tbuckley/cabot-search huggingface dataset:
Osteoglycin Prevents Cardiac Dilatation and Dysfunction After Myocardial Infarction Through Infarct Collagen Strengthening
Authors: Lucas N.L. Van Aelst, Sandra Voss, Paolo Carai, Rick Van Leeuwen, Davy Vanhoutte, Sandra Sanders-van Wijk, Luc Eurlings, Melissa Swinnen, Fons K. Verheyen, Eric Verbeken, Holger Nef, Christian Troidl, Stuart A. Cook, Hans-Peter Brunner-La Rocca, Helge Möllmann, Anna-Pia Papageorgiou, Stephane Heymans
Journal: Circulation Research (2014)

Rationale: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy. Objective: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI). Methods and Results: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-β signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis. Conclusions: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure.
Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation
Authors: None Akimoto, None Ishikawa, None Igarashi, None Kurosawa, None Miyachi
Journal: British Journal of Dermatology (1998)

To determine the distribution, tryptase/chymase phenotypes and degranulation of mast cells (MCs) in the dermis of patients with scleroderma, we examined MC density in the skin of 22 patients with systemic sclerosis (SSc) and 11 with localized scleroderma (LSc). We used antitryptase and antichymase antibodies after Carnoy's fixation. Detailed reports of two representative patients with SSc and LSc are included. In the scleroedematous stage (grade 1) showing oedema in both papillary and reticular dermis with variable homogenization of collagen bundles in the reticular dermis, MC skin density was variable in each specimen although MC skin density, as a whole, was significantly increased as compared with normal skin (P < 0.05). In the sclerotic stage (grade 2) characterized by homogenization of collagen bundles in the entire dermis, MC skin density was significantly decreased as compared with normal skin (P < 0.005). LSc showed changes similar to those in SSc. The ratio of MCTC cells (both tryptase- and chymase-positive MC) to MCT cells (tryptase-positive but chymase-negative MC) was variable in SSc and LSc. MCT cells were exclusively dominant in three patients with SSc and two with LSc. In a patient with SSc (patient 1) showing remarkable perivascular and interstitial oedema in the upper dermis, MC skin density was increased in the oedematous portion and tryptase-positive granules were distributed in extracellular locations. In another patient with LSc (patient 2), tryptase positivity increased and chymase positivity decreased in both number and intensity as the skin sclerosis progressed. MCs must have variable interactions with the lesional skin in SSc and LSc. The present study suggests that MCs are involved in the development of interstitial oedema.
Neurocognitive Function in Unmedicated Manic and Medicated Euthymic Pediatric Bipolar Patients
Authors: Mani N. Pavuluri, Lindsay S. Schenkel, Subhash Aryal, Erin M. Harral, S. Kristian Hill, Ellen S. Herbener, John A. Sweeney
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: A systematic evaluation of neuropsychological functioning in individuals with pediatric bipolar disorder is necessary to clarify the types of cognitive deficits that are associated with acutely ill and euthymic phases of the disorder and the effects of medication on these deficits. METHOD: Unmedicated (N=28) and medicated (N=28) pediatric bipolar patients and healthy individuals (N=28) (mean age=11.74 years, SD=2.99) completed cognitive testing. Groups were matched on age, sex, race, parental socioeconomic status, general intelligence, and single-word reading ability. A computerized neurocognitive battery and standardized neuropsychological tests were administered to assess attention, executive function, working memory, verbal memory, visual memory, visuospatial perception, and motor skills. RESULTS: Subjects with pediatric bipolar disorder, regardless of medication and illness status, showed impairments in the domains of attention, executive functioning, working memory, and verbal learning compared to healthy individuals. Also, bipolar subjects with comorbid attention deficit hyperactivity disorder (ADHD) performed worse on tasks assessing attention and executive function than patients with bipolar disorder alone. CONCLUSIONS: The absence of differences in the deficits of neurocognitive profiles between acutely ill unmedicated patients and euthymic medicated patients suggests that these impairments are trait-like characteristics of pediatric bipolar disorder. The cognitive deficits found in individuals with pediatric bipolar disorder suggest significant involvement of frontal lobe systems supporting working memory and mesial temporal lobe systems supporting verbal memory, regardless of ADHD comorbidity.
Identification of asthma clusters in two independent Korean adult asthma cohorts
Authors: Tae-Bum Kim, An-Soo Jang, Hyouk-Soo Kwon, Jong-Sook Park, Yoon-Seok Chang, Sang-Heon Cho, Byoung Whui Choi, Jung-Won Park, Dong-Ho Nam, Ho-Joo Yoon, Young-Joo Cho, Hee-Bom Moon, You Sook Cho, Choon-Sik Park
Journal: European Respiratory Journal (2012)

