tbuckley/cabot-search huggingface dataset:
Disturbed B Cell Homeostasis in Newly Diagnosed Giant Cell Arteritis and Polymyalgia Rheumatica
Authors: Kornelis S. M. van der Geest, Wayel H. Abdulahad, Paulina Chalan, Abraham Rutgers, Gerda Horst, Minke G. Huitema, Mirjam P. Roffel, Caroline Roozendaal, Philip M. Kluin, Nicolaas A. Bos, Annemieke M. H. Boots, Elisabeth Brouwer
Journal: Arthritis & Rheumatology (2014)

Several lines of evidence indicate that B cells may be involved in the immunopathology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). This study was undertaken to examine the distribution of defined B cell subsets, including effector B (Beff) cells and regulatory B (Breg) cells, in patients with GCA and patients with PMR before and after corticosteroid treatment.Circulating B cells were analyzed in 34 newly diagnosed, untreated patients with GCA or PMR, and in 44 followup samples from patients with GCA or PMR who received corticosteroids for 2 weeks or 3 months. For comparison, 40 age-matched healthy controls and 11 rheumatoid arthritis (RA) patients were included. Serum BAFF levels were determined, and temporal arteries were studied by immunohistochemistry.Patients newly diagnosed as having GCA or PMR, but not patients with RA, had decreased numbers of circulating B cells compared to healthy controls. B cell numbers recovered rapidly in treated patients with GCA and PMR in remission. This recovery was not achieved by compensatory hyperproliferation or enhanced bone marrow production. B cell numbers inversely correlated with erythrocyte sedimentation rates, C-reactive protein levels, and serum BAFF levels. Tumor necrosis factor α-positive Beff cells, but not interleukin-10 (IL-10)-positive Breg cells, were decreased in patients newly diagnosed as having GCA or PMR. Following treatment, circulating numbers of Beff cells normalized. The returning Beff cells demonstrated an enhanced capacity to produce IL-6. Few B cells were found in temporal artery biopsy specimens from GCA patients.We show for the first time that the distribution of B cells is highly disturbed in GCA and PMR and that B cells likely contribute to the enhanced IL-6 response in both diseases.
Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease
Authors: Joan C. Gill, Giancarlo Castaman, Jerzy Windyga, Peter Kouides, Margaret Ragni, Frank W. G. Leebeek, Ortrun Obermann-Slupetzky, Miranda Chapman, Sandor Fritsch, Borislava G. Pavlova, Isabella Presch, Bruce Ewenstein
Journal: Blood (2015)
Abstract 17341: The Matricellular Protein CCN2/CTGF Enhances Scar Healing After Myocardial Infarction and Inhibits TGFβ-Induced Myofibroblast Differentiation Limiting Myocardial Fibrosis
Authors: Ole J Kaasboell, Geir Florholmen, Else Marie V Hagelin, Mohammed Shakil Ahmed, Håvard Attramadal, Erhe Gao, Walter J Koch
Journal: Circulation (2013)

Adequate scar healing is critical after myocardial infarction (MI). However, prolonged activity of myofibroblasts may cause excessive myocardial fibrosis leading to impaired cardiac function. We have previously shown that myocardial expression of CCN2 is substantially increased in ischemic heart failure. Yet, the role of CCN2 in healing of MI and in regulation of myocardial fibrosis is still poorly understood. Thus, the objective of this study is to investigate the role of CCN2 in infarct healing and myocardial fibrosis following MI. MI was induced by ligation of the left coronary artery in transgenic mice with cardiac-restricted overexpression of CCN2 (Tg-CCN2) and in non-transgenic control (NTC) mice. Fibroblasts were isolated from NTC mice and stimulated with or without recombinant (r)CCN2 (250 nmol/L) and/or TGFβ-1 (2.5 μg/ml) after first passage. Area of necrosis 24 hours after induction of MI was similar in Tg-CCN2 and NTC mice. Deposition of collagen in the infarct region was higher and increased more rapidly in Tg-CCN2 mice than in NTC mice (day 5 post-MI collagen content NTC 16.6 ± 0.8 vs Tg-CCN2 21.3 ± 0.4 μg/mg dry weight, p
Association between SSRIs and upper gastrointestinal bleeding
Authors: D Williams
Journal: BMJ (2000)

