tbuckley/cabot-search huggingface dataset:
Interleukin-8. Differential expression in lone fibrosing alveolitis and systemic sclerosis.
Authors: A M Southcott, K P Jones, D Li, S Majumdar, A D Cambrey, P Pantelidis, C M Black, G J Laurent, B H Davies, P K Jeffery
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Fibrosing alveolitis may occur alone (CFA) or in association with systemic sclerosis (FASSc). FASSc was recently shown to have a prognostic advantage over CFA. Because interleukin-8 (IL-8) is likely to be a major determinant of neutrophil alveolitis, we evaluated IL-8 expression in patients with CFA and FASSc and compared it with that in normal individuals and sarcoidosis and systemic sclerosis patients without pulmonary involvement (SSc no FA). IL-8 protein in bronchoalveolar lavage fluid (BALF) was assessed by immunoassay, and IL-8 mRNA expression was assessed using Northern analysis and reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization of lung parenchyma. Compared with normal subjects, IL-8 concentration was significantly greater in both CFA (p < 0.001) and FASSc groups (p < 0.05) but no different in sarcoidosis. The IL-8 concentration in CFA was higher than in FASSc (p < 0.01) and was related to BAL % neutrophils (rs = 0.48, p < 0.01). IL-8 mRNA expression evaluated by Northern analysis was seen only in patients with CFA and FASSc and was related to BAL % neutrophils (rs = 0.63, p < 0.01). We suggest that IL-8 is a key factor in the pathogenesis of fibrosing alveolitis and that the poorer prognosis of CFA compared with FASSc is related to higher levels of IL-8 within the lower respiratory tract.
Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells
Authors: Jun Wu, Zhongji Meng, Min Jiang, Rongjuan Pei, Martin Trippler, Ruth Broering, Agnes Bucchi, Jan-Peter Sowa, Ulf Dittmer, Dongliang Yang, Michael Roggendorf, Guido Gerken, Mengji Lu, Joerg F. Schlaak
Journal: Hepatology (2008)

Abstract We have previously shown that Toll-like receptor (TLR)-activated murine nonparenchymal liver cells [(NPC); Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC)] can suppress hepatitis B virus (HBV) replication. Therefore, the aim of this study was to investigate whether HBV has the ability to counteract the TLR-mediated control of its replication. Freshly purified murine hepatocytes and NPCs obtained from C57BL6 mice were stimulated by TLR 1-9 ligands in the presence or absence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), HBV virions, or supernatants from HBV-producing HBV-Met cells, and HBV replication was suppressed by anti- hepatitis B virus X protein (HBx) small interfering RNA (siRNA) in HBV-Met cells. Supernatants were collected and tested for antiviral cytokines by viral protection assay. HBV gene expression and replication was analyzed by southern blot. RNA and proteins were analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) or western blot and enzyme-linked immunosorbent assay, respectively. Pretreatment of hepatocytes and NPCs with HBV-Met cells supernatants, HBsAg, HBeAg, or HBV virions almost completely abrogated TLR-induced antiviral activity, which correlated with suppression of interferon beta (IFN-β) production and subsequent interferon-stimulated gene induction as well as suppressed activation of interferon regulatory factor 3 (IRF-3), nuclear factor kappa B (NF-κB), and extracellular signal-regulated kinase (ERK) 1/2. In HBV-infected HBV-Met cells, TLR stimulation did not induce antiviral cytokines in contrast to primary hepatocytes. TLR-stimulated expression of proinflammatory cytokines [tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6)], and activation of IRF-3 was suppressed after up-regulation of HBV replication in HBV-Met cells. Accordingly, suppression of HBV replication by siRNA led to activation or expression of proinflammatory transcription factors and cytokines. Conclusion: Our data indicate that HBV can suppress the TLR-induced antiviral activity of liver cells. This has major implications for the interaction between HBV and the immune system. (Hepatology 2009.)
Leptin-induced cardiