tbuckley/cabot-search huggingface dataset:
Asymptomatic bronchial hyperresponsiveness in adolescents and young adults
Authors: BG Kolnaar, H Folgering, HJ van den Hoogen, C van Weel
Journal: European Respiratory Journal (1997)

The clinical significance of asymptomatic bronchial hyperresponsiveness (BHR) is not well-known. The aim of this study was to explore, in a cross-sectional analysis, the characteristics of adolescent subjects with asymptomatic BHR, as compared to nonhyperresponsive subjects and those with symptomatic BHR. The subjects were selected by date of birth from the register of general practitioners. The hypothesis that both asymptomatic and symptomatic BHR are related to early childhood lower respiratory tract infections was also tested, in a historical cohort analysis. Respiratory morbidity was studied in early childhood and BHR in adolescence and young adulthood, in a population of 551 subjects aged 10-23 yrs. Morbidity had been recorded prospectively since birth in the general practice. Data on chronic respiratory symptoms, smoking behaviour, airways obstruction, BHR and allergy were collected during this investigation. BHR was present in 42% of the subjects, of which 70% were asymptomatic. The occurrence of symptomatic BHR was related to acute bronchitis in early childhood, allergy, airways obstruction and recent asthma, acute bronchitis and hay fever; whereas, asymptomatic BHR was not. Characteristics of subjects with asymptomatic BHR did not differ significantly from those without BHR, with respect to these factors. We conclude that asymptomatic bronchial hyperresponsiveness in adolescence and young adulthood is not related to lower respiratory infections in early childhood. Furthermore, subjects with asymptomatic bronchial hyperresponsiveness have similar characteristics to those without bronchial hyperresponsiveness, but differ strongly from subjects with symptomatic hyperresponsiveness. Asymptomatic bronchial hyperresponsiveness may not be the link between early childhood lower respiratory morbidity and asthma in later life, nor a risk factor for later asthma.
Absence of Progression As Assessed by Response Evaluation Criteria in Solid Tumors Predicts Survival in Advanced GI Stromal Tumors Treated With Imatinib Mesylate: The Intergroup EORTC-ISG-AGITG Phase III Trial
Authors: Axel Le Cesne, Martine Van Glabbeke, Jaap Verweij, Paolo G. Casali, Michael Findlay, Peter Reichardt, Rolf Issels, Ian Judson, Patrick Schoffski, Serge Leyvraz, Binh Bui, Pancras C.W. Hogendoorn, Raf Sciot, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2009)

From February 2001 to February 2002, 946 patients with advanced GI stromal tumors (GISTs) treated with imatinib were included in a controlled EORTC/ISG/AGITG (European Organisation for Research and Treatment of Cancer/Italian Sarcoma Group/Australasian Gastro-Intestinal Trials Group) trial. This analysis investigates whether the response classification assessed by RECIST (Response Evaluation Criteria in Solid Tumors), predicts for time to progression (TTP) and overall survival (OS).Per protocol, the first three disease assessments were done at 2, 4, and 6 months. For the purpose of the analysis (landmark method), disease response was subclassified in six categories: partial response (PR; > 30% size reduction), minor response (MR; 10% to 30% reduction), no change (NC) as either NC- (0% to 10% reduction) or NC+ (0% to 20% size increase), progressive disease (PD; > 20% increase/new lesions), and subjective PD (clinical progression).A total of 906 patients had measurable disease at entry. At all measurement time points, complete response (CR), PR, and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. Patients were subsequently classified as responders (CR/PR/MR), NC (NC+/NC-), or PD. This three-class response categorization was found to be highly predictive of further progression or survival for the first two measurement points. After 6 months of imatinib, responders (CR/PR/MR) had the same survival prognosis as patients classified as NC.RECIST perfectly enables early discrimination between patients who benefited long term from imatinib and those who did not. After 6 months of imatinib, if the patient is not experiencing PD, the pattern of radiologic response by tumor size criteria has no prognostic value for further outcome. Imatinib needs to be continued as long as there is no progression according to RECIST.
Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis?
Authors: P Ranganathan
Journal: Annals of the Rheumatic Diseases (2002)

