tbuckley/cabot-search huggingface dataset:
Brain Angiotensin-Converting Enzyme Type 2 Shedding Contributes to the Development of Neurogenic Hypertension
Authors: Huijing Xia, Srinivas Sriramula, Kavaljit H. Chhabra, Eric Lazartigues
Journal: Circulation Research (2013)

Rationale : Overactivity of the brain renin–angiotensin system is a major contributor to neurogenic hypertension. Although overexpression of angiotensin-converting enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming angiotensin II into angiotensin-(1–7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension. Objective : We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension. Methods and Results : To test this hypothesis, we used the deoxycorticosterone acetate–salt model of neurogenic hypertension in nontransgenic and syn-hACE2 mice overexpressing ACE2 in neurons. Deoxycorticosterone acetate–salt treatment in nontransgenic mice led to significant increases in blood pressure, hypothalamic angiotensin II levels, inflammation, impaired baroreflex sensitivity, and autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, although these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled an increase in ACE2 activity in the cerebrospinal fluid of nontransgenic mice after deoxycorticosterone acetate–salt treatment and were accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function. Conclusions : Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension.
Phenotypic Expansion of DGKE-Associated Diseases
Authors: Rik Westland, Monica Bodria, Alba Carrea, Sneh Lata, Francesco Scolari, Veronique Fremeaux-Bacchi, Vivette D. D’Agati, Richard P. Lifton, Ali G. Gharavi, Gian Marco Ghiggeri, Simone Sanna-Cherchi
Journal: Journal of the American Society of Nephrology (2014)

Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complement activation. The recent discovery of loss-of-function mutations in DGKE in patients with aHUS and normal complement levels challenged this observation. DGKE, encoding diacylglycerol kinase-ε, has not been implicated in the complement cascade but hypothetically leads to a prothrombotic state. The discovery of this novel mechanism has potential implications for the treatment of infants with aHUS, who are increasingly treated with complement blocking agents. In this study, we used homozygosity mapping and whole-exome sequencing to identify a novel truncating mutation in DGKE (p.K101X) in a consanguineous family with patients affected by thrombotic microangiopathy characterized by significant serum complement activation and consumption of the complement fraction C3. Aggressive plasma infusion therapy controlled systemic symptoms and prevented renal failure, suggesting that this treatment can significantly affect the natural history of this aggressive disease. Our study expands the clinical phenotypes associated with mutations in DGKE and challenges the benefits of complement blockade treatment in such patients. Mechanistic studies of DGKE and aHUS are, therefore, essential to the design of appropriate therapeutic strategies in patients with DGKE mutations.
1148-266 Reverse left ventricular remodeling by carvedilol reduces the spatial dispersion of QRS duration in patients with chronic heart failure: A prospective placebo-controlled study
Authors: Takahisa Yamada, Tsuyoshi Shimonagata, Naoyuki Misaki, Mitsutoshi Asai, Nobuhiko Makino, Hidetaka Kioka, Shunsuke Tamaki, Masatake Fukunami
Journal: Journal of the American College of Cardiology (2004)
Late relapse in primary central nervous system lymphoma: clonal persistence
Authors: L. Nayak, C. Hedvat, M. K. Rosenblum, L. E. Abrey, L. M. DeAngelis
Journal: Neuro-Oncology (2011)

