tbuckley/cabot-search huggingface dataset:
Small Open Reading Frames Pack a Big Punch in Cardiac Calcium Regulation
Authors: Benjamin R. Nelson, Douglas M. Anderson, Eric N. Olson
Journal: Circulation Research (2014)

C ardiac contraction requires continuous cycles of calci- um release and reuptake between the sarcoplasm and sarcoplasmic reticulum.In vertebrate cardiomyocytes, resequestration of calcium to the sarcoplasmic reticulum is accomplished by the SERCA whose activity is dampened by interaction with the small integral membrane proteins, phospholamban and sarcolipin.In a recent report published in Science, Magny et al identify 2 small peptides in Drosophila encoded in a putative long noncoding RNA that buffers calcium reuptake by sarco/endoplasmic reticulum Ca 2+ -ATPase 2a in a similar manner to sarco/endoplasmic reticulum Ca 2+ -ATPase 2a regulation by phospholamban and sarcolipin.These findings demonstrate that regulation of Ca 2+ -ATPases by small transmembrane peptides is a conserved and ancient strategy.Furthermore, this study highlights the possibility that there may be many undiscovered small peptides encoded within putative long noncoding RNAs that regulate important biological pathways.
Developing a universal model of reading necessitates cracking the orthographic code
Authors: Colin J. Davis
Journal: Behavioral and Brain Sciences (2012)

Abstract I argue, contra Frost, that when prime lexicality and target density are considered, it is not clear that there are fundamental differences between form priming effects in Semitic and European languages. Furthermore, identifying and naming printed words in these languages raises common theoretical problems. Solving these problems and developing a universal model of reading necessitates “cracking” the orthographic input code.
ACTIVATION OF HAGEMAN FACTOR IN SOLID AND FLUID PHASES
Authors: C. G. Cochrane, S. D. Revak, K. D. Wuepper
Journal: The Journal of Experimental Medicine (1973)

The activation of Hageman factor in solid and fluid phase has been analyzed. Activation of highly purified Hageman factor occurred after it interacted with and became bound to a negatively charged surface. Activation was observed in the absence of enzymes that are inhibitable with diisopropylfluorophosphate, phenyl methyl sulfonyl fluoride and ϵ-amino-n-caproic acid. The binding of [125I]Hageman factor to the negatively charged surface was markedly inhibited by plasma or purified plasma proteins. Activation of Hageman factor in solution (fluid phase) was obtained with kallikrein, plasmin, and Factor XI (plasma thromboplastin antecedent). Kallikrein was greater than 10 times more active in its ability to activate Hageman factor than plasmin and Factor XI. The data offer a plausible explanation for the finding that highly purified kallikrein promotes clotting of normal plasma. In addition, the combined results of this and previously reported data from this laboratory indicate that the reciprocal activation of Hageman factor by kallikrein in fluid phase is essential for normal rate of activation of the intrinsic-clotting, kinin-forming, and fibrinolytic systems. Activation of Hageman factor was associated with three different structural changes in the molecule: (a) Purified Hageman factor, activated on negatively charged surfaces retained its native mol wt of 80–90,000. Presumably a conformational change accompanied activation. (b) In fluid phase, activation with kallikrein and plasmin did not result in cleavage of large fragments of rabbit Hageman factor, although the activation required hydrolytic capacity of the enzymes. (c) Activation of human Hageman factor with kallikrein or plasmin was associated with cleavage of the molecule to 52,000, 40,000, and 28,000 mol wt fragments. Activation of rabbit Hageman factor with trypsin resulted in cleavage of the molecule into three fragments, each of 30,000 mol wt as noted previously. This major cleavage occurred simultaneously with activation.
Adrenomedullin Administration Immediately After Myocardial Infarction Ameliorates Progression of Heart Failure in Rats
Authors: Ryosai Nakamura, Johji Kato, Kazuo Kitamura, Hisamitsu Onitsuka, Takuroh Imamura, Yuanning Cao, Kousuke Marutsuka, Yujiro Asada, Kenji Kangawa, Tanenao Eto
Journal: Circulation (2004)

Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats.Rats were infused with 1.0 microg/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%; P<0.05) and body weight gain (32%; P<0.01) and reduced heart weight (-28%; P<0.01), lung weight (-26%; P<0.01), left ventricular (LV) end-diastolic pressure (11.4+/-2.0 versus 4.0+/-0.6 mm Hg, mean+/- SEM; P<0.01), collagen volume fraction of noninfarcted LV (-39%; P<0.05), and plasma levels of endogenous rat AM (-38%; P<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (-61%; P<0.01) and noninfarcted LV mRNA levels of ACE (-31%; P<0.05) and p22-phox (-30%; P<0.05).AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.
Voluntary fluid intake and core temperature responses in adolescent tennis players: sports beverage versus water
Authors: M F Bergeron, J L Waller, E L Marinik
Journal: British Journal of Sports Medicine (2006)