Childhood obesity Breast feeding is importantEditor-Frühbeck does not consider the role of infant feeding in the aetiology of childhood overweight and obesity. 1 Dewey et al found that formula fed infants were heavier than those who received no milk other than breast milk in the first 12 months, although they were of similar length and head circumference. 2 The study also found that the energy intake of breastfed infants was lower than that of formula fed infants, even after the introduction of solids, and suggested that relatively low energy intakes are a function of self regulation in breastfed infants.Von Kries et al found in children aged 5 and 6 years a substantial, dose dependent, protective effect of breast feeding on obesity and overweight: three to five months of exclusive breast feeding was associated with a 35% reduction in obesity at the age of 5 to 6 years.They discuss the evidence for a programming effect of breast feeding in preventing obesity and overweight in later life. 3 Breast feeding mothers lose weight after pregnancy more effectively than those who feed artificially, an advantage seen over at least the first 12 months of breast feeding. 4t seems that promoting and supporting breast feeding should be part of the initiative to tackle the "epidemic of obesity." 5
Abstract 15669: Generation and LDLR Functional Correction of Familial Hypercholesterolemia iPSC With Physiologically Responsive Non-Integrating BAC Vector
Authors: Venkat M Ramakrishnan, Jeong Yeh Yang, Patrick O Burchell, Kevin T Tien, Braden R Bocard, John G Maijub, Stuart K Williams, Richard Wade-Martins, Franklin D West, Nolan L Boyd
Journal: Circulation (2014)

Familial Hypercholesterolemia (FH) is a monogenic disorder of low-density lipoprotein receptor (LDLR) dysfunction, resulting in pathological LDL cholesterol levels and accelerated cardiovascular disease. Many FH patients are refractory to pharmacologic therapies and require cholesterol apheresis or liver transplant. Induced pluripotent stem cells (iPSC) are a promising cell-based option for ameliorating such disorders, though clinically relevant approaches for their functional correction remain to be explored. Homozygous FH fibroblasts were used to generate iPSC (FH-iPSC) using non-integrating synthetic modified mRNAs. Pluripotence was confirmed via immunocytochemistry (OCT4, SOX2, SSEA4, TRA 1-60 &amp; TRA 1-81), in vitro spontaneous differentiation, and in vivo teratoma formation. To mitigate LDLR dysfunction, FH-iPSC were non-virally transfected with a physiologically sensitive episomal LDLR BAC-based plasmid, circumventing cytotoxic LDLR over-expression, insertional mutagenesis, and transgene activation. Transfected colonies (FH-iPSC-LDLR) were selected via Hygromycin-B resistance. After six months of continuous culture, the plasmid was rescued by alkaline lysis, isolated, and introduced into CHO-a7 (LDLR-/-) cells. AgeI restriction digest analysis was performed and DiI-LDL uptake qualitatively demonstrated plasmid functionality. FH-iPSC were also differentiated into hepatocyte-like cells (FH-HLC) and tested for definitive endoderm (SOX17, HNF4α, GATA4) and hepatocyte lineage (AFP, Albumin) markers via PCR and immunocytochemistry. FH-HLC stored lipids and cleared Indocyanine Green. Corrected FH-HLC (FH-HLC-LDLR) qualitatively exhibited markedly increased DiI-LDL internalization compared to dysfunctional FH-HLC (Figure 1). These experiments support a proof-of-principle that patient-specific iPSC can be generated and functionally rescued with clinically relevant vectors to produce therapeutic cell lines.
Abstract 12193: Cardiovascular Toxicity of Carfilzomib on Vascular Tone, Vascular Reactivity and Endothelial Function
Authors: Tiziano Scarabelli, Mara Gavazzoni, Carol Chen-Scarabelli, Gagan Sahni, Louis Saravolatz, Jagat Narula, Riccardo Raddino
Journal: Circulation (2014)

