tbuckley/cabot-search huggingface dataset:
Right and left ventricular geometry and myocyte contractile processes with dilated cardiomyopathy: myocyte growth and -adrenergic responsiveness
Authors: W. S. McMahon, R. Mukherjee, P. C. Gillette, F. A. Crawford, F. G. Spinale
Journal: Cardiovascular Research (1996)

Comparison of the effects of supraventricular tachycardia-induced dilated cardiomyopathy on left and right ventricular isolated myocyte geometry and function.Chronic ventricular tachycardia and supraventricular tachycardia cause left ventricular dilation and dysfunction in humans. However, it is unknown whether supraventricular tachycardia-induced dilated cardiomyopathy is a homogenous process for both the left and right ventricles.Dilated cardiomyopathy was induced by rapid atrial pacing (240 beats/min, 3 weeks) in 5 pigs. Five age- and weight-matched pigs served as controls. Ventricular mass was measured, myocyte dimensions were obtained, and isolated right and left ventricular myocyte contractile performance was evaluated at baseline and after beta-adrenergic receptor stimulation.With the development of dilated cardiomyopathy, there was no change in left ventricular mass. In contrast, right ventricular mass was increased, as was right ventricular myocyte cross-sectional area. In the control group, baseline right ventricular myocyte contractile function was increased compared to left ventricular myocytes. beta-adrenergic receptor stimulation increased myocyte contractile function in both left and right ventricular myocytes. With supraventricular tachycardia-induced cardiomyopathy, both left and right ventricular myocyte contractile function and beta-adrenergic responsiveness were reduced.This study demonstrated differences in left and right ventricular myocyte growth with supraventricular tachycardia-induced dilated cardiomyopathy and this differential growth response was associated with changes in contractile performance. Thus, in this model of cardiomyopathic disease, left and right ventricular growth and changes in contractile performance are not a homogenous process.
P21-Activated Kinase 1 (PAK1) as a Therapeutic Target in BRAF Wild-Type Melanoma
Authors: Christy C. Ong, Adrian M. Jubb, Diana Jakubiak, Wei Zhou, Joachim Rudolph, Peter M. Haverty, Marcin Kowanetz, Yibing Yan, Jarrod Tremayne, Richard Lisle, Adrian L. Harris, Lori S. Friedman, Marcia Belvin, Mark R. Middleton, Elizabeth M. Blackwood, Hartmut Koeppen, Klaus P. Hoeflich
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundAlthough remarkable clinical response rates in melanoma have been observed using vemurafenib or dabrafenib in patients with tumors carrying oncogenic mutations in BRAF, a substantial unmet medical need remains for the subset of patients with wild-type BRAF tumors.
Molecular Characterization of Virus-induced Autoantibody Responses
Authors: Burkhard Ludewig, Philippe Krebs, Helen Metters, Jutta Tatzel, Özlem Türeci, Ugur Sahin
Journal: The Journal of Experimental Medicine (2004)

Here we present a comprehensive molecular mapping of virus-induced autoimmune B cell responses obtained by serological identification of antigens by recombinant expression cloning analysis. Immunoscreening of cDNA expression libraries of various organs (lung, liver, and spleen) using sera from mice infected with cytopathic (vaccinia virus [VV]) or noncytopathic (lymphocytic choriomeningitis virus [LCMV]) viruses revealed a broad specificity of the elicited autoantibody response. Interestingly, the majority of the identified autoantigens have been previously described as autoantigens in humans. We found that induction of virus-induced autoantibodies of the immunoglobulin G class largely depends on the CD40–CD40L-mediated interaction between T and B cells. Furthermore, antibody titers against a number of autoantigens were comparable to the concomitantly induced antiviral antibody response. Comparison of serum reactivity against a selected panel of autoantigens after infection with VV, LCMV, or vesicular stomatitis virus showed that the different virus infections triggered distinct autoantibody responses, suggesting that virus infections may leave specific “autoantibody fingerprints” in the infected host.
SWINE INFLUENZA
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1931)