Recurrence of primary central nervous system lymphoma (PCNSL) after initial diagnosis and treatment occurs within 2 years in most patients, and relapse after 5 years is rare. We evaluated late relapse in our PCNSL population. We identified 10 patients from our database of 378 patients (268 achieved a complete response and 230 had relapse) with PCNSL who had relapse ≥5 years after initial diagnosis. At initial diagnosis, their median age was 47 years; all patients had brain involvement and achieved a complete response to initial therapy (9 received high-dose methotrexate). Median time to first relapse was 7.4 years (range, 5.2-14.6 y). Eight patients had relapse in the brain, 1 had ocular relapse, and 1 had a systemic relapse. The histologic specimens at initial diagnosis and relapse were examined for clonal rearrangement in 3 patients; 1 had the identical clone at initial diagnosis and relapse 13.8 years later, and the other 2 were uninformative. All patients received salvage therapy (9 received systemic therapy and 1 received intraocular chemotherapy. Nine patients achieved a complete response to salvage therapy and 1 achieved a partial response. Four patients had relapse a second time. The median progression-free survival after first relapse was 31 months (range, 7.9-82.4). Late relapses accounted for 4% of all recurrences (10 of 230 patients) in our PCNSL population. Long-term persistence of the PCNSL clone was observed in one patient. Patients with late relapses have a good response to salvage therapy and prolonged survival.
Everolimus for the Prevention of Allograft Rejection and Vasculopathy in Cardiac-Transplant Recipients
Authors: Howard J. Eisen, E. Murat Tuzcu, Richard Dorent, Jon Kobashigawa, Donna Mancini, Hannah A. Valantine-von Kaeppler, Randall C. Starling, Keld Sørensen, Manfred Hummel, Joan M. Lind, Kamal H. Abeywickrama, Peter Bernhardt
Journal: New England Journal of Medicine (2003)

Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant.A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise.At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group.Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.
Hepatic and Peripheral Insulin Sensitivity and Diabetes Remission at 1 Month After Roux-en-Y Gastric Bypass Surgery in Patients Randomized to Omentectomy
Authors: Julia P. Dunn, Naji N. Abumrad, Igal Breitman, Pamela A. Marks-Shulman, Charles Robb Flynn, Kareem Jabbour, Irene D. Feurer, Robyn A. Tamboli
Journal: Diabetes Care (2011)

Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB.We studied 40 obese (BMI 48 ± 8 kg/m(2)) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity.Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP.Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.
First clinical use of a bioprosthetic total artificial heart: report of two cases
Authors: Alain Carpentier, Christian Latrémouille, Bernard Cholley, David M Smadja, Jean-Christian Roussel, Elodie Boissier, Jean-Noël Trochu, Jean-Pierre Gueffet, Michèle Treillot, Philippe Bizouarn, Denis Méléard, Marie-Fazia Boughenou, Olivier Ponzio, Marc Grimmé, Antoine Capel, Piet Jansen, Albert Hagège, Michel Desnos, Jean-Noël Fabiani, Daniel Duveau
Journal: The Lancet (2015)
Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis
Authors: H Nikki March, Alistair G Rust, Nicholas A Wright, Jelle ten Hoeve, Jeroen de Ridder, Matthew Eldridge, Louise van der Weyden, Anton Berns, Jules Gadiot, Anthony Uren, Richard Kemp, Mark J Arends, Lodewyk F A Wessels, Douglas J Winton, David J Adams
Journal: Nature Genetics (2011)
Clinical implications of late proven patency after successful coronary angioplasty.
Authors: W S Weintraub, Z M Ghazzal, C L Cohen, J S Douglas, H Liberman, D C Morris, S B King
Journal: Circulation (1991)

