tbuckley/cabot-search huggingface dataset:
DNA Variants in Region for Noncoding Interfering Transcript of <i>Dihydrofolate Reductase</i> Gene and Outcome in Childhood Acute Lymphoblastic Leukemia
Authors: Fidaa Al-Shakfa, Stphanie Dulucq, Ivan Brukner, Iva Milacic, Marc Ansari, Patrick Beaulieu, Albert Moghrabi, Caroline Laverdire, Stephen E. Sallan, Lewis B. Silverman, Donna Neuberg, Jeffery L. Kutok, Daniel Sinnett, Maja Krajinovic
Journal: Clinical Cancer Research (2009)

Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event-free survival correlated with haplotype *1, defined by A(-317) and C(-1610) alleles. Haplotype *1 was also associated higher DHFR expression.Here, we analyzed adjacent 400-bp region participating in DHFR regulation as both a major promoter and a noncoding minor transcript.Six polymorphisms were identified, of which five were single nucleotide polymorphisms and one was length polymorphism composed of variable number of 9-bp elements and 9-bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into five subtypes (*1a-*1e). DNA variations of major promoter/noncoding transcript region and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower event-free survival was associated with an A allele of G(308)A polymorphism (P = 0.02) and with *1b haplotype (P = 0.01). This association was particularly striking in high-risk patients (P = 0.001) and was subsequently confirmed in independent patient cohort (P = 0.02). Haplotype *1b was the only haplotype *1 subtype associated with higher mRNA levels.The study provides a new insight into DHFR regulatory variations predisposing to an event in ALL patients.
ANTIBIOTIC PROPHYLAXIS OF TRAVELLERS' DIARRHOEA IN ATHLETES:
Authors: M Rossiter
Journal: British Journal of Sports Medicine (2014)

Aims With the improved fitness and conditioning of athletes, the most common reason to miss training or competition, whilst abroad, is illness; especially Traveller's diarrhoea (TD) with an athlete potentially unable to compete for up to 3 days and after that not performing at optimum level for several more days. Results Venue Duration (weeks) Male Athletes Female Athletes Staff Prophylaxis (Male) Prophylaxis (Female) Prophylaxis (Staff) Cases of TD (Athletes) Cases of TD (Staff) Av Days missed Training Delhi (World Cup) 3 18 0 7 0 n/a 7 (Ciprofloxacin) 8 1 2 Delhi (Commonwealth Games) 3 20 18 14 0 0 12 (Ciprofloxacin) 10 Male 2 Female 3 (1 on Prophylaxis) 2 South Africa 3 18 0 7 20 (Rifaxamin) n/a 7 (Rifaxamin) (2 stopped due to side effects) 0 0 0 Malaysia 3 18 0 10 18 n/a 6 0 1 0 Methods Approaches to reduce TD include selecting clean food and bottled drinks, probiotics and Bovine colostrum. The fluroquinolones ( Ciprofloxacin ) have been the most effective both for prophylaxis and treatment of TD.1 2 However, in the athletic population there is a theoretical risk of tendon rupture with this class of drug. Therefore only non-athletes have used Ciprofloxacin as prophylaxis. Rifaxamin has poor bioavailability and is therefore poorly systemically absorbed thus acting locally in the intestine. As such, it has few side effects and a very low risk of tendon rupture due to its non-systemic absorption. There has only been one (very small) previous study on the use of Rifaxamin for TD.3 Historically, there has been a high incidence of TD in Hockey athletes when travelling to countries such as India, South Africa and Malaysia, not only from food but unclean water in the showers and on the pitch, on which they can dive and thus at risk of ingesting dirty water. Therefore Rifaxamin was trialled as TD prophylaxis as shown below: Conclusions The results show that the introduction of prophylactic Rifaxamin has produced a significant reduction in the number of cases of TD. Oral Rifaxamin is now routinely offered (and accepted) by Hockey teams travelling to countries with high risk of TD and the incidence has reduced to almost negligible levels, thus ensuring athletes, and staff, are available for training and matches more often. After 18 months, there have been no cases of tendon rupture, which has been the worry when taking oral Ciprofloxacin .
Goal-oriented treatment and combination therapy for pulmonary arterial hypertension
Authors: M. M. Hoeper, I. Markevych, E. Spiekerkoetter, T. Welte, J. Niedermeyer
Journal: European Respiratory Journal (2005)