Asthma is a heterogeneous airway disease with various clinical phenotypes. It is crucial to clearly identify clinical phenotypes to achieve better asthma management. We used cluster analysis to classify the clinical groups of 724 asthmatic patients from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), and in 1843 subjects from another independent Korean asthma cohort of Soonchunhyang University Asthma Genome Research Centre (SCH) (Bucheon, Republic of Korea). Hierarchical cluster analysis was performed by Ward's method, followed by κ-means cluster analysis. Cluster analysis of the COREA cohort indicated four asthma subtypes: 1) smoking asthma; 2) severe obstructive asthma; 3) early-onset atopic asthma; and 4) late-onset mild asthma. An independent cluster analysis of the SCH cohort also indicated four clusters that were similar to the COREA clusters. Our results indicate that adult Korean asthma patients can be classified into four distinct clusters.
The role of hepatobiliary scintigraphy in cystic fibrosis
Authors: P J O’Connor, K W Southern, I M Bowler, H C Irving, P J Robinson, J M Littlewood
Journal: Hepatology (1996)

This was a prospective open study that examined the quantitative and qualitative analysis of hepatobiliary scintigraphy (DISIDA) in detecting liver involvement in cystic fibrosis (CF). Forty-four adult and pediatric patients (median age, 12.1 years; range, 1.1-36.3 years) were divided into three groups: group 1, no evidence of liver involvement (n = 8); group 2, biochemical evidence of liver involvement on two or more occasions (n = 26); and group 3, clinical evidence of liver disease (n = 10). In groups 1 and 2, the most common qualitative scintigraphic finding was focal intrahepatic retention of tracer (26/34 patients, 12 of whom had normal findings on ultrasonography). This finding corresponds to focal cholestasis and may warrant treatment with the choleretic agent ursodeoxycholic acid (UDCA). In the group 3 patients, the abnormal qualitative scintigraphic appearances (heterogeneous uptake of tracer and nodular liver outline) added little to the findings on ultrasonography; however, these patients had a prolonged mean hepatic clearance time compared with those in groups 1 and 2 (one-way ANOVA; P < .015). It is proposed that scintigraphy with DISIDA has a role in the detection of early liver involvement in cystic fibrosis.
Single-Gene Mutations and Increased Left Ventricular Wall Thickness in the Community
Authors: Hiroyuki Morita, Martin G. Larson, Scott C. Barr, Ramachandran S. Vasan, Christopher J. O’Donnell, Joel N. Hirschhorn, Daniel Levy, Diane Corey, Christine E. Seidman, J.G. Seidman, Emelia J. Benjamin
Journal: Circulation (2006)

Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown.We studied 1862 unrelated participants (52% women; age, 59+/-9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy-causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT (maximum LVWT >13 mm). Fifty eligible participants (9 women) had unexplained increased LVWT. We detected 8 mutations in 9 individuals (2 women); 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3), and 1 GLA mutation. In individuals with increased LVWT, participants with sarcomere protein and storage mutations were clinically indistinguishable from those without mutations.In a community-based cohort, about 3% of eligible participants had increased LVWT, of whom 18% had sarcomere protein or lipid storage gene mutations. Increased LVWT in the community is a very heterogeneous condition, which sometimes may arise from single-gene variants in one of a number of genes.
PWE-001 Ambulant high resolution manometry studies of the mechanisms of gastro-oesophageal reflux in patients with and without evidence of hiatus hernia
Authors: B T Theron, A Yamamoto, H Aladin, N Trudgill
Journal: Gut (2012)