Objective: To examine differences in ad libitum fluid intake, comparing a 6% carbohydrate/electrolyte drink (CHO-E) and water, and associated differences in core temperature and other selected physiological and perceptual responses in adolescent athletes during tennis training in the heat. Methods: Fourteen healthy, fit, young tennis players (nine male; five female; mean (SD) age 15.1 (1.4) years; weight 60.6 (8.3) kg; height 172.8 (8.6) cm) completed two 120 minute tennis specific training sessions on separate days (randomised, crossover design) in a warm environment (wet bulb globe temperature: CHO-E, 79.3 (2.6) °F; water, 79.9 (2.2) °F; p&gt;0.05). Results: There were no significant differences (p&gt;0.05) between the trials with respect to fluid intake, urine volume, fluid retention, sweat loss, perceived exertion, thirst, or gastrointestinal discomfort. However, there was a difference (p&lt;0.05) in the percentage body weight change after training (CHO-E, −0.5 (0.7)%; water, −0.9 (0.6)%). Urine specific gravity before training (CHO-E, 1.024 (0.006); water, 1.025 (0.005)) did not correlate significantly (p&gt;0.05) with any of these measurements or with core body temperature. In examining the main effect for trial, the CHO-E trial showed a significantly lower (p&lt;0.001) mean body temperature (irrespective of measurement time) than the water trial. However, the mean body temperature in each trial was not associated (p&gt;0.05) with fluid intake, fluid retention, sweat loss, or percentage body weight change. Conclusion: Ad libitum consumption of a CHO-E drink may be more effective than water in minimising fluid deficits and mean core temperature responses during tennis and other similar training in adolescent athletes.
Depigmented–polymerized mixed grass/birch pollen extract immunotherapy is effective in polysensitized patients
Authors: O. Pfaar, T. Biedermann, L. Klimek, A. Sager, D. S. Robinson
Journal: Allergy (2013)

Abstract Background Although many patients with allergic rhinoconjunctivitis have symptoms due to sensitization with more than one pollen allergen, and mixed pollen extracts are widely used for allergen immunotherapy in practice, there are few published trials. Methods We performed a 2‐year multicentre, double‐blind, placebo‐controlled trial of subcutaneous immunotherapy with mixed depigmented–polymerized birch and grass pollen extract in 285 patients with allergic rhinoconjunctivitis symptomatic during both birch and grass pollen seasons. Primary outcome was combined symptom and medication score (SMS) assessed by daily visual analogue scales (VAS). Analysis included a placebo‐based analysis examining the effect of treatment only on days when placebo patients were symptomatic. Results There was a significant reduction in median SMS for actively treated patients (median 5.70 (interquartile range 2.62–10.02) compared with 7.07 (3.47–10.71) for placebo, P = 0.0385). Rhinitis quality‐of‐life scores were significantly better for active compared with placebo, and other secondary endpoints were not significantly different. Placebo‐based analysis showed a 33.7% reduced SMS at year 2 for active treatment compared with placebo on days when placebo patients were symptomatic. Both birch pollen‐ and grass pollen‐specific IgG 4 increased with active treatment. Conclusions This study shows efficacy of mixed pollen extracts for immunotherapy for patients symptomatic to both birch and grass pollen allergens. The relatively modest effect may reflect 50% dose reduction for each allergen in the mixture. It supports VAS for symptom assessment and placebo‐based analysis as useful for the analysis of immunotherapy trials. The safety of modified extracts may allow study of mixed extracts without dose reduction to improve efficacy.
“Companion Diagnostics”: Has Their Time Come and Gone?
Authors: Fred R. Hirsch, Paul A. Bunn, Roy S. Herbst
Journal: Clinical Cancer Research (2014)

Abstract Rapid development of molecularly targeted drugs requires a “companion diagnostic” that could delay drug development and limit availability of active drugs for relevant patients. Were the negative results from MetMab studies in patients with advanced non–small cell lung cancer due to drug failure or failure of the right companion diagnostic? Clin Cancer Res; 20(17); 4422–4. ©2014 AACR.
Do Sensor Glucose Levels Accurately Predict Plasma Glucose Concentrations During Hypoglycemia and Hyperinsulinemia?
Authors: Teresa P. Monsod, Daniel E. Flanagan, Fran Rife, Rebecca Saenz, Sonia Caprio, Robert S. Sherwin, William V. Tamborlane
Journal: Diabetes Care (2002)