Background: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of Multiple Myeloma (MM). Cardiac failure events (7.2%) and myocardial ischemia have occurred following administration CFZ. Infusion reactions also include chest thightness and angina of unknown mechanism. Aim of study: To investigate whether CFZ exerts in vitro effects on vascular tone and reactivity in an isolated experimental model of rabbit thoracic aortic-strips. Methods and Results: We evaluated first the effect of single injections of CFZ on the basal tone of isolated aortic strips (n= 6) placed in 10 ml organ bath at 37°C containing Krebs-Henseleit solution. Vasoconscriction, as documented by an overall increase in tension of 0.5 g, was observed with increasing concentrations of CFZ (from 1 x 10-9 to 10 -7 mol/L; p:0.041). In a second set of experiments, the effect of three different spasmogenic agents [potassium chloride (KCl) (n= 6), noradrenaline (NA) (n= 6), and angiontensin II (A) (n= 6)] on naive aortic strips (group 1) was compared to that on aortic strips pretrated for 60 minutes with CFZ at a concentration of 15 nmol/L (group 2). Pretreatment with CFZ resulted in amplified vasocostriction (2.4±0.4 g vs 2.1±0.3 g for KCl administration; 2.5±0.3 g vs 2.0±0.2 g for NA; 2.6±0.2 g vs 2.0±0.2 g for A; all p&lt;0.005) and impaired vasodilation following administration of nitroglycerin (NTG) on the plateau of contraction induced by each spasmogenic agent (100% vs 82% for KCl; 100% vs 67% for NA and 100% vs 51% for A; all p&lt;0.05). Finally, aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to naive strips (100 % versus 40% in tension reduction; p:0.028), following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction. Conclusions: CFZ increased the resting vasoconstricting tone and amplified the spasmogenic effect of different agents. Moreover, preincubation with CFZ decreased the anti-spasmogenic activity of NTG and reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation by inducing endothelial dysfunction. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.
Early outcome after sirolimus-eluting stent implantation in patients with acute coronary syndromes
Authors: Pedro A Lemos, Chi-hang Lee, Muzaffer Degertekin, Francesco Saia, Kengo Tanabe, Chourmouzios A Arampatzis, Angela Hoye, Marco van Duuren, Giorgios Sianos, Pieter C Smits, Pim de Feyter, Willem J van der Giessen, Ron T van Domburg, Patrick W Serruys
Journal: Journal of the American College of Cardiology (2003)
Abstract 15716: Non-Targeted Metabolomic Profiling Identifies Novel Markers of Insulin Resistance
Authors: John F O’Sullivan, Daniel J Cuthbertson, Robert E Gerszten
Journal: Circulation (2014)