Methotrexate (MTX) remains the most commonly used disease modifying antirheumatic drug in rheumatoid arthritis (RA) because of its cost and experience in its use, despite the availability of new treatments such as leflunomide and the biological agents. However, a significant number of patients with RA either do not benefit from the drug or are unable to tolerate it. Pharmacogenetic approaches may help optimise treatment with MTX, and also other agents, in RA.
Influence of prior pregnancies on disease course and cause of death in systemic sclerosis
Authors: C M Artlett
Journal: Annals of the Rheumatic Diseases (2002)

Background: Microchimerism from fetal or maternal cells transferred during pregnancy has been implicated in the pathogenesis of systemic sclerosis (SSc). Objective: To determine whether a prior pregnancy influenced disease progression and cause of death in patients with SSc. Patients and methods: The patients comprised a retrospective study cohort of 111 women with SSc: 78 patients with prior pregnancies (PP) and 33 who were never pregnant (NP), followed up at Thomas Jefferson University. Differences in age at onset, disease subset, organ involvement, cause of death, and type of antinuclear autoantibodies were evaluated statistically, including regression analysis. Results: The age at onset of SSc in NP patients was 32.0 years compared with 45.7 years in patients with one or two prior pregnancies (p&lt;0.0001), 46.6 years in patients with three or four pregnancies (p&lt;0.0001), and 51.3 years in patients with five to seven pregnancies (p&lt;0.0005). In the 16 patients who had an elective pregnancy termination, 14/16 (87.5%) had diffuse SSc <i>v</i> 2/16 (12.5%) with limited SSc (p&lt;0.0001; odds ratio (OR)=49.0). Of the NP women, 7/30 (23%) died from SSc related causes <i>v</i> 3/78 (4%) women who had pregnancies (p=0.0058; OR=7.6). A carbon monoxide transfer factor (Tlco) of &lt;60% and disease duration &gt;10 years was found in 10/13 (77%) NP patients <i>v</i> 10/23 (43%) patients who had pregnancies (p=0.05; OR=4.7), and a Tlco &lt;50% and disease duration &gt;10 years was identified in 7/13 (54%) NP patients <i>v</i> 6/23 (26%) of the patients who had pregnancies (p=0.09; OR=3.2). Conclusions: There are differences in the age at onset, clinical course, severity of lung involvement, and cause of death in women who develop SSc before pregnancy compared with those who develop it after pregnancies. The NP patients with SSc had onset of disease at an earlier age, more severe lung involvement, and higher rate of death due to SSc.
Real-Time 3-Dimensional Transesophageal Echocardiography in the Evaluation of a Patient With Concomitant Double-Orifice Mitral Valve, Bicuspid Aortic Valve, and Coarctation of the Aorta
Authors: Gunjan Aggarwal, Dominik Schlosshan, Con Arronis, Gita Mathur, Greg Cranney
Journal: Circulation (2009)
Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Steven T. Harris, Nelson B. Watts, Harry K. Genant, Clark D. McKeever, Thomas N. Hangartner, Michael Keller, Charles H. Chesnut Iii, Jacques Brown, Erik F. Eriksen, Mohammad S. Hoseyni, Douglas W. Axelrod, Paul D. Miller
Journal: JAMA (1999)

ContextRisedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.ObjectiveTo test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998.InterventionsSubjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low.Main Outcome MeasuresIncidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry.ResultsThe 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41% (95% confidence interval [CI], 18%-58%) over 3 years (11.3% vs 16.3%;P=.003). A fracture reduction of 65% (95% CI, 38%-81%) was observed after the first year (2.4% vs 6.4%; P&lt;.001). The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61%) (5.2% vs 8.4%; P=.02). Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1%), femoral neck (1.6% vs −1.2%), femoral trochanter (3.3% vs −0.7%), and midshaft of the radius (0.2% vs −1.4%). Bone formed during risedronate treatment was histologically normal. The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo.ConclusionsThese data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis.
Sodium Reduction and Weight Loss in the Treatment of Hypertension in Older Persons
Authors: Paul K. Whelton, Lawrence J. Appel, Mark A. Espeland, William B. Applegate, Walter H. Ettinger, Jr, John B. Kostis, Shiriki Kumanyika, Clifton R. Lacy, Karen C. Johnson, Steven Folmar, Jeffrey A. Cutler, None for the TONE Collaborative Research Group
Journal: JAMA (1998)