OBJECTIVE—The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three or more fingerstick glucose levels daily. The objective of the present study was to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance. RESEARCH DESIGN AND METHODS—Arterialized plasma glucose, sensor glucose, and interstitial fluid glucose were measured by microdialysis in 11 healthy subjects during a 1.0 mU · kg−1 · min−1 stepped euglycemic-hypoglycemic-hyperglycemic (plasma glucose ∼5, 3.1, and 8.6 mmol/l, respectively) insulin clamp that raised plasma insulin to ∼360–390 pmol/l. RESULTS—When the CGMS was calibrated versus plasma glucose levels before insulin infusion, basal sensor and plasma glucose were similar (5.0 ± 0.3 vs. 5.2 ± 0.3 mmol/l, respectively); dialysate glucose was 3.3 ± 0.9 mmol/l. During the hyperinsulinemic-euglycemia study (plasma glucose 4.9 ± 0.3 mmol/l), dialysate glucose fell by 30–35%, accompanied by a significant reduction in sensor glucose (to 3.7 ± 0.6 mmol/l; P &amp;lt; 0.001 vs. plasma). Subsequently, sensor levels remained lower than plasma values during mild hypoglycemia (2.5 ± 0.6 vs. 3.1 ± 0.3 mmol/l; P &amp;lt; 0.01) and during recovery from hypoglycemia (7.3 ± 1.2 vs. 8.6 ± 0.6; P &amp;lt; 0.01). However, when the CGMS was calibrated against plasma glucose levels before and during each step of the clamp, sensor glucose levels increased throughout the study and did not differ from plasma glucose values during hypoglycemia. CONCLUSIONS—Although hyperinsulinemia may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels.
Outcome of Listing for Cardiac Transplantation for Failed Fontan
Authors: D. Bernstein, D. Naftel, C. Chin, L.J. Addonizio, P. Gamberg, E.D. Blume, D. Hsu, C.E. Canter, J.K. Kirklin, W.R. Morrow
Journal: Circulation (2006)

Background— The Fontan procedure is a successful palliation for children with single-ventricle physiology; however, many will eventually require heart transplantation. The purpose of this study was to determine risk factors for death awaiting transplantation and to examine results after transplantation in Fontan patients. Methods and Results— A retrospective, multi-institutional review was performed of 97 Fontan patients &lt;18 years of age listed at 17 Pediatric Heart Transplant Study centers from 1993 to 2001. Mean age at listing was 9.7 years (0.5 to 17.9 years); 25% were &lt;4 years old; 53% were United Network for Organ Sharing status 1; 18% required ventilator support. Pretransplantation survival was 78% at 6 months and 74% at 12 months and was similar to 243 children with other congenital heart disease (CHD) and 747 children without congenital heart disease (No-CHD), who were also awaiting transplantation. Patients who were younger, status 1, had shorter interval since Fontan, or were on a ventilator were more likely to die while waiting. At 6 months, the probability of receiving a transplant was similar for status 1 and 2 (65% versus 68%); however, the probability of death was higher for status 1 (22% versus 5%). Seventy patients underwent transplantation. Survival was 76% at 1 year, 70% at 3 years, and 68% at 5 years, slightly less than CHD and No-CHD patients. Causes of death included infection (30%), graft failure (17%), rejection (13%), sudden death (13%), and graft coronary artery disease (9%). Protein-losing enteropathy (present in 34 patients) resolved in all who survived &gt;30 days after transplantation. Conclusions— Heart transplantation is an effective therapy for pediatric patients with a failed Fontan. Although early posttransplantation survival is slightly lower than other patients with CHD, long-term results are encouraging, and protein-losing enteropathy can be expected to resolve.
Phase I Study of Immunization with Dendritic Cells Modified with Fowlpox Encoding Carcinoembryonic Antigen and Costimulatory Molecules
Authors: Michael A. Morse, Timothy M. Clay, Amy C. Hobeika, Takuya Osada, Shubi Khan, Stephen Chui, Donna Niedzwiecki, Dennis Panicali, Jeffrey Schlom, H. Kim Lyerly
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. Experimental Design: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2–restricted peptide derived from cytomegalovirus pp65 protein. Results: Fourteen patients (11 with colorectal cancer and 3 with non–small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/105 peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4+ and CD8+ T cells in all immune responders. Conclusion: This immunization strategy is safe and activates potent CEA-specific immune responses.
Novel identification of the <i>IRF7</i> region as an anticentromere autoantibody propensity locus in systemic sclerosis
Authors: F David Carmona, Ramana Gutala, Carmen P Simeón, Patricia Carreira, Norberto Ortego-Centeno, Esther Vicente-Rabaneda, Francisco J García-Hernández, Paloma García de la Peña, Mónica Fernández-Castro, Lina Martínez-Estupiñán, María Victoria Egurbide, Betty P Tsao, Pravitt Gourh, Sandeep K Agarwal, Shervin Assassi, Maureen D Mayes, Frank C Arnett, Filemon K Tan, Javier Martín
Journal: Annals of the Rheumatic Diseases (2011)

