tbuckley/cabot-search huggingface dataset:
Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease.
Authors: R S Williams, R A McKinnis, F R Cobb, M B Higginbotham, A G Wallace, R E Coleman, R M Califf
Journal: Circulation (1984)

To address the hypothesis that physical conditioning may improve left ventricular function in patients with coronary artery disease, we performed first-pass radionuclide ventriculography in 53 patients at rest and during upright bicycle exercise before and after 6 to 12 months of exercise training. The peak bicycle workload achieved before the onset of fatigue, dyspnea, or angina increased by an average of 22% (p = .0001) after training, and mean heart rate at a workload equal to the pretraining maximum workload was decreased by 10 beats/min after training (p = .0002). Of 21 subjects with angina or exertional ST segment depression before training, 15 (71%) were able to exercise to the same workload without these manifestations of ischemia after training. Whereas neither mean resting left ventricular ejection fraction (LVEF) nor LVEF at peak exertion was significantly altered, mean LVEF at the pretraining maximum workload was increased from 0.50 to 0.54 (p = .002) after training. There was a significant correlation between the magnitude of training bradycardia and the increment in LVEF at the pretraining maximum workload (p = .009). We conclude that the relative bradycardia at comparable exercise workloads produced by exercise conditioning is associated with improvements in left ventricular performance as assessed by the LVEF. This observation is compatible with the hypothesis that training bradycardia in conditioned subjects with ischemic heart disease is associated with lower myocardial oxygen demand and lesser degrees of ischemia at comparable workloads. However, training effects on ventricular afterload or on ischemia contractile performance of the heart cannot be excluded.
Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination
Authors: Yuqi Wang, Henrik G. Dohlman
Journal: Circulation Research (2006)

Guanine nucleotide binding proteins (G proteins) and mitogen-activated protein kinases are highly conserved signaling molecules engaged in a wide variety of cellular processes. The strength and duration of signaling mediated by G proteins and mitogen-activated protein kinases are well known to be regulated via phosphorylation of pathway components. Over the past few years, it has become evident that many of the same signaling proteins also undergo ubiquitination, a posttranslational modification that typically leads to protein degradation. Consequently the strength and duration of signaling can also be modulated by regulating the abundance of signaling proteins. This article describes G protein– and mitogen-activated protein kinase–mediated signaling pathways that are known to be regulated by ubiquitination. The focus is on studies performed in the budding yeast Saccharomyces cerevisiae , as many principles governing this new regulatory mechanism were initially discovered in this model organism. Similar mechanisms uncovered in other model systems are also briefly discussed to illustrate the importance and universality of signaling regulation by ubiquitination.
Role for Genetic Anticipation in Lynch Syndrome
Authors: Mef Nilbert, Susanne Timshel, Inge Bernstein, Klaus Larsen
Journal: Journal of Clinical Oncology (2008)

Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum.In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation.Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated.The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.
A6: Tapering and Withdrawal of Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis in Inactive Disease: Results From an Alternative Dosing Regimen in the TENDER Study
Authors: Fabrizio De Benedetti, Nicolino Ruperto, Hermine Brunner, Alexei A. Grom, Nico Wulffraat, Michael Henrickson, Rita Jerath, Yuki Kimura, Alysha K. Kadva, Jianmei Wang, Alberto Martini, Daniel J. Lovell
Journal: Arthritis & Rheumatology (2014)