Combination therapy may improve outcome in patients with severe pulmonary arterial hypertension (PAH). PAH patients were treated according to a goal-oriented therapeutic strategy. Patients who did not reach the treatment goals with monotherapy received combination treatment according to a predefined strategy, including bosentan, sildenafil and inhaled iloprost. Intravenous iloprost and lung transplantation were reserved for treatment failures. End points were overall survival, transplantation-free survival, and survival free from transplantation and intravenous prostanoid treatment. Between January 2002 and December 2004, 123 consecutive patients with PAH were treated according to the novel approach. Survival at 1, 2 and 3 yrs was 93.0, 83.1 and 79.9%, respectively, which was significantly better than the survival of a historical control group, as well as the expected survival. Compared to the historical control group, the use of combination treatment also significantly improved the combined end point of death, lung transplantation and need for intravenous iloprost treatment. In conclusion, a therapeutic approach utilising combinations of bosentan, sildenafil and inhaled iloprost in conjunction with a goal-oriented treatment strategy provides acceptable long-term results in patients with severe pulmonary arterial hypertension, and reduces the need for intravenous prostaglandin treatment and lung transplantation.
Bone Marrow Neovascularization, Plasma Cell Angiogenic Potential, and Matrix Metalloproteinase-2 Secretion Parallel Progression of Human Multiple Myeloma
Authors: Angelo Vacca, Domenico Ribatti, Marco Presta, Monica Minischetti, Monica Iurlaro, Roberto Ria, Adriana Albini, Federico Bussolino, Franco Dammacco
Journal: Blood (1999)
Heart rate variability response to submaximal exercise in children with cystic fibrosis
Authors: Vanessa Resqueti, Rêncio Florêncio, Silvia Brilhante, Illia Lima, Fernando Lavezzo, Guilherme Fregonezi
Journal: European Respiratory Journal (2012)

Background: Rehabilitation or physical activity can improve chronic respiratory disease as a Cystic Fibrosis. Nevertheless, because autonomic dysfunction is common in CF, heart control may be affected in response to exercise.

Objective: To assess the cardiac autonomic control using heart rate variability (HRV) analysis before and after a six-minute walking test (6MWT). Methods: We studied lung function at baseline and HRV before and after 6MWT in children's with CF and matched healthy control group. Results: Thirteen children in the CF group (6 male) mean age: 12±2.7 years, with obstructive disease (FEV1/FVC: 0.83±0.11, FEV1: 71.4±21 %pred) and 12 healthy children (6 male), mean age 11.4 ± 2.4 years, with normal lung function (FEV1/FVC: 0.93 ± 0.12, FEV1: 91.6 ± 17.4 %pred) were evaluated. Baseline HRV was different between CF and CG in LFnu: 53.18 ± 15.01 vs. 32.79 ±7.91, p = 0.0003; HF%: 25.45 ± 18.43 vs. 53 ± 9.56, p = 0.0018; HFnu: 47.32±14.68 vs. 68.34 ± 8.67, p<0.0019; and LF/HF: 1.25 ± 0.72 vs. 0.49 ± 0.18, p < 0.0066. After the 6MWT was observed significant differences between groups for LF(m/s2): 846.69 ± 754.81 vs. 345.58 ± 197.18, p=0.027; LF%: 35.44 ± 8.06 vs. 25.88 ± 6.20, p=0.0024; LFnu: 60.04 ± 16.27 vs. 34.9 ± 8.71, p<0.0001; HF%: 27.42 ± 13.73 vs. 48.13 ± 6,33, p=0.0003; HFnu: 40.45 ±15.8 vs. 65.59 ± 8.18, p =0.0003; and LF/HF: 1.9 ± 1.7 vs. 0.53 ± 0.21, p=0.0001. Conclusion: Children with CF had higher sympathetic drive at baseline and after a submaximal exercise test compared to the CG, suggesting a sympatho-vagal dysfunction.
Programmed Necrosis in the Cross Talk of Cell Death and Inflammation
Authors: Francis Ka-Ming Chan, Nivea Farias Luz, Kenta Moriwaki
Journal: Annual Review of Immunology (2014)

Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity, or immunodeficiency. Programmed necrosis or necroptosis is a form of nonapoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF, or DAI to signal for necroptosis in response to death receptor or Toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membranes. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.
Dynamic visualization of RANKL and Th17-mediated osteoclast function
Authors: Junichi Kikuta, Yoh Wada, Toshiyuki Kowada, Ze Wang, Ge-Hong Sun-Wada, Issei Nishiyama, Shin Mizukami, Nobuhiko Maiya, Hisataka Yasuda, Atsushi Kumanogoh, Kazuya Kikuchi, Ronald N. Germain, Masaru Ishii
Journal: Journal of Clinical Investigation (2013)

Osteoclasts are bone resorbing, multinucleate cells that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursor cells. Although previous studies have revealed important molecular signals, how the bone resorptive functions of such cells are controlled in vivo remains less well characterized. Here, we visualized fluorescently labeled mature osteoclasts in intact mouse bone tissues using intravital multiphoton microscopy. Within this mature population, we observed cells with distinct motility behaviors and function, with the relative proportion of static – bone resorptive (R) to moving – nonresorptive (N) varying in accordance with the pathophysiological conditions of the bone. We also found that rapid application of the osteoclast-activation factor RANKL converted many N osteoclasts to R, suggesting a novel point of action in RANKL-mediated control of mature osteoclast function. Furthermore, we showed that Th17 cells, a subset of RANKL-expressing CD4+ T cells, could induce rapid N-to-R conversion of mature osteoclasts via cell-cell contact. These findings provide new insights into the activities of mature osteoclasts in situ and identify actions of RANKL-expressing Th17 cells in inflammatory bone destruction.
Profiling serum biomarkers in patients with COPD: associations with clinical parameters
Authors: V. Pinto-Plata, J. Toso, K. Lee, D. Park, J. Bilello, H. Mullerova, M. M De Souza, R. Vessey, B. Celli
Journal: Thorax (2007)

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology.Forty-eight patients (65% men) with COPD (forced expiratory volume in 1 s <55%) and 48 matched controls were studied. Anthropometric parameters, pulmonary function tests, 6-minute walk distance, the BODE index and the number of exacerbations were measured and the association of these outcomes with the baseline levels of 143 serum biomarkers measured by PMP was explored.Thirty biomarker clusters were identified and ranked by computing the predictive value of each cluster for COPD (partial least squares discriminant analysis). From the 19 best predictive clusters, 2-3 biomarkers were selected based on their pathophysiological profile (chemoattractants, inflammation, tissue destruction and repair) and the statistical significance of their relationship with clinically important end points was tested. The selected panel of 24 biomarkers correlated (p<0.01) with forced expiratory volume in 1 s, carbon monoxide transfer factor, 6-minute walk distance, BODE index and exacerbation frequency.PMP technology can be useful in identifying potential biomarkers in patients with COPD. Panels of selected serum markers are associated with important clinical predictors of outcome in these patients.
Tumor necrosis factor alpha is involved in mouse growth and lymphoid tissue development.
Authors: S de Kossodo, G E Grau, T Daneva, P Pointaire, L Fossati, C Ody, J Zapf, P F Piguet, R C Gaillard, P Vassalli
Journal: The Journal of Experimental Medicine (1992)