Background: Targeted metabolomic profiling has identified metabolite classes associated with insulin resistance (IR) and incident metabolic disease, including branched-chain (BCAAs) and aromatic amino acids (AAAs). Emerging non-targeted profiling methods, which facilitate screening of many-fold more metabolites, hold great promise for the identification of additional disease biomarkers and pathways. We developed a non-targeted workflow to determine differentially regulated metabolites in two groups that differed by the homeostatic model assessment of IR (HOMA-IR). Methods: We analyzed fasting plasma from subjects with IR (HOMA-IR ≥ 2.6) (mean age = 67 ± 1.49; BMI = 28 ± 0.63; HOMA-IR = 7.94 ± 1.67) and normal subjects (HOMA-IR ≤ 1.85) (mean age = 68 ± 2.42; BMI = 26 ± 0.86; HOMA-IR = 1.13 ± 0.08), using HILIC chromatography coupled to an Agilent™ 6550 iFunnel Q-TOF mass spectrometer operated in positive ion mode. Batch recursive metabolite feature extraction was performed using MH Profinder software followed by differential metabolite analysis and identification using MPP software. Results: We identified 56 differentially abundant compounds [p &lt; 0.05; unpaired t-test with Benjamini-Hochberg FDR (B-H FDR) correction] in a derivation cohort (n=15 IR; n=15 control) and validated 28 of these compounds in a similarly sized independent cohort (p &lt;0.05, BH-FDR corrected). As expected, we confirmed compounds known to be associated with IR, including the BCAA valine (p=2.9E-3), the AAA tryptophan (p=1.01E-2), and a hexanoylcarnitine (p=4.8E-2). In addition, we made putative identifications of novel compounds that were significantly elevated in IR subjects in both cohorts, including aminooctanoic acid (+41%, p=3.68E-3), methylhistidine (+92%, p=4.78E-3), and methylinosine (+51%, p=3.29E-2). Novel compounds that were significantly decreased in IR subjects included isovalerylglycine (-48%, p=2.03E-2). Conclusions: We have developed a non-targeted metabolite profiling platform and detected novel compounds associated with IR. Future work includes unambiguous identification and quantification of these metabolites using isotope-labeled standards, as well as evaluation of these markers in large, heterogeneous clinical populations.
Clonal Hematopoiesis and Blood-Cancer Risk
Authors: Giulio Genovese, Siddhartha Jaiswal, Benjamin L Ebert, Steven A McCarroll
Journal: New England Journal of Medicine (2015)

To the Editor: Genovese et al. (Dec. 25 issue)1 report that activating mutations in FLT3 were not observed in participants with subclinical clonal expansions. We note from the Supplementary Appendix, available with the full text of the article at NEJM.org, that the variant-calling algorithm used in their study was the Genome Analysis Toolkit (GATK). It has been reported by others that internal tandem duplications (ITDs) in FLT3 are not detected by the GATK2 and that Pindel appears to be a better algorithm.2,3 We wonder whether ITDs in FLT3 might be detected in the data set of Genovese et al. if a different algorithm is used.
Active ascertainment of recurrence rate after treatment of primary basal cell carcinoma (BCC)
Authors: Murad Alam, Shraddha Desai, Michael Nodzenski, Meghan Dubina, Natalie Kim, Mary Martini, Douglas Fife, David Reid, Megan Pirigyi, Emily Poon, Jeffrey Hsu, Simon Yoo, Ashish Bhatia
Journal: Journal of the American Academy of Dermatology (2015)
The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone
Authors: D S Charney, G R Heninger, H D Kleber
Journal: American Journal of Psychiatry (1986)

Combined clonidine and naltrexone treatment allowed 38 of 40 patients addicted to methadone to withdraw completely in 4-5 days. For most patients naltrexone was gradually increased from 1 mg/day to 50 mg/day over 4 days. Clonidine reduced the intensity of naltrexone-induced withdrawal symptoms. Clonidine significantly decreased blood pressure without producing syncope and caused sedation but no other clinical problems. The withdrawal symptoms of anxiety, anorexia, insomnia, restlessness, and muscular aching were most resistant but were mild or nonexistent at discharge. Clonidine-naltrexone treatment should succeed with patients receiving methadone doses up to 50 mg/day, facilitate naltrexone maintenance, and apply to many clinical settings.
Abstract 18215: Prostacyclin Secretion From Stably Engineered Rat CD45-VEGFR2+ Endothelial Progenitor Cells Preserves Potassium Channel Activity Of Human Smooth Muscle Cells Under Hypoxia
Authors: Qi Liu, Yutao Xi, Toya Terry, Shui-Ping So, Geru Wu, Shahrzard Abbasi, Jie Cheng, Ke-He Ruan, James T Willerson, Richard A Dixon
Journal: Circulation (2010)