Background/Purpose: The TENDER clinical trial is a 3‐part, 5‐year, phase 3 study with tocilizumab (TCZ) in patients with active systemic juvenile idiopathic arthritis (sJIA). After 2 years of treatment, sJIA patients who have maintained clinically inactive disease for 3 months are given the option to participate in an alternative TCZ dosing regimen aimed at spacing the infusions and eventually withdrawing TCZ. Herein we describe the patients registered to participate in the optional alternative dosing schedule in the TENDER study. Methods: To qualify for the optional alternative dosing schedule, patients had to be in the study for 2 years and had to achieve American College of Rheumatology JIA inactive disease status. Among the 112 patients enrolled, 39 (35%) entered the optional alternative dosing regimen. This entailed a staged prolongation of the time interval between TCZ infusions from 2 weeks (standard interval) to 3 weeks, then 4 weeks, with the option of terminating TCZ after the discontinuation of any treatment. Results: Twenty‐three male and 16 female patients entered the optional alternative dosing schedule. Their mean baseline characteristics were 14.2 active joints, 15.4 joints with limitation of motion, physician global VAS score of 58.5, CHAQ‐DI score of 1.62, and erythrocyte sedimentation rate (ESR) of 56.8. Fifteen had fever. Of these 39 patients, 13 patients lost clinically inactive disease status while on the optional alternative dosing schedule. In these 13 patients, the time to loss of inactive disease status ranged from 1.4 to 16.8 months from initiation of the optional alternative dosing schedule (n = 4 on 3‐week dosing; n = 6 on 4‐week dosing; n = 3 off TCZ). Risk for losing inactive disease status on the optional alternative dosing schedule was similar in patients treated with methotrexate (6/16, 37.5% flared) and in those not treated with methotrexate (7/23, 30.4% flared). Inactive disease status was maintained in 26 of the 39 patients entering the optional alternative dosing schedule. Dosing intervals were every 3 weeks in 3 patients and every 4 weeks in 14 patients; 9 patients have been able to discontinue TCZ (range of time since discontinuation: 3.6–13.4 months). At baseline, these 9 patients were clinically similar to other patients entering the optional alternative dosing schedule (mean characteristics: age 9.1 years, 10.9 active joints, 10.9 joints with limitation of motion, physician global VAS score of 45.4, CHAQ‐DI score of 1.4, ESR of 47.2; 4 patients with fever at baseline). Conclusion: Patients with sJIA who maintain clinically inactive disease status can progressively space TCZ infusions, with one‐fourth of them able to discontinue all treatments, including TCZ.
Bleeding in Very Old Patients on Vitamin K Antagonist Therapy
Authors: Jack Ansell
Journal: Circulation (2011)

A common topic in clinical anticoagulation research used to be bleeding risk in old age.Times have changed, as well as the population of patients on anticoagulants, and the topic now is bleeding risk in very old patients.What is it about age that stimulates clinical investigators to launch studies of age and bleeding risk with vitamin K antagonist (VKA) therapy?First, the decision to initiate a VKA must always follow a consideration of the risks and benefits of therapy, regardless of age, and one should have a reasonable knowledge of the risk of bleeding at various age intervals.Second, the elderly, however defined, are the major users of oral anticoagulants because the 2 most common indications for such treatment, atrial fibrillation (AF) and venous thromboembolism, are most prevalent in the elderly.2][3][4] Fourth, the perception, real or not, that older age is associated with a greater risk of bleeding represents a barrier to the treatment of the elderly with oral anticoagulants for well-established indications.6][7][8] The consequence of this paradox is exemplified by the recent Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) study with a new direct factor Xa inhibitor, apixaban, in which investigators randomized patients with AF who were thought to be poor candidates for a VKA (mean age, 70Ϯ10 years) to apixaban versus aspirin. 9The principal criticism of this study was the rationale behind the decisions not to treat patients with a VKA, which in many cases was that they were thought to be at too high a risk for such therapy. 10The outcome overwhelmingly favored the anticoagulant, as was the case in trials of warfarin versus aspirin in AF, 11 without an increased incidence of major bleeding compared with aspirin alone, thus indicating that anticoagulation therapy really is safe for these individuals.Finally, there are ongoing debates and contradictory evidence 12 as to whether older age is a risk factor for major bleeding and, if so, if is it an independent risk factor for major bleeding.A number of bleeding risk indexes incorporate age as an independent risk factor and have been validated prospectively such as the Outpatient Bleeding Risk Index, 13 the HEMORR 2 HAGES score, 14 and the HAS-BLED index.
Contribution of Macrophages to Pulmonary Nitric Oxide Production in Septic Shock
Authors: YOSHITAKA FUJII, PETER GOLDBERG, SABAH N. A. HUSSAIN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Bacterial lipopolysaccharide (LPS) is known to induce the expression of inducible nitric oxide synthase (iNOS) in the lung and to lead to increased pulmonary nitric oxide (NO) production. The contribution of various pulmonary cells to this phenomenon remains unclear. In this study, we used gadolinium chloride, a blocker of macrophage activation, to assess the role of macrophages in LPS-induced pulmonary NO production. Anesthetized, mechanically ventilated rats were injected with either saline or LPS (Escherichia coli endotoxin) and studied for 5 h. Two other groups of rats were pretreated 24 h earlier with gadolinium chloride. Unlike control rats, rats injected with LPS showed a progressive decline in arterial pressure and a several-fold rise in lung iNOS activity and exhaled NO concentration. Large numbers of alveolar macrophages also expressed iNOS after LPS injection. Gadolinium chloride pretreatment eliminated the rise in lung iNOS activity and protein expression and significantly attenuated the increase in pulmonary exhaled NO product, but it had no effect on arterial pressure. Fewer numbers of alveolar macrophages expressed iNOS protein after gadolinium pretreatment. We conclude that macrophage activation plays a critical role in enhancing NO production in the respiratory system, but it is of less importance in mediating hemodynamic alterations of acute endotoxemia.
Dendritic Cells Initiate Immune Control of Epstein-Barr Virus Transformation of B Lymphocytes In Vitro
Authors: Kara Bickham, Kiera Goodman, Casper Paludan, Sarah Nikiforow, Ming Li Tsang, Ralph M. Steinman, Christian Münz
Journal: The Journal of Experimental Medicine (2003)