Nonpharmacologic interventions are frequently recommended for treatment of hypertension in the elderly, but there is a paucity of evidence from randomized controlled trials in support of this recommendation.To determine whether weight loss or reduced sodium intake is effective in the treatment of older persons with hypertension.Randomized controlled trial.A total of 975 [corrected] men and women aged 60 to 80 years with systolic blood pressure lower than 145 mm Hg and diastolic blood pressure lower than 85 mm Hg while receiving treatment with a single antihypertensive medication.Four academic health centers.The 585 obese participants were randomized to reduced sodium intake, weight loss, both, or usual care, and the 390 nonobese participants were randomized to reduced sodium intake or usual care. Withdrawal of antihypertensive medication was attempted after 3 months of intervention.Diagnosis of high blood pressure at 1 or more follow-up visits, or treatment with antihypertensive medication, or a cardiovascular event during follow-up (range, 15-36 months; median, 29 months).The combined outcome measure was less frequent among those assigned vs not assigned to reduced sodium intake (relative hazard ratio, 0.69; 95% confidence interval [CI], 0.59-0.81; P<.001) and, in obese participants, among those assigned vs not assigned to weight loss (relative hazard ratio, 0.70; 95% CI, 0.57-0.87; P<.001). Relative to usual care, hazard ratios among the obese participants were 0.60 (95% CI, 0.45-0.80; P<.001) for reduced sodium intake alone, 0.64 (95% CI, 0.49-0.85; P=.002) for weight loss alone, and 0.47 (95% CI, 0.35-0.64; P<.001) for reduced sodium intake and weight loss combined. The frequency of cardiovascular events during follow-up was similar in each of the 6 treatment groups.Reduced sodium intake and weight loss constitute a feasible, effective, and safe nonpharmacologic therapy of hypertension in older persons.
310Plasma exosomes from rats and humans protect the myocardium from ischemia-reperfusion injury
Authors: JM Vicencio, Y Zheng, D Das, C Boi-Doku, V Sivaraman, AR Hall, DM Yellon, SM Davidson
Journal: Cardiovascular Research (2014)

Introduction: Ischemia-reperfusion injury (IR) is a hallmark of cardiovascular disease and a major cause of death worldwide. Cardiac preconditioning is known to protect the heart from IR by activating several pro-survival transductional pathways. The fact that cardiac protection can also be achieved when preconditioning is applied to an organ remote from the heart (Remote Ischemic Preconditioning, RIPC) means that humoral factors are released from ischemic limbs into the circulation, potentially carrying a pro-survival message. Exosomes are nanometer-sized circulating vesicles, which mediate inter-cellular communication by ferrying diverse proteins and nucleic acids. Here we studied exosomes as possible mediators of RIPC. Methods: We isolated exosomes from plasma of rats or humans subjected to RIPC (3 cycles of 5 min limb-ischemia/5-min reperfusion). We characterized control (non-RIPC) or RIPC exosomes by electron microscopy, flow cytometry, western blot and nanoparticle tracking analysis. Exosomes were used in survival experiments and the signaling pathways leading to cardioprotection were studied. Results: Exosome concentration in plasma increased following RIPC in humans (from 3.5±0.3x108 to 1.1±0.3x109 exosomes/ml plasma; p<0.01, n=6), and administration of purified exosomes protected the heart from infarction in different settings including an in vivo rat model (vehicle: 48±7%; RIPC-Exosomes: 21±4%Infarct/AAR; p<0.01), ex vivo Langendorff (vehicle: 35±3%; RIPC-Exosomes: 21±3%Infarct/AAR; p<0.01), and in vitro hypoxia-reoxygenation of cardiomyocytes (43±7% reduction in cell death, p<0.01). RIPC-Exosomes triggered rapid ERK and Hsp27 phosphorylation in cultured cardiomyocytes, and the inhibition of upstream kinases MEK, or p38MAPK abolished ERK/Hsp27 phosphorylation and inhibited cardioprotection. Non-RIPC exosomes exerted similar protective properties. We propose a signaling mechanism of exosomal Hsp70, TLR4 activation, MEK/ERK/p38MAPK/Hsp27 mediating protection. Conclusions: We demonstrate that RIPC dramatically increases the concentration of exosomes in the circulation of humans and rats. Exosomes from both RIPC and non-RIPC plasma acutely activated pro-survival kinases that rapidly protected the heart against ischaemia-reperfusion injury. Exosomes may represent a novel agent with the potential to be an endogenous multi-signaling tool for cardioprotection.
CHK It Out! Blocking WEE Kinase Routs <i>TP53</i> Mutant Cancer
Authors: Julie E. Bauman, Christine H. Chung
Journal: Clinical Cancer Research (2014)