Background: Prostacyclin (PGI2) is a potent vasodilator and important mediator of vascular homeostasis. However, its less than 2 minute half-life makes clinical application cumbersome. Thus, we hyp...
Abstract 15043: Circulating microRNA as Novel Biomarkers of Doxorubicin Induced Cardiotoxicity
Authors: Yuri D’Alessandra, Marta Pontremoli, Giuseppina Milano, Alessandro Scopece, Giulio Pompilio, Gualtiero I Colombo
Journal: Circulation (2014)

Background: Cardiotoxicity is a well-known side effect of Doxorubicin (Dox), leading to drug-induced heart dysfunction. Early prediction of disease onset is difficult, thus a new class of heart impairment biomarkers is needed. A role for miRNAs as circulating biomarkers of Dox-mediated heart dysfunction has never been tested. Purpose: To identify differentially expressed circulating miRNAs of early and late Dox-induced cardiotoxicity using an animal model. Methods: Healthy mice were administered 24 mg/Kg cumulative dose of Dox during a period of 2 weeks followed by 2-month recovery. Cardiotoxicity insurgence was detectable by echocardiography as early as 1 week after treatment. The expression of 367 miRNAs was analyzed in plasma samples from treated and untreated animals (n=6/group) at the end of the treatment (2 weeks) and 2 months post-administration (recovery phase) followed by singleplex qPCR validation of all miRNAs of interest. Results: We identified 5 Dox-regulated miRNAs of acute phase. MiR-34a, -34c, and -133a showed an upregulation (6.5, 14.9, and 15 folds, respectively, p≤0.01), whereas miR-16 and miR-451 were negatively regulated by the drug (-2.7 and -2.8 folds, respectively, p&lt;0.05). We then investigated the expression of these miRNAs 2 months after the end of the treatment, but none showed a significant modulation. Conversely, miR-326 was positively regulated by Dox in the plasma of mice after 2 months of recovery (1.53 folds, p&lt;0.05). Conclusions: This is the first study investigating the possible use of circulating miRNAs as biomarkers of both early and post-treatment Dox-induced cardiotoxicity. Our results revealed a strong regulation of 5 plasmatic miRNAs in response to early damage. Early responders returned to basal levels of expression 2 months after drug administration, indicating an acute damage induced release. This prompts for further studies in the clinical setting to test their suitability as toxicity markers beside cardiac troponin. By contrast, we could not identify strong markers of late damage, apart from a marginal difference in miR-326 circulating levels.
Abstract 3629: Crucial Role of Nitric Oxide Synthases System in Endothelium-Dependent Hyperpolarization in Mice
Authors: Aya Takaki, Keiko Morikawa, Yoshinori Murayama, Ender Tekes, Hiroto Yamagishi, Junko Ohashi, Masato Tsutsui, Toyotaka Yada, Nobuyuki Yanagihara, Hiroaki Shimokawa
Journal: Circulation (2008)