The initiation of cell-mediated immunity to Epstein-Barr virus (EBV) has been analyzed with cells from EBV-seronegative blood donors in culture. The addition of dendritic cells (DCs) is essential to prime naive T cells that recognize EBV-latent antigens in enzyme-linked immunospot assays for interferon γ secretion and eradicate transformed B cells in regression assays. In contrast, DCs are not required to control the outgrowth of EBV-transformed B lymphocytes from seropositive donors. Enriched CD4+ and CD8+ T cells mediate regression of EBV-transformed cells in seronegative and seropositive donors, but the kinetics of T-dependent regression occurs with much greater speed with seropositives. EBV infection of DCs cannot be detected by reverse transcription–polymerase chain reaction with primers specific for mRNA for the EBNA1 U and K exons. Instead, DCs capture B cell debris and generate T cells specific for EBV latency antigens. We suggest that the cross-presentation of EBV-latent antigens from infected B cells by DCs is required for the initiation of EBV-specific immune control in vivo and that future EBV vaccine strategies should target viral antigens to DCs.
Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis
Authors: Manish Pareek, John P Watson, L Peter Ormerod, Onn Min Kon, Gerrit Woltmann, Peter J White, Ibrahim Abubakar, Ajit Lalvani
Journal: The Lancet Infectious Diseases (2011)

BackgroundContinuing rises in tuberculosis notifications in the UK are attributable to cases in foreign-born immigrants. National guidance for immigrant screening is hampered by a lack of data about the prevalence of, and risk factors for, latent tuberculosis infection in immigrants. We aimed to determine the prevalence of latent infection in immigrants to the UK to define which groups should be screened and to quantify cost-effectiveness.MethodsIn our multicentre cohort study and cost-effectiveness analysis we analysed demographic and test results from three centres in the UK (from 2008 to 2010) that used interferon-γ release-assay (IGRA) to screen immigrants aged 35 years or younger for latent tuberculosis infection. We assessed factors associated with latent infection by use of logistic regression and calculated the yields and cost-effectiveness of screening at different levels of tuberculosis incidence in immigrants' countries of origin with a decision analysis model.FindingsResults for IGRA-based screening were positive in 245 of 1229 immigrants (20%), negative in 982 (80%), and indeterminate in two (0·2%). Positive results were independently associated with increases in tuberculosis incidence in immigrants' countries of origin (p=0·0006), male sex (p=0·046), and age (p<0·0001). National policy thus far would fail to detect 71% of individuals with latent infection. The two most cost-effective strategies were to screen individuals from countries with a tuberculosis incidence of more than 250 cases per 100 000 (incremental cost-effectiveness ratio [ICER] was £17 956 [£1=US$1·60] per prevented case of tuberculosis) and at more than 150 cases per 100 000 (including immigrants from the Indian subcontinent), which identified 92% of infected immigrants and prevented an additional 29 cases at an ICER of £20 819 per additional case averted.InterpretationScreening for latent infection can be implemented cost-effectively at a level of incidence that identifies most immigrants with latent tuberculosis, thereby preventing substantial numbers of future cases of active tuberculosis.FundingMedical Research Council and Wellcome Trust.
Association of serum leptin with hypoventilation in human obesity
Authors: P R Phipps
Journal: Thorax (2002)

Background: Leptin is a protein hormone produced by fat cells of mammals. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. Plasma leptin levels correlate closely with total body fat mass operating via a central feedback mechanism. In human obesity serum leptin levels are up to four times higher than in lean subjects, indicating a failure of the feedback loop and central leptin resistance. In leptin deficient obese mice (<i>ob/ob</i> mice) leptin infusion reverses hypoventilation. It was hypothesised that a relative deficiency in CNS leptin, indicated by high circulating leptin levels, may be implicated in the pathogenesis of obesity hypoventilation syndrome (OHS). Methods: Fasting morning leptin levels were measured in obese and non-obese patients with and without daytime hypercapnia (n=56). Sleep studies, anthropometric data, spirometric parameters, and awake arterial blood gas tensions were measured in each patient. Results: In the whole group serum leptin levels correlated closely with % body fat (<i>r</i>=0.77). Obese hypercapnic patients (mean (SD) % body fat 43.8 (6.0)%) had higher fasting serum leptin levels than eucapnic patients (mean % body fat 40.8 (6.2)%), with mean (SD) leptin levels of 39.1 (17.9) and 21.4 (11.4) ng/ml, respectively (p&lt;0.005). Serum leptin (odds ratio (OR) 1.12, 95% CI 1.03 to 1.22) was a better predictor than % body fat (OR 0.92, 95% CI 0.76 to 1.1) for the presence of hypercapnia. Conclusions: Hyperleptinaemia is associated with hypercapnic respiratory failure in obesity. Treatment with leptin or its analogues may have a role in OHS provided central leptin resistance can be overcome.
RRM1 single nucleotide polymorphism -37C→A correlates with progression-free survival in NSCLC patients after gemcitabine-based chemotherapy
Authors: Song Dong, Ai-Lin Guo, Zhi-Hong Chen, Zhen Wang, Xu-Chao Zhang, Ying Huang, Zhi Xie, Hong-Hong Yan, Hua Cheng, Yi-Long Wu
Journal: Journal of Hematology & Oncology (2010)