1. It has been possible to demonstrate, in Berkefeld filtrates of infectious material from experimental cases of swine influenza, a virus which when administered intranasally to susceptible swine induced a mild, usually afebrile illness of short duration. The changes in the respiratory tract resembled those in swine influenza but were usually much less extensive. When the filtrable virus was mixed with pure cultures of H. influenzae suis and administered to swine a disease identical clinically and pathologically with swine influenza was induced. The data presented indicate that the filtrable virus of swine influenza and H. influenzae suis act in concert to produce swine influenza and that neither alone is capable of inducing the disease. 2. One attack of swine influenza usually renders an animal immune to reinfection. Blood serum from an animal made immune in this way neutralizes infectious material from swine influenza in vitro, as shown by the failure of the mixture to produce disease in a susceptible animal. 3. The virus can be stored in a dried state or in glycerol for several weeks at least. In one instance dried material apparently retained both the virus and H. influenzas suis in viable form for a period of 54 days. 4. Fatal cases of experimental swine influenza have been observed in which H. influenzae suis was the only organism that could be cultivated from the respiratory tract. 5. Attention has been called to some features of marked similarity between epizootic swine influenzae and epidemic influenzae in man.
Long-term Protection From Myocardial Ischemic Events in a Randomized Trial of Brief Integrin β3 Blockade With Percutaneous Coronary Intervention
Authors: Eric J. Topol, James J. Ferguson, Harlan F. Weisman, James E. Tcheng, Stephen G. Ellis, Neal S. Kleiman, Russell J. Ivanhoe, Ann L. Wang, David P. Miller, Keaven M. Anderson, Robert M. Califf
Journal: JAMA (1997)

<h3>Context.</h3> —Avciximab,lonal antibody fragment against the platelet receptor α<sub>llb</sub>β<sub>3</sub>integrin, prevents platelet aggregation. A randomized, placebo-controlled study showed that abciximab improves outcomes for patients undergoing percutaneous coronary angioplasty at 30 days and at 6 months. <h3>Objective.</h3> —to determine whether abciximab improves outcomes 3 years after coronary angioplasty. <h3>Design.</h3> —Double-blind, placebo-controlled, randomized trial. <h3>Setting.</h3> —A total of 56 academic and community hospitals in the United States. <h3>Patients.</h3> —A total of 2099 high-risk patients undergoing coronary angioplasty were randomized. Sufficient time elapsed for 2.5 years of follow-up among 2001 patients and for 3 years of follow-up among 1599 patients. <h3>Intervention.</h3> —Abciximab bolus of 0.25 mg/kg followed by infusion at 10 μg/min for 12 hours; abciximab bolus of 0.25 mg/kg followed by placebo infusion; or placebo bolus followed by placebo infusion. <h3>Main Outcomes Measures.</h3> —The primary outcome was the composite of death, myocardial infarction, or coronary revascularization. Secondary outcomes were death, myocardial infarction, or coronary revascularization individually. Subgroups having refractory unstable angina or evolving myocardial infarction and having different elevations of creatine kinase during initial angioplasty were analyzed. <h3>Results.</h3> —At 3 years, composite end points occurred in 41.1% of those receiving abciximab bolus plus infusion; 47.4% of those receiving abciximab bolus only; and 47.2% of those receiving placebo only (for abciximab bolus plus infusion vs placebo,<i>P</i>=.009). Death occurred in 6.8%, 8.0%, and 8.6%, respectively (for abciximab bolus plus infusion vs placebo,<i>P</i>=.20); myocardial infarction in 10.7%, 12.2%, and 13.6%, respectively (for abciximab bolus plus infusion vs placebo,<i>P</i>=.08); and revascularization in 34.8%, 38.6%, and 40.1%, respectively (for abciximab bolus plus infusion vs placebo,<i>P</i>=.02). Among those with refractory unstable angina or evolving myocardial infarction, death occurred in 5.1%, 9.2%, and 12.7%, respectively (for abciximab bolus plus infusion vs placebo,<i>P</i>=.01). Death rates increased as periprocedural creatine kinase levels increased. <h3>Conclusions.</h3> —Adciximab bolus with infusion given at the time of coronary angioplasty improves outcomes as long as 3 years after the procedure.
Higher occurrence of asthma-related symptoms in an urban than a suburban area in adults, but not in children
Authors: M.H. Wieringa, P.A. Vermeire, H.P. Van Bever, V.J. Nelen, J.J. Weyler
Journal: European Respiratory Journal (2001)

In young adults, a higher occurrence of asthma-related symptoms was found in an urban than an adjacent suburban area in a survey performed in 1991. The authors now wondered whether such differences could be established in other age groups. The present study (in 1996) included 14,299 subjects, aged 5–75 yrs, of a random sample of the general population in the same two adjacent areas: the centre of Antwerp (Belgium) and its south suburban border. The standardized European Community Respiratory Health Survey (ECRHS) and International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires were used to assess the occurrence of asthma-related symptoms. Higher rates were confirmed in urban compared to suburban Antwerp in adults (20–75 yrs), but no such area differences were found in children (5–8 and 12–15 yrs). Adjustment for a number of recorded risk factors did not seem to affect the area differences in asthma-related symptoms. Comparing the survey results of 1991 and 1996 in 20–44 yr old adults, the findings suggest a slight increase in reported respiratory symptoms in both areas. A higher occurrence of asthma symptoms was observed in the urban than suburban area in adults, but not in children. This might be explained by a progressive effect of long-term exposure to the “urban environment”. However, longitudinal studies are necessary to further clarify the factors accounting for these age-related area differences.
Induction of interleukin 1 alpha mRNA during the antigen-dependent interaction of sensitized T lymphoblasts with macrophages.
Authors: S Koide, R M Steinman
Journal: The Journal of Experimental Medicine (1988)