Tumor necrosis factor alpha (TNF-alpha), a major mediator of inflammation, also possesses a wide pleiotropism of actions, suggesting its involvement in physiological conditions. TNF-alpha mRNA is present in mouse embryonic tissues and also in fetal thymus and spleen. Repeated injections of a monospecific polyclonal rabbit anti-mouse TNF-alpha antibody in mice, starting either during pregnancy or at birth, led to a severe but transient growth retardation, already present at birth, reaching a 35% decrease in body weight at 3 wk, with complete recovery at 8 wk. The insulin growth factor I (IGF-I) blood levels were decreased to about 50%; growth hormone release and other endocrine functions were unaltered. A marked atrophy of the thymus, spleen, and lymph nodes was also observed, with lymphopenia and impaired development of T and B cell peripheral lymphoid structures. The pathways involving TNF-alpha in IGF-I release and early body growth are probably distinct from those by which TNF-alpha participates in early development of lymphoid tissues, where its low physiological release may contribute to enhance lymphoid cell expansion.
A SCHEME FOR AUXILIARY CIVILIAN HOSPITALS
Authors: F. C. Bottomley
Journal: BMJ (1919)

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the latest introduction into the armamentarium of diabetes care in the present decade. By virtue of their beneficial effects, such as blood pressure-lowering, bodyweight reduction and significant renal and cardioprotective effects which extends beyond their glycaemic control effects, SGLT2i have become one of the most preferred oral antihyperglycaemic agents of recent times. However, they can influence tubular handling of electrolytes that can result in some electrolyte disturbances such as alteration in the serum levels of magnesium, potassium and phosphate levels. Some of these changes are mild or transient and may not have significant clinical implications. The underlying putative mechanism(s) responsible for disturbances of electrolytes are yet to be deciphered. In this review, we aim to describe electrolytes and acid–base abnormalities due to SGLT2i as well as to elucidate the underlying mechanism.
Glucose Absorption in Gestational Diabetes Mellitus During an Oral Glucose Tolerance Test
Authors: Christian Anderwald, Andrea Tura, Yvonne Winhofer, Michael Krebs, Christine Winzer, Martin G. Bischof, Anton Luger, Giovanni Pacini, Alexandra Kautzky-Willer
Journal: Diabetes Care (2011)

Women with gestational diabetes mellitus (GDM) show reduced insulin sensitivity and markedly elevated glucose excursions. After delivery, GDM mostly reverts to normal glucose tolerance (NGT), although leaving an increased risk of type 2 diabetes. Because gastrointestinal function changes during pregnancy causing vomiting, constipation, or reduced motility, we thought that gut glucose absorption in GDM or pregnancy might be altered to affect circulating glucose excursions.By undergoing 180-min oral glucose tolerance tests (OGTTs), pregnant women with GDM (GDMpreg; n=15, BMI=32±2 kg/m2, aged 33±1 years) were compared with NGT women (NGTpreg; n=7, BMI=28±1 kg/m2, aged 34±2 years), matching for major anthropometric characteristics (each P>0.2). After delivery (6-7 months later), both groups were studied the same way. We computed and mathematically modeled gut glucose absorption from insulin-mediated glucose disappearance and endogenous glucose production (EGP). Whole-body insulin sensitivity was calculated using the Clamp-like Index.GDMpreg showed 16-25% higher plasma glucose concentrations (P<0.04) during the final 2 h of OGTT, similar EGP, but lower (P<0.01) insulin sensitivity (2.7±0.2 mg·kg(-1)·min(-1) vs. NGTpreg: 4.5±0.8 mg·kg(-1)·min(-1)). In GDMpreg, gut glucose absorption rates were ≤52% lower from 30 to 120 min (P<0.03 vs. conditions after delivery or NGTpreg). In contrast, glucose absorption rates in NGTpreg were comparable during and after pregnancy. None of the studied women developed diabetes after delivery.In GDMpreg, OGTT gut glucose absorption is markedly lower during hyperglycemia, whereas both glycemia and glucose absorption in NGTpreg are comparable between pregnant and postpartum states. Thus, hyperglycemia in GDM does not seem to result from too rapid or increased glucose absorption.
Cardiac Arrhythmias Produced by Catecholamines in Anesthetized Dogs
Authors: E. NEIL MOORE, HOWARD T. MORSE, HENRY L. PRICE
Journal: Circulation Research (1964)