Abstract Mutations in TP53, encoding the master tumor suppressor p53, have posed a developmental therapeutic dilemma due to inability to target loss of function. Inhibition of WEE1 or CHK1 kinase, negative regulators of the G2–M checkpoint, selectively sensitizes p53-deficient cells to exogenous DNA damage, abrogating G2 arrest and precipitating mitotic catastrophe. Clin Cancer Res; 20(16); 4173–5. ©2014 AACR.
Abnormal fMRI Brain Activation in Euthymic Bipolar Disorder Patients During a Counting Stroop Interference Task
Authors: Stephen M. Strakowski, Caleb M. Adler, Scott K. Holland, Neil P. Mills, Melissa P. DelBello, James C. Eliassen
Journal: American Journal of Psychiatry (2005)

Background: Bipolar disorder is characterized by disturbed mood homeostasis accompanied by cognitive impairments that appear to persist during euthymia. Cognitive probes, coupled with neuroimaging, provide an approach toward clarifying the neurophysiology of bipolar disorder. METHOD: Sixteen patients with euthymic bipolar disorder and 16 healthy subjects underwent functional magnetic resonance imaging (fMRI) while performing a counting Stroop interference task and a control condition. Task performance was correlated with regional brain activation differences between groups, and the effect on brain activation of receiving versus not receiving medications was evaluated. RESULTS: Bipolar patients exhibited impaired task performance relative to the healthy subjects. In addition, the two groups demonstrated significantly different patterns of brain activation during the interference task. Healthy subjects exhibited relatively increased activation in temporal cortical regions, middle frontal gyrus, putamen, and midline cerebellum. Bipolar subjects exhibited relatively greater activation in the medial occipital cortex. The groups demonstrated different associations between task performance and fMRI activation in these brain regions. No differences in activation in these regions were observed between patients who were versus those who were not receiving medications; however, patients receiving medications exhibited greater activation in the anterior cingulate and dorsolateral prefrontal cortex. CONCLUSIONS: These differences suggest that patients with euthymic bipolar disorder fail to activate brain regions associated with performance of an interference task, which may contribute to impaired task performance. Medications do not explain these differences but may influence activation of brain regions primarily associated with performing an interference task.
Association between type 1 diabetes and Haemophilus influenzae type b vaccination: birth cohort study
Authors: M. Karvonen, Z. Cepaitis, J. Tuomilehto
Journal: BMJ (1999)