DNA-RNA hybridization with an IL-1 alpha cDNA probe was used to monitor the induction of IL-1 in macrophages that were acting as accessory cells for the proliferation of T lymphocytes. Mouse peritoneal macrophages bound and stimulated T lymphocytes in the presence of the mitogens, Con A, or anti-CD3 mAb, but little or no IL-1 mRNA was detectable. In contrast, if the T cells were first sensitized in a mixed leukocyte reaction with dendritic cells and then added to macrophages, IL-1 mRNA was clearly induced. Induction of the IL-1 alpha gene seemed to require the recognition of class II MHC products on the macrophage because of the following observations: specific rather than third-party macrophages were responsive to the T blast but not to T cell-conditioned media; induction was blocked by an anti-Ia mAb; CD4+ rather than CD8+ blasts were active; and polyclonal Con A blasts were much less efficient than antigen-specific T cells. Our data indicate that the strongest signal for IL-1 production during the macrophage-T cell interaction occurs in the efferent limb of the response, after rather than before the formation of class II MHC-restricted T lymphoblasts.
Mechanism of exercise hypotension in patients with ischemic heart disease. Role of neurocardiogenically mediated vasodilation.
Authors: S S Lele, G Scalia, H Thomson, D Macfarlane, D Wilkinson, W Stafford, F Khafagi, M Frenneaux
Journal: Circulation (1994)

BACKGROUND Exercise-induced hypotension in patients with coronary artery disease (CAD) has been considered to be due to an inability to achieve an adequate increase in cardiac output to match the demands of exercise. We investigated 10 consecutive patients (9 men and 1 woman; age, 38 to 71 years; mean, 52 years) with angiographically documented CAD and exercise-induced hypotension (EIH) (BPPeak &lt; BPRest). Ten approximately age- and sex-matched patients with documented CAD and normal exercise blood pressure response (NBP) served as control subjects. METHODS AND RESULTS Nine patients with EIH and all 10 control subjects underwent forearm plethysmography and radionuclide ventriculography (RNV) during semierect cycle exercise. Forearm vascular resistance (FVR) fell by 35 +/- 21% in exercise-induced hypotension patients versus an increase of 78 +/- 65% in patients with an NBP response (P &lt; .0001). Left ventricular ejection fraction increased by 5.1 +/- 7.5% in the group with EIH versus a fall of 4.1 +/- 6.2% in the control group (P = .004). Cardiac output at peak exercise (RNV) increased by 2.2 +/- 0.89-fold in the group with EIH versus 1.49 +/- 0.47-fold in the control group (P = .04). The tenth patient in the group with EIH underwent invasive hemodynamic evaluation during erect exercise. Systolic blood pressure fell (136/80Rest to 50/40Peak) and cardiac output (Fick) tripled, whereas calculated systemic vascular resistance decreased by a factor of 10. Successful angioplasty to an isolated circumflex lesion resulted in resolution of symptoms and abnormal hemodynamic responses during exercise. CONCLUSIONS Abnormal vasodilation associated with a normal or even increased rather than decreased cardiac output response appears to be an important mechanism underlying EIH in some patients with CAD. In the present study, this appears to have been the dominant mechanism in 8 and contributory in 2 of the consecutive patients studied.
New Ulceration, New Major Amputation, and Survival Rates in Diabetic Subjects Hospitalized for Foot Ulceration From 1990 to 1993
Authors: Ezio Faglia, Fabrizio Favales, Alberto Morabito
Journal: Diabetes Care (2001)