The introduction of percutaneous transluminal coronary angioplasty (PTCA) has changed the pattern of intervention in coronary artery disease. However, the long-term results in patients undergoing successful, elective, native-vessel PTCA are not yet fully characterized. Because the healing and subsequent proliferative response after angioplasty are time related, it was the purpose of the present study to determine the long-term outcome in patients whose dilated arteries have been demonstrated to be patent 4-12 months after successful, uncomplicated PTCA.The patients were grouped on the basis of the 4-12 month catheterization into those whose vessels were angiographically "normal" or had luminal irregularities only at the PTCA sites (396 patients), those whose vessels also had luminal irregularities elsewhere with or without PTCA site luminal irregularities (680 patients), and those with significant obstructive disease (more than 50% diameter narrowing) at sites other than the PTCA sites (426 patients). Of 1,502 such patients, long-term follow-up was available in 1,491. At the time of the original angioplasty, the normal patients had a 1.8% incidence of multivessel disease; luminal irregularity patients, 9.4%; and obstructive disease patients, 58.7%. At angiographic restudy, 16.4% of the obstructive disease patients continued to have multivessel disease. The patients were followed for the events of death, myocardial infarction, coronary surgery, and repeat PTCA. The 6-year survival rate was 95%; cardiac survival, 96%; and freedom from all events, 65%. The strongest correlate of events during follow-up was the angiographic status of the undilated segments. At 6 years, freedom from cardiac events was noted in 77% of the normal group, 61% of the luminal irregularity group, and 55% of the obstructive disease group. Diabetes and hypertension were also independent correlates of events.Results from the present study show that associated disease in undilated segments is a strong predictor of late events in patients after successful, uncomplicated, reatenosis-free PTCA. However, the need for further revascularization was frequent even in patients without obstructive disease. Completeness of revascularization is appropriate when possible, and limiting progression of coronary disease at sites remote from those dilated should improve on these late results.
Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial
Authors: Michael Gnant, Georg Pfeiler, Peter C Dubsky, Michael Hubalek, Richard Greil, Raimund Jakesz, Viktor Wette, Marija Balic, Ferdinand Haslbauer, Elisabeth Melbinger, Vesna Bjelic-Radisic, Silvia Artner-Matuschek, Florian Fitzal, Christian Marth, Paul Sevelda, Brigitte Mlineritsch, Günther G Steger, Diether Manfreda, Ruth Exner, Daniel Egle, Jonas Bergh, Franz Kainberger, Susan Talbot, Douglas Warner, Christian Fesl, Christian F Singer
Journal: The Lancet (2015)
Reliability of the Food Allergy Quality of Life Questionnaires (FAQLQs) for Children, Teenagers and Adults
Authors: B FLOKSTRADEBLOK, J VANDERVELDE, A DUNNGALVIN, J OUDEELBERINK, B VLIEGBOERSTRA, E DUIVERMAN, J SCHOUTEN, J HOURIHANE, A DUBOIS
Journal: Journal of Allergy and Clinical Immunology (2008)
Cross-sectional echocardiography. I. Analysis of mathematic models for quantifying mass of the left ventricle in dogs.
Authors: H L Wyatt, M K Heng, S Meerbaum, J D Hestenes, J M Cobo, R M Davidson, E Corday
Journal: Circulation (1979)

Cross-sectional echocardiography was used to quantify left ventricular mass noninvasively in 21 dogs. Short- and long-axis cross-sectional images of the left ventricle were reproducibly traced at endocardial and epicardial borders during stop-motion video-tape replay. We used area, length and diameter measurements to calculate left ventricular mass by seven mathematic models, including the standard formulas used with M-mode echocardiography and cineangiography. Calculated mass was compared with excised weight of the left ventricle by regression and percent error analyses. Formulas using short-axis areas and long-axis length resulted in higher correlation coefficients (0.94--0.95) and lower mean errors (6--7%) than for standard formulas. Since short-axis areas account for regional left ventricular irregularities, noninvasive quantification of left ventricular mass by cross-sectional echocardiography in dogs is most accurate with formulas using short-axis areas.
Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis
Authors: Masha Fridkis-Hareli, Laura Santambrogio, Joel N.H. Stern, Lars Fugger, Celia Brosnan, Jack L. Strominger
Journal: Journal of Clinical Investigation (2002)

Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four–amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99–specific HLA-DR2–restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2s) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
Long-term effectiveness and cost-effectiveness of smoking cessation interventions in patients with COPD
Authors: M. Hoogendoorn, T. L. Feenstra, R. T. Hoogenveen, M. P. M. H. Rutten-van Molken
Journal: Thorax (2010)