Objective Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. Methods Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. Results Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: p FDR =6.14 × 10 −4 , OR=0.78; rs4963128: p FDR =6.14 × 10 −4 , OR=0.79; rs702966: p FDR =3.83 × 10 −3 , OR=0.82; and rs2246614: p FDR =3.83 × 10 −3 , OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. Conclusions The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.
Influence of Acute Variations in Hematocrit on the QRS Complex of the Frank Electrocardiogram
Authors: AMNON ROSENTHAL, NORMA J. RESTIEAUX, STEPHEN A. FEIG
Journal: Circulation (1971)

The influence of acute variations in hematocrit on the QRS complex of the Frank scalar electrocardiogram was studied in 31 patients with severe polycythemia secondary to cyanotic congenital heart disease and in eight patients with anemia due to thalassemia. Moderate reduction of the hematocrit in the polycythemic group resulted in a significant increase in the magnitude and a delay in both left maximal spatial voltage (LMSV) and maximal anterior force. Raising the hematocrit in the anemic group decreased the magnitude of LMSV and maximal anterior force. A change in the orientation of the spatial vector frequently accompanied induced variations in the hematocrit. Experimental and theoretical studies suggest that alterations in the hematocrit and, hence, intracardiac electrical resistivity distort the magnitude and orientation of the surface-recorded QRS voltages. It is postulated that the effect of high intracavitary blood hematocrit in polycythemia in reducing early QRS voltages is due to its influence on radial myocardial excitation propagated from endocardium to epicardium. Anemia, on the other hand, enhances the voltages due to radial spread of impulses in the myocardium, resulting in an increased magnitude of the LMSV and usually also of the maximal anterior force.
Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids
Authors: Lirui Wang, Phillipp Hartmann, Michael Haimerl, Sai P. Bathena, Christopher Sjöwall, Sven Almer, Yazen Alnouti, Alan F. Hofmann, Bernd Schnabl
Journal: Journal of Hepatology (2014)
Fibromyalgia: A Stress Disorder?
Authors: Boudewijn van Houdenhove, Ulrich T. Egle
Journal: Psychotherapy and Psychosomatics (2004)

Fibromyalgia (FM) is a controversial syndrome, characterised by persistent widespread pain, abnormal pain sensitivity and additional symptoms such as fatigue and sleep disturbance. The syndrome largely overlaps with other functional somatic disorders, particularly chronic fatigue syndrome (CFS). Although the exact aetiology and pathogenesis of FM are still unknown, it has been suggested that stress may play a key role in the syndrome. This article first reviews the function of the stress response system, placing special emphasis on the relationships between adverse life experiences, stress regulation and pain-processing mechanisms, and summarising the evidence for a possible aetiopathogenetic role of stress in FM. Finally, an integrative biopsychosocial model that conceptualises FM as a stress disorder is proposed, and the clinical and research implications of the model are discussed.
Rectification of the Background Potassium Current
Authors: Faramarz H. Samie, Omer Berenfeld, Justus Anumonwo, Sergey F. Mironov, Sharda Udassi, Jacques Beaumont, Steven Taffet, Arkady M. Pertsov, José Jalife
Journal: Circulation Research (2001)

Ventricular fibrillation (VF) is the leading cause of sudden cardiac death. Yet, the mechanisms of VF remain elusive. Pixel-by-pixel spectral analysis of optical signals was carried out in video imaging experiments using a potentiometric dye in the Langendorff-perfused guinea pig heart. Dominant frequencies (peak with maximal power) were distributed throughout the ventricles in clearly demarcated domains. The fastest domain (25 to 32 Hz) was always on the anterior left ventricular (LV) wall and was shown to result from persistent rotor activity. Intermittent block and breakage of wavefronts at specific locations in the periphery of such rotors were responsible for the domain organization. Patch-clamping of ventricular myocytes from the LV and the right ventricle (RV) demonstrated an LV-to-RV drop in the amplitude of the outward component of the background rectifier current ( I B ). Computer simulations suggested that rotor stability in LV resulted from relatively small rectification of I B (presumably I K1 ), whereas instability, termination, and wavebreaks in RV were a consequence of strong rectification. This study provides new evidence in the isolated guinea pig heart that a persistent high-frequency rotor in the LV maintains VF, and that spatially distributed gradients in I K1 density represent a robust ionic mechanism for rotor stabilization and wavefront fragmentation.
Delayed Anaphylactic Reactions to Mammalian Meat are not Associated with an Increased Prevalence of Asthma
Authors: L.A. Kelly, S.L. Pochan, H.R. James, L.J. Workman, P.W. Heymann, S.P. Commins, T.A.E. Platts-Mills
Journal: Journal of Allergy and Clinical Immunology (2011)