To evaluate 1) the new ulceration, the new major amputation, and the survival rates of 115 diabetic subjects hospitalized for foot ulceration from 1990 to 1993, with an average follow-up of 6.5 years, and 2) the demographic and clinical characteristics associated with these events.A total of 115 subjects, 31 women and 84 men, were monitored until 31 December 1998. All subjects were provided with therapeutic shoes and received intense education. Data concerning new ulceration, new major amputation, and reamputation events and the date and cause of death were recorded for each patient. The prognostic factors for these events were then evaluated.The average follow-up was 78.3 +/- 15.3 months (range 60-106). During this time, 13 homolateral and 12 contralateral episodes of new ulceration occurred. At univariate analysis, none of the variables considered were significantly associated with the new ulceration. There were three major amputations: two of the limb previously healed and one of the contralateral limb. Of the 115 subjects, 51 (44.3%) died: 24 of the 31 women (77.4%) and 27 of the 84 men (32.1%). Ischemic cardiopathy was the most frequent cause of death (60.8%). Mortality concerned 20 of the 27 subjects (74.1%) undergoing major amputation from 1990 to 1993 and 31 of the 88 healed subjects (35.2%), with a significant difference (P < 0.0001). Multivariate analysis showed the independent role of the ankle-brachial index < or =0.5 (P = 0.005), age (P = 0.003), and female sex (P = 0.027).We believe that the use of therapeutic shoes and intense educational training, including the education of the family, have contributed to the low incidence of new ulceration and major amputation in our study population. The high frequency of ischemic cardiopathy as a cause of death should, perhaps, lead to a more aggressive diagnostic and therapeutic attitude toward this pathology in diabetic subjects admitted to hospitals for foot ulceration.
Modifiable Etiological Factors and the Burden of Stroke from the Rotterdam Study: A Population-Based Cohort Study
Authors: Michiel J. Bos, Peter J. Koudstaal, Albert Hofman, M. Arfan Ikram
Journal: PLoS Medicine (2014)

Background Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke. Methods and Findings This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990–1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population. The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41–0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41–0.68) for ischemic stroke and 0.70 (95% CI 0.45–0.87) for hemorrhagic stroke. The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population. Conclusions About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors. Please see later in the article for the Editors' Summary
Overcoming bias and systematic errors in next generation sequencing data
Authors: Margaret A Taub, Hector Corrada Bravo, Rafael A Irizarry
Journal: Genome Medicine (2010)

Considerable time and effort has been spent in developing analysis and quality assessment methods to allow the use of microarrays in a clinical setting. As is the case for microarrays and other high-throughput technologies, data from new high-throughput sequencing technologies are subject to technological and biological biases and systematic errors that can impact downstream analyses. Only when these issues can be readily identified and reliably adjusted for will clinical applications of these new technologies be feasible. Although much work remains to be done in this area, we describe consistently observed biases that should be taken into account when analyzing high-throughput sequencing data. In this article, we review current knowledge about these biases, discuss their impact on analysis results, and propose solutions.
How genomics has informed our understanding of the pathogenesis of osteoporosis
Authors: Mark L Johnson, Nuria Lara, Mohamed A Kamel
Journal: Genome Medicine (2009)

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes a person to an increased risk of fracture. Osteoporosis is a complex trait that involves multiple genes, environmental factors, and gene-gene and gene-environment interactions. Twin and family studies have indicated that between 25% and 85% of the variation in bone mass and other skeletal phenotypes is heritable, but our knowledge of the underlying genes is limited. Bone mineral density is the most common assessment for diagnosing osteoporosis and is the most often used quantitative value in the design of genetic studies. In recent years, our understanding of the pathophysiology of osteoporosis has been greatly facilitated by advances brought about by the Human Genome Project. Genetic approaches ranging from family studies of monogenic traits to association studies with candidate genes, to whole-genome scans in both humans and animals have identified a small number of genes that contribute to the heritability of bone mass. Studies with transgenic and knockout mouse models have revealed major new insights into the biology of many of these identified genes, but much more needs to be learned. Ultimately, we hope that by revealing the underlying genetics and biology driving the pathophysiology of osteoporosis, new and effective treatment can be developed to combat and possibly cure this devastating disease. Here we review the rapidly evolving field of the genomics of osteoporosis with a focus on important gene discoveries, new biological/physiological paradigms that are emerging, and many of the unanswered questions and hurdles yet to be overcome in the field.
Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy
Authors: Peter Jacobsen, Steen Andersen, Berit R. Jensen, Hans-Henrik Parving
Journal: Journal of the American Society of Nephrology (2003)

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m2. Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg ( versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN. E-mail: pkjacobsen@dadlnet.dk
Ecologic Studies Revisited
Authors: Jonathan Wakefield
Journal: Annual Review of Public Health (2007)

Ecologic studies use data aggregated over groups rather than data on individuals. Such studies are popular because they use existing databases and can offer large exposure variation if the data arise from broad geographical areas. Unfortunately, the aggregation of data that define ecologic studies results in an information loss that can lead to ecologic bias. Specifically, ecologic bias arises from the inability of ecologic data to characterize within-area variability in exposures and confounders. We describe in detail particular forms of ecologic bias so that their potential impact on any particular study may be assessed. The only way to overcome such bias, while avoiding uncheckable assumptions concerning the missing information, is to supplement the ecologic with individual-level information, and we outline a number of proposals that may achieve this aim.