<h3>Introduction</h3> Recent studies have shown that high resolution manometry (HRM) detects more transient lower oesophageal relaxation (tLOSR) than the established sleeve sensor. Previous studies using the sleeve sensor have suggested that when a hiatus hernia (HH) is present and in patients with more severe oesophagitis, gastro-oesophageal reflux (GOR) more commonly occurs due to mechanisms other than TLOSR. We have developed a unique ambulatory HRM system to study mechanisms of GORD under more physiological conditions in patients with reflux oesophagitis or Barrett9s oesophagus, with and without hiatus hernia. <h3>Methods</h3> 10 patients with HH and six patients without HH (all with an endoscopic diagnosis of reflux oesophagitis) were studied after a fast for at least 4 h. A 36 channel solid state HRM/impedance catheter was placed spanning the stomach to pharynx. A pH electrode was placed 5 cm above the GOJ. Patients were studied at rest and during 15 min of standardised exercise on an exercise bike, before and after a meal (sausage or bacon with egg sandwich with 500 mls of milkshake—736 calories). In addition subjects walked for 30 min in the post-prandial period. <h3>Results</h3> 12 patients were male; median age 60 (range 35–76) years; six patients had LA A/B oesophagitis and 10 patients had LA C/D (5) or Barrett9s oesophagus (5). Acid reflux episodes in patients with HH were due to tLOSR in 90%, low LOS pressure in 6% and swallowing in 4%, whereas in patients without HH they were due to tLOSR in 88%, low LOS pressure in 4% and swallowing in 8%. tLOSR appeared to be more frequent in patients with HH (13.5 (IQR 11.1–18.7) per hour vs 10 (IQR 7.6–15.6) per hour) but this difference fell short of statistical significance (p=0.06). There was no difference in the proportion of TLOSR associated with acid reflux in patients with (59%) and without HH (47%) but patients with HH were more likely to have impedance evidence of gas or liquid reflux during tLOSR than patients without HH (96% vs 83%, p&lt;0.001). <h3>Conclusion</h3> Prolonged ambulant studies of the mechanisms associated with acid gastro-oesophageal reflux reveal that tLOSRs are the predominant mechanism associated with acid reflux in patients with oesophagitis or Barrett9s oesophagus both with and without HH. tLOSR appeared to be more common in patients with HH but this difference fell short of statistical significance. Patients with HH were more likely to have evidence of reflux during tLOSR. <h3>Competing interests</h3> None declared.
Clinical Rejection Is Distinguished from Subclinical Rejection by Increased Infiltration by a Population of Activated Macrophages
Authors: PAUL C. GRIMM, RACHEL MCKENNA, PETER NICKERSON, MARY E. RUSSELL, JIM GOUGH, ELZBIETA GOSPODAREK, BIN LIU, JOHN JEFFERY, DAVID N. RUSH
Journal: Journal of the American Society of Nephrology (1999)

Abstract. It has been reported previously that one-third of protocol renal biopsies in asymptomatic, biochemically stable renal transplant recipients in the first 6 mo show unsuspected subclinical graft rejection (both infiltrate and tubulitis) and that subclinical rejection is a risk factor for chronic renal dysfunction. This study was performed to determine whether differences in phenotype or activation status of graft-infiltrating cells underlie these different manifestations of acute rejection. Biopsies with normal histology ( n = 10), subclinical rejection ( n = 13), and clinical rejection ( n = 9) were studied using immunohistochemistry and computerized image analysis. Subclinical and clinical rejections had similar histologic Banff scores. Univariate analysis showed a trend for a higher infiltration with CD8+ ( P = 0.053) and CD68+ ( P = 0.06) cells in clinical rejection. Of the activation markers studied (CD25, perforin, tumor necrosis factor-α), only allograft inflammatory factor-1 +-activated macrophages were significantly ( P = 0.014) increased in the infiltrate of clinical rejection biopsies. These data suggest that activated macrophages or their products are responsible for acute renal dysfunction associated with clinical rejection episodes.
Hyperphosphorylation of Mouse Cardiac Titin Contributes to Transverse Aortic Constriction-Induced Diastolic Dysfunction
Authors: Bryan Hudson, Carlos Hidalgo, Chandra Saripalli, Henk Granzier
Journal: Circulation Research (2011)

Rationale: Mechanisms underlying diastolic dysfunction need to be better understood. Objective: To study the role of titin in diastolic dysfunction using a mouse model of experimental heart failure induced by transverse aortic constriction. Methods and Results: Eight weeks after transverse aortic constriction surgery, mice were divided into heart failure (HF) and congestive heart failure (CHF) groups. Mechanical studies on skinned left ventricle myocardium measured total and titin-based and extracellular matrix-based passive stiffness. Total passive stiffness was increased in both HF and CHF mice, and this was attributable to increases in both extracellular matrix-based and titin-based passive stiffness, with titin being dominant. Protein expression and titin exon microarray analysis revealed increased expression of the more compliant N2BA isoform at the expense of the stiff N2B isoform in HF and CHF mice. These changes are predicted to lower titin-based stiffness. Because the stiffness of titin is also sensitive to titin phosphorylation by protein kinase A and protein kinase C, back phosphorylation and Western blot assays with novel phospho-specific antibodies were performed. HF and CHF mice showed hyperphosphorylation of protein kinase A sites and the proline glutamate valine lysine (PEVK) S26 protein kinase C sites, but hypophosphorylation of the PEVK S170 protein kinase C site. Protein phosphatase I abolished differences in phosphorylation levels and normalized titin-based passive stiffness levels between control and HF myocardium. Conclusion: Transverse aortic constriction-induced HF results in increased extracellular matrix-based and titin-based passive stiffness. Changes in titin splicing occur, which lower passive stiffness, but this effect is offset by hyperphosphorylation of residues in titin spring elements, particularly of PEVK S26. Thus, complex changes in titin occur that combined are a major factor in the increased passive myocardial stiffness in HF.
Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome
Authors: Fukiko Ichida, Shinichi Tsubata, Karla R. Bowles, Noriyuki Haneda, Keiichiro Uese, Toshio Miyawaki, W. Jeffrey Dreyer, John Messina, Hua Li, Neil E. Bowles, Jeffrey A. Towbin
Journal: Circulation (2001)