We have previously demonstrated that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor (EDHF) in mouse and human mesenteric arteries and porcine coronary microvessels. We also have demonstrated that endothelial NO synthase (eNOS) is a major source of EDHF/H 2 O 2 , where Cu,Zn-superoxide dismutase (SOD) plays an important role to dismutate eNOS-derived superoxide anions to EDHF/H 2 O 2 in animals and humans. However, the mechanism for the endothelial production of H 2 O 2 as an endogenous EDHF remains to be elucidated. Indeed, some EDHF-mediated responses still remain in singly eNOS −/− mice and the remaining responses are also sensitive to catalase that dismutates H 2 O 2 to form water and oxygen. It is widely known that 3 NOS isoforms (neuronal, inducible, and endothelial) compensate each other. In this study, we examined the effects of genetic disruption of all NOS isoforms (n/i/eNOS −/− ) on EDHF responses in mice. We examined the contribution of the whole NOS system to EDHF-mediated responses in eNOS −/− , n/eNOS −/− and n/i/eNOS −/− mice that we have recently generated. Isometric tensions and membrane potentials were recorded by organ chamber experiments and microelectrode technique, respectively. EDHF-mediated relaxations and hyperporalizations in response to acetylcholine of mesenteric arteries were progressively reduced as the number of disrupted NOS genes increased (n=6 each), whereas vascular smooth muscle functions were preserved (n=6 each). Expressions of endothelial NOS isoforms in the NOSs −/− mice were compensated by NOS gene that had not been disrupted (n=5 each). Laser confocal microscopic examination demonstrated that endothelial H 2 O 2 and superoxide production was absent in n/i/eNOS −/− mice (n=3–5), whereas antihypertensive treatment with hydralazine failed to improve the EDHF-mediated responses (n= 4). Involvement of NOS uncoupling was ruled out as modulation of BH 4 synthesis had no effects (n=6–7) and BH 4 /BH 2 ratio (an index of BH 4 bioavailability) was preserved (n=4). These results provide the first direct evidence that EDHF-mediated responses are totally dependent on endothelial NOSs system in mouse mesenteric arteries.
Abstract 16115: Artioventricular Conduction Time in Mice; Hcls1 is a Candidate Gene
Authors: Reuben Howden, Laura Miller-DeGraff, Christopher Walker, James Clark, Page Myers, Clay Rouse, Steven Kleeberger
Journal: Circulation (2011)

Introduction Changes in atrioventricular conduction time (PR-interval) can indicate an increased risk of important cardiac dysfunctions, including atrial fibrillation. Therefore, understanding the ...
Abstract 13220: Cardiovascular Impact of Testosterone Therapy in Men with Low Testosterone Levels
Authors: Jeffrey L Anderson, Heidi T May, Donald L Lappé, Tami L Bair, Viet T Le, Joseph B Muhlestein
Journal: Circulation (2014)

Introduction: Epidemiologic studies have identified low testosterone (T) levels as an independent risk factor for cardiovascular (CV) and total mortality. However, the impact of T therapy on CV outcomes is controversial. A small trial in older men at high risk was stopped early due to increased CV events (NEJM 2010; 363:109). A recent observational study in veterans suggested modest risk (JAMA 2013; 3310:1829). We sought to assess the impact of T supplementation and achieved T levels across Intermountain Healthcare (IHC) facilities using a virtual controlled study design. Methods: IHC electronic medical records were searched between 1996 and 2011 to identify subjects who had a low initial total T level, a subsequent T level, and ≤3y follow-up. Levels were correlated with T supplement use. Primary outcomes were a composite of death, nonfatal myocardial infarction, and stroke (MACE) and death alone (D). Hazard ratios (HRs) comparing groups of persistent low (&lt;212 ng/dL, n=1142), normal (212-742 ng/dL, n=2634), and high (&gt;742 ng/dL, n=1919) achieved T were calculated by Cox regression, adjusting for 17 baseline variables. Results: A total of 5,695 men (age 62.3 ± 9.3 y, diabetes: 28%, CAD: 22%) were studied. Event rates at 1 and 3-y by T level, and adjusted HRs, are shown in the Table. Overall 3-y rates of MACE and D were 8.6% and 6.4%, respectively. Subjects supplemented to normal/high T had reduced 3-y MACE (HR 0.55, 95% CI 0.46-0.67) and D (HR 0.43, CI 0.35-0.54) compared to persistent low T subjects, with no signal for effect attenuation for MACE or D with higher T. Results were similar for 1-y MACE (HR 0.51, p&lt;0.0001) and D (HR 0.38, p&lt;0.0001). Conclusions: In a large general healthcare population, T therapy in men with low T was associated with reduced MACE and D over 3-y compared to no or ineffective supplementation. Resolving the difference in CV risk impact of T therapy between this, and previous studies, warrants a large randomized clinical trial in a similar, younger population.