<h3>Background</h3> The aim of this study was to estimate the long-term (cost-) effectiveness of smoking cessation interventions for patients with chronic obstructive pulmonary disease (COPD). <h3>Methods</h3> A systematic review was performed of randomised controlled trials on smoking cessation interventions in patients with COPD reporting 12-month biochemical validated abstinence rates. The different interventions were grouped into four categories: usual care, minimal counselling, intensive counselling and intensive counselling + pharmacotherapy (‘pharmacotherapy’). For each category the average 12-month continuous abstinence rate and intervention costs were estimated. A dynamic population model for COPD was used to project the long-term (cost-) effectiveness (25 years) of 1-year implementation of the interventions for 50% of the patients with COPD who smoked compared with usual care. Uncertainty and one-way sensitivity analyses were performed for variations in the calculation of the abstinence rates, the type of projection, intervention costs and discount rates. <h3>Results</h3> Nine studies were selected. The average 12-month continuous abstinence rates were estimated to be 1.4% for usual care, 2.6% for minimal counselling, 6.0% for intensive counselling and 12.3% for pharmacotherapy. Compared with usual care, the costs per quality-adjusted life year (QALY) gained for minimal counselling, intensive counselling and pharmacotherapy were €16 900, €8200 and €2400, respectively. The results were most sensitive to variations in the estimation of the abstinence rates and discount rates. <h3>Conclusion</h3> Compared with usual care, intensive counselling and pharmacotherapy resulted in low costs per QALY gained with ratios comparable to results for smoking cessation in the general population. Compared with intensive counselling, pharmacotherapy was cost saving and dominated the other interventions.
A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder
Authors: C J McDougle, L E Kresch, W K Goodman, S T Naylor, F R Volkmar, D J Cohen, L H Price
Journal: American Journal of Psychiatry (1995)

The purpose of this study was to investigate the types of repetitive thoughts and behavior demonstrated by adults with autistic disorder and compare them with those of age- and sex-matched adults with obsessive-compulsive disorder.Fifty consecutive patients admitted to the Yale Adult Pervasive Developmental Disorders (Autism) Clinic with a primary diagnosis of autistic disorder (DSM-III-R and DSM-IV) completed the symptom checklist of the Yale-Brown Obsessive Compulsive Scale. Types of current obsessions and compulsions were evaluated. The comparison group consisted of 50 age- and sex-matched adults with obsessive-compulsive disorder (without tics) (DSM-III-R and DSM-IV).Direct discriminant function analysis showed that the patients with autistic disorder could be distinguished from those with obsessive-compulsive disorder on the basis of the types of current repetitive thoughts and behavior that they demonstrated. Compared to the obsessive-compulsive group, the autistic patients were significantly less likely to experience thoughts with aggressive, contamination, sexual, religious, symmetry, and somatic content. Repetitive ordering; hoarding; telling or asking (trend); touching, tapping, or rubbing; and self-damaging or self-mutilating behavior occurred significantly more frequently in the autistic patients, whereas cleaning, checking, and counting behavior was less common in the autistic group than in the patients with obsessive-compulsive disorder. In addition, a specific subset of seven obsessive-compulsive variables from the Yale-Brown Obsessive Compulsive Scale symptom checklist was identified that reliably predicted membership in the autistic group.These results suggest that the repetitive thoughts and behavior characteristics of autism differ significantly from the obsessive-compulsive symptoms displayed by patients with obsessive-compulsive disorder. Future studies are warranted to assess the treatment response and neurobiological underpinnings of repetitive thoughts and behavior in patients with autism and obsessive-compulsive disorder.
Further insight into the structural and regulatory properties of the cGMP-gated channel
Authors: Robert S. Molday, Yi-Te Hsu
Journal: Behavioral and Brain Sciences (1995)

Abstract Recent studies from several different laboratories have provided further insight into structure-function relationships of cyclic nucleotide-gated channel and in particular the cCMPgated channel of rod photoreceptors. Site-directed mutagenesis and rod-olfactory chimeria constructs have defined important amino acids and peptide segments of the channel that are important in ion blockage, ligand specificity, and gating properties. Molecular cloning studies have indicated that cyclic nucleotide-gated channels consist of two subunits that are required to reproduce the properties of the native channels. Biochemical analysis of the cGMP-gated channel of rodcells have indicated that the 240 kDa protein that co-purifies with the 63 kDa channel subunit contains both the previously cloned second subunit of the channel and a glutamic acid-rich protein. The regulatory properties of the cGMP-gated channel from rod cells has also been studied in more detail. Studies indicate that the beta subunit of the cGMP-gated channel of rod cells contains the binding site for calmodulin. Interaction of calmodulin with the channel alters the apparent affinity of the channel for cGMP in all in vitro systems that have been studied. The significance of these recent studies are discussed in relation to the commentaries on the target article.