christiansen, Anne Kaltoft, Jens F. Lassen, Hans Erik Bøtker, Stephan Achenbach
Journal: Journal of the American College of Cardiology (2014)
Association between childhood overweight measures and adulthood knee pain, stiffness and dysfunction: a 25-year cohort study
Authors: Benny Antony, Graeme Jones, Alison Venn, Flavia Cicuttini, Lyn March, Leigh Blizzard, Terence Dwyer, Marita Cross, Changhai Ding
Journal: Annals of the Rheumatic Diseases (2013)

To describe the associations between overweight measures in childhood and knee pain, stiffness and dysfunction among adults 25 years later.Subjects broadly representative of the Australian population (n=449, aged 31-41 years, female 48%) were selected from the Australian Schools Health and Fitness Survey of 1985. Height, weight and knee injury were recorded and knee pain was assessed using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Childhood height, weight and knee injury had been measured according to standard protocols 25 years earlier and body mass index (BMI) and percentage overweight were calculated.The prevalence of knee pain was 34% and overweight in childhood and adulthood was 7% and 48%, respectively. Overall, there were no significant associations between childhood overweight measures and total WOMAC knee pain, stiffness and dysfunction scores in adulthood. However, in men, overweight in childhood was associated with adulthood WOMAC pain (relative risk (RR) 1.72, 95% CI 1.11 to 2.69) and childhood weight and BMI were associated with WOMAC stiffness and dysfunction. Childhood weight, BMI and overweight were all associated with the presence of adulthood walking knee pain in men and the whole sample. Most of these associations were independent of adult overweight measures. Subjects who were overweight in both childhood and adult life had a significant increase in the risk and prevalence of adulthood walking pain (RR=2.42, 95% CI 1.06 to 5.53).Childhood overweight measures were significantly associated with adulthood knee mechanical joint pain, stiffness and dysfunction among men, independent of adult overweight, suggesting that childhood overweight may lead to later knee symptoms in men.
Mesenchymal stromal cells and the acute respiratory distress syndrome (ARDS): challenges for clinical application
Authors: J. E. Millar, J. F. Fraser, D. F. McAuley
Journal: Thorax (2015)

In contemporary reports, approximately 30% of patients with acute respiratory distress syndrome (ARDS) will die1 and up to 70% of survivors have persistent significant disability.2 Several interventions which limit injurious ventilation have been shown to reduce mortality, primarily: low-tidal volume ventilation,3 prone positioning,4 early neuromuscular blockade5 and possibly extracorporeal membrane oxygenation (ECMO).6 To date, no intervention targeted at the underlying pathophysiological process has been shown to be beneficial, including recent studies of β-agonists and statins.7 ,8

Given the failure of pharmacological interventions in ARDS, increasing interest has been shown in the potential of mesenchymal stromal cells (MSCs). While the complex actions of MSCs are not yet fully understood, they appear to attenuate lung injury via three broad mechanisms. First, they have an immunomodulatory ability, influencing both innate and adaptive immunity. This is achieved by the secretion of anti-inflammatory soluble factors, including interleukin 10 (IL-10), IL-1 receptor antagonist and prostaglandin E2.9 Second, MSCs directly augment the host response to sepsis. LL-37 is a peptide secreted by MSCs which has direct antimicrobial properties and has previously been shown to increase bacterial clearance in an Escherichia coli model of lung injury after the intratracheal administration of MSCs.10 Third, MSCs play an important role in the repair and regeneration of lung tissue following injury. This ability appears to be mediated by the secretion of several growth factors, including vascular endothelial growth factor and keratinocyte growth factor.9

In this edition of Thorax , Devaney et al …
IgE responses to exogenous and endogenous allergens in atopic dermatitis patients under long‐term systemic cyclosporine A treatment
Authors: S. Lucae, P. Schmid‐Grendelmeier, B. Wüthrich, D. Kraft, R. Valenta, B. Linhart
Journal: Allergy (2015)

Abstract Atopic dermatitis ( AD ) patients mount IgE antibody responses to a variety of environmental allergens and also to autoantigens. We analyzed serum samples from four AD patients who had received oral cyclosporine A (CyA) treatment for up to 17 months regarding IgE autoreactivity to nitrocellulose‐blotted human epithelial cell extracts and IgE levels to environmental allergens by quantitative ImmunoCap measurements. Skin inflammation was assessed by SCORAD . During full‐dose treatment, a strong reduction in T‐cell‐mediated skin symptoms was observed which reappeared when CyA treatment was reduced or stopped. The intensity of IgE autoreactivity seemed to follow skin inflammation as it was reduced during full‐dose treatment and increased upon inflammation. Interestingly, IgE levels to exogenous allergens were boosted by allergen exposure, declined thereafter, and seemed to be unaffected by CyA. Our data thus indicate that allergen‐specific IgE production is boosted by allergen contact and cannot be reduced by CyA‐mediated T‐cell suppression.
GABAergic System Gene Expression Predicts Clinical Outcome in Patients With Neuroblastoma
Authors: Stephen S. Roberts, Motomi Mori, Patrick Pattee, Jodi Lapidus, Ravi Mathews, Jean P. O'Malley, Yi Ching Hsieh, Mark A. Turner, Zhaohong Wang, Qi Tian, Matthew J. Rodland, C. Patrick Reynolds, Robert C. Seeger, Srinivasa R. Nagalla
Journal: Journal of Clinical Oncology (2004)

Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction.The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated.SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor-associated protein (GABARAP) gene expression predict decreased survival among all patients. GABA(A) delta receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABA(A) receptor subunits was identified (GABA(A) profile [GAP score]). Patients with a higher GAP score (> -1) had a survival advantage. Multivariate analysis showed that GABARAP and GABA(A) alpha2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators.Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.