To determine the effect of Haemophilus influenzae type b vaccination and its timing on the risk of type 1 diabetes in Finnish children.Cumulative incidence and relative risk of type 1 diabetes was compared among three birth cohorts of Finnish children: those born during the 24 months before the H influenzae type b vaccination trial, those in the trial cohort who were vaccinated at 3 months of age and later with a booster vaccine, and those in the trial cohort who were vaccinated at 24 months of age only. The probability of type 1 diabetes was estimated using regression analysis assuming that there were no losses to 10 year follow up and no competing risks.Finland (total population 5 million and annual birth rate 1.3%).128 936 children born from 1 October 1983 to 1 September 1985, and 116 352 children born from 1 October 1985 to 31 August 1987.Probability of type 1 diabetes among children vaccinated with H influenzae type b and non-vaccinated children.No statistically significant difference was found at any time during the 10 year follow up in the risk of type 1 diabetes between the children born before the vaccination period and those vaccinated at the age of 24 months only (relative risk 1.01). The difference in the risk between the cohort vaccinated first at the age of 3 months and the cohort vaccinated at the age of 24 months only was not statistically significant either (1.06).It is unlikely that H influenzae type b vaccination or its timing cause type 1 diabetes in children.
Aluminium Phosphate but Not Calcium Phosphate Stimulates the Specific IgE Response in Guinea Pigs to Tetanus Toxoid
Authors: Tchavdar L. Vassilev
Journal: Allergy (1978)

The ability of aluminium phosphate and calcium phosphate to stimulate the synthesis of tetanus toxoid-specific anaphilactic and antitoxic antibodies is compared. The observed differences in the kinetics of IgG1a, IgG1b and antitoxines are quantitative--titres after application of aluminium phosphate are higher. Booster immunization with aluminium but not calcium phosphate-adsorbed toxoid leads to a prolonged synthesis of specific IgE. It is hypothesized that the regular application of aluminium compound-containing vaccines on the entire population could be one of the factors leading to the observed increase of allergic diseases.
MPs approve greater powers for UK government to close hospitals, but with a CCG veto
Authors: A. O'Dowd
Journal: BMJ (2014)

MPs have voted for a change in the law that will give the government more power to close well performing hospitals that are in the same area as poorer performing neighbours.

However, last minute concessions were made to give clinical commissioning groups the power to stop any moves that might use successful hospitals to help solve problems at failing trusts.

MPs in the House of Commons debated an amendment (clause 119) to the Care Bill on 10 and 11 March, which could allow services at well performing trusts to be shut or downgraded as part of a wider plan to reconfigure health services across a whole region on the recommendation of a government appointed trust special administrator at a nearby failing trust.

After a lengthy debate held over two …
Hypertension and Diabetes: Should We Treat Early Surrogates?
Authors: Peter M. Nilsson
Journal: Diabetes Care (2009)

Type 2 diabetes, a major public health problem of great concern, affects millions of patients in both developed and developing countries. These patients run a well-documented increased risk of cardiovascular disease (CVD), the risk of which is two- to threefold greater than that seen in nondiabetic subjects (1). Despite modern methods for treatment of diabetes and its risk factors and complications, the increased risk is still substantial. This is so even if data on risk factor control in national surveys, repeated on an annual basis, have shown improving trends for blood pressure and lipid control, e.g., in the National Diabetes Register in Sweden (2). Because hypertension and lipid disturbances are currently relatively easy to treat pharmacologically, this denotes that the majority of patients with diabetes are also to some extent receiving treatment for their CVD risk factors. Ideally, only studies that could prove the effect on clinical end points should be accepted as fundamental for evidence-based medicine in national or international guidelines. However, in addition, intermediate end points have been advocated for evaluation of intervention effects, as recently shown in studies evaluating drug effects on carotid or coronary atherosclerosis. This has provoked a clinical debate as that related in the following two sets of arguments, i.e., pro or con regarding the use of intermediate end points when hypertension in diabetes is treated.

On the pro side, arguments are concentrated in defense of using left ventricular hypertrophy, albuminuria, or arterial stiffness as useful surrogate markers, or intermediary end points, to guide the intensity and mode of treatment. However, on the con side, other more critical arguments are given to state that only drugs that are also able to decrease the rate of clinical events should be used, e.g., those shown to reduce CVD, including myocardial infarction and stroke, and in addition …