1. Electrograms have been recorded simultaneously from the right atrium, bundle of His, and both ventricles, together with the lead II electrocardiogram in dogs receiving cyclopropane and oxygen. Following the administration of norepinephrine, both bigeminal rhythms and monofocal ventricular tachycardias were observed. 2. In our studies both the coupled and the monofocal ventricular beats originated distal to the His electrode. 3. The mechanism of the coupled beats could not be analyzed using either gross or intracellular recording methods; the monofocal tachycardias appeared to result from increased pacemaker activity in the ventricular conducting system. 4. The present results emphasize the hazards of proposing mechanisms to explain arrhythmias solely on the basis of electrocardiographic evidence.
EPHEDRINE SULPHATE AND BARIUM CHLORIDE IN THE PREVENTION OF STOKES-ADAMS SEIZURES
Authors: A. R. Gilchrist
Journal: BMJ (1934)

The peculiar syncopal attacks which are named after Stokes and Adams have as their predominant feature either a complete and transient cessation of ventricular beating or else the temporary development of such an extremely slow ventricular rate than an adequate cerebral circulation is not maintained.Complete ventricular arrest is the commoner variety.Recovery of the heart beat may take place after a pause of some seconds', or even of five minutes', duration.'1Extreme bradycardia is a less frequent cause of Stokes-Adams seizures.Should the ventricular rate fall to less than nine or ten beats per minute then a semi-conscious stuporose state is apt to arise.This persists until a greater rate of blood flow through the brain is brought about by an increase in the rate or power of the ventricles.On the other hand, a further reduction in rate, perhaps to six or seven beats per minute, is accompanied by loss of consciousness, cyanosis, muscular twitchings, and a deepening coma, which can only be relieved by a more efficient pumping action of the heart.
Breath analysis in relapsing polychondritis using ion mobility spectrometry
Authors: Ayano Usuba, Hiroshi Handa, Teppei Inoue, Mariko Okamoto, Mamichi Minashita, Sasidhar Maddula, Jorg Ingo Baumbach, Teruomi Miyazawa
Journal: European Respiratory Journal (2014)

Background: Ion Mobility Spectrometry (IMS) is a useful method in the rapid identification of volatile organic compound (VOC) peaks in respiratory diseases. Relapsing polychondritis (RP) is a rare systemic inflammatory disease that is characterized by recurrent inflammatory changes in cartilage tissues in the auricle, nose, and lower respiratory tract.About 50% of RP patients experience respiratory tract complications, and 10% of RP patients die from these complications. Thus, early diagnosis in respiratory involvement is critically important in RP with respiratory symptoms.  Aim: To identify specific VOC peaks in RP.  Methods: Breath samples of 10 patients with RP and 19 healthy volunteers were analyzed using IMS coupled to a multi-capillary column (MCC/IMS) from August 2011 to February 2013. Diagnosis of RP was made according to the diagnostic criteria of McAdam et al. or Damiani and Levine.  Results: Eighty-nine VOC peaks were detected. Eighteen VOC peaks in RP patients were significantly higher than in healthy volunteers and 14 VOC peaks were identified.  Conclusion: IMS could detect biomarkers related to RP. Volatile metabolites occurring in exhaled air are postulated and correlated directly to different respiratory diseases.
Prevalence and Prognosis of Unrecognized Myocardial Infarction Determined by Cardiac Magnetic Resonance in Older Adults
Authors: Erik B. Schelbert, Jie J. Cao, Sigurdur Sigurdsson, Thor Aspelund, Peter Kellman, Anthony H. Aletras, Christopher K. Dyke, Gudmundur Thorgeirsson, Gudny Eiriksdottir, Lenore J. Launer, Vilmundur Gudnason, Tamara B. Harris, Andrew E. Arai
Journal: JAMA (2012)

Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI).Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals.ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes.Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI).Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001).In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk.clinicaltrials.gov Identifier: NCT01322568.