Abstract Background The ribonucleotide reductase M1 (RRM1) gene encodes the regulatory subunit of ribonucleotide reductase, the molecular target of gemcitabine. The overexpression of RRM1 mRNA in tumor tissues is reported to be associated with gemcitabine resistance. Thus, single nucleotide polymorphisms (SNPs) of the RRM1 gene are potential biomarkers of the response to gemcitabine chemotherapy. We investigated whether RRM1 expression in peripheral blood mononuclear cells (PBMCs) or SNPs were associated with clinical outcome after gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods PBMC samples were obtained from 62 stage IIIB and IV patients treated with gemcitabine-based chemotherapy. RRM1 mRNA expression levels were assessed by real-time PCR. Three RRM1 SNPs, -37C→A, 2455A→G and 2464G→A, were assessed by direct sequencing. Results RRM1 expression was detectable in 57 PBMC samples, and SNPs were sequenced in 56 samples. The overall response rate to gemcitabine was 18%; there was no significant association between RRM1 mRNA expression and response rate ( P = 0.560). The median progression-free survival (PFS) was 23.3 weeks in the lower expression group and 26.9 weeks in the higher expression group ( P = 0.659). For the -37C→A polymorphism, the median PFS was 30.7 weeks in the C(-)37A group, 24.7 weeks in the A(-)37A group, and 23.3 weeks in the C(-)37C group ( P = 0.043). No significant difference in PFS was observed for the SNP 2455A→G or 2464G→A. Conclusions The RRM1 polymorphism -37C→A correlated with PFS in NSCLC patients treated with gemcitabine-based chemotherapy. No significant correlation was found between PBMC RRM1 mRNA expression and the efficacy of gemcitabine.
The Circus Comes to the Emergency Department
Authors: Neal Baer
Journal: JAMA Internal Medicine (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Association of FKBP5 Polymorphisms With Suicidal Events in the Treatment of Resistant Depression in Adolescents (TORDIA) Study
Authors: David Brent, Nadine Melhem, Robert Ferrell, Graham Emslie, Karen Dineen Wagner, Neal Ryan, Benedetto Vitiello, Boris Birmaher, Taryn Mayes, Jamie Zelazny, Matthew Onorato, Bernie Devlin, Greg Clarke, Lynn DeBar, Marty Keller
Journal: American Journal of Psychiatry (2009)

The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents.
Correlation of Tumor Growth Inhibitory Activity of Macrophages Exposed to Adriamycin and Adriamycin Sensitivity of the Target Tumor Cells234
Authors: Raffaella Giavazzi, Corazon D. Bucana, Ian R. Hart
Journal: JNCI Journal of the National Cancer Institute (1984)

Variant cell lines of the murine fibrosarcoma UV-2237, selected for doxorubicin [adriamycin (ADM)] resistance, were used to study the tumoricidal activity of macrophages that had been exposed to ADM. Free ADM (0.01-1 microgram/ml) was cytotoxic to the sensitive UV-2237M parent and to the partially sensitive UV-2237M-revertant cell lines, whereas the ADM-resistant UV-2237M ADMR line was unaffected by these levels of ADM. Macrophages harvested from the peritoneal cavities of mice given ip injections of 10 mg ADM/kg body weight 1 day or 4 days previously inhibited proliferation of the 3 cell lines, an effect that was directly correlated to the degree of ADM sensitivity of each cell line. Macrophages exposed in vitro to ADM (from 0.01 to 1 microgram/ml) inhibited the growth of, and eventually were cytolytic to, the parent and the revertant cell lines; these ADM-exposed macrophages did not affect the UV-2237M-ADMR cell line. The correlation between the antitumor effects of macrophages exposed to ADM and the ADM susceptibility of tumor cells suggests that ADM-exposed macrophages exert their effect by the release or transfer of the stored drug.