Background —Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. Methods and Results —DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C→T mutation was identified at nucleotide 362 of α -dystrobrevin , changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T→A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of G4.5 (398-2 A→G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS. Conclusions —These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, α -dystrobrevin , identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.
Sequential contribution of L- and P-selectin to leukocyte rolling in vivo.
Authors: K Ley, D C Bullard, M L Arbonés, R Bosse, D Vestweber, T F Tedder, A L Beaudet
Journal: The Journal of Experimental Medicine (1995)

Leukocyte recruitment into inflammatory sites is initiated by a reversible transient adhesive contact with the endothelium called leukocyte rolling, which is thought to be mediated by the selectin family of adhesion molecules. Selectin-mediated rolling precedes inflammatory cell emigration, which is significantly impaired in both P- and L-selectin gene-deficient mice. We report here that approximately 13% of all leukocytes passing venules of the cremaster muscle of wild-type mice roll along the endothelium at &amp;lt; 20 min after surgical dissection. Rolling leukocyte flux fraction reaches a maximum of 28% at 40-60 min and returns to 13% at 80-120 min. In P-selectin-deficient mice, rolling is absent initially and reaches 5% at 80-120 min. Rolling flux fraction in L-selectin-deficient mice is similar to wild type initially and declines to 5% at 80-120 min. In both wild-type and L-selectin-deficient mice, initial leukocyte rolling (0-60 min) is completely blocked by the P-selectin monoclonal antibody (mAb) RB40.34, but unaffected by L-selectin mAb MEL-14. Conversely, rolling at later time points (60-120 min) is inhibited by mAb MEL-14 but not by mAb RB40.34. After treatment with tumor necrosis factor (TNF)-alpha for 2 h, approximately 24% of all passing leukocytes roll in cremaster venules of wild-type and P-selectin gene-deficient mice. Rolling in TNF-alpha-treated mice is unaffected by P-selectin mAb or E-selectin mAb 10E9.6. By contrast, rolling in TNF-alpha-treated P-selectin-deficient mice is completely blocked by L-selectin mAb. These data show that P-selectin is important during the initial induction of leukocyte rolling after tissue trauma. At later time points and in TNF-alpha-treated preparations, rolling is largely L-selectin dependent. Under the conditions tested, we are unable to find evidence for involvement of E-selectin in leukocyte rolling in mice.
Utility of p16 Immunohistochemistry for the Identification of Lynch Syndrome
Authors: Artemio Payá, Cristina Alenda, Lucía Pérez-Carbonell, Estefanía Rojas, José-Luis Soto, Carmen Guillén, Adela Castillejo, Victor M. Barberá, Alfredo Carrato, Antoni Castells, Xavier Llor, Montserrat Andreu, Jim Koh, Greg H. Enders, Susana Benlloch, Rodrigo Jover
Journal: Clinical Cancer Research (2009)

Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1 expression are due to sporadic hypermethylation of the MLH1 promoter. These tumors can also show epigenetic silencing of other genes, such as p16. The aim of our study is to evaluate the utility of p16 immunohistochemistry in the prediction of MLH1 germline mutations.
THE ROLE OF HUMORAL ANTIBODY IN THE REJECTION OF PRIMARY RENAL ALLOGRAFTS IN SHEEP
Authors: Niels C. Pedersen, Bede Morris
Journal: The Journal of Experimental Medicine (1974)

Antibody which had cytotoxic and agglutinating activity against donor lymphocytes appeared in the blood stream of primary renal allograft recipients usually within 48 h of the graft being finally rejected. Appearance of the antibody See PDF for Structure in the blood was associated with severe alterations in vascular permeability and this led to increases in the numbers of red cells and in the protein content of the lymph coming from the allograft. It was possible to elute cytotoxic and agglutinating antibody from renal allograft tissue, showing that this type of antibody was bound to graft antigens during the rejection process. The transfusion of whole serum or serum globulins obtained from sheep that had previously rejected allografts led to the destruction of recently installed renal grafts and the histological changes produced in these grafts and the alterations in the composition of the lymph coming from them were similar to those seen in the terminal stages of primary rejection. These findings have led us to the conclusion that in the sheep, at least the terminal stage of primary renal allograft rejection is mediated by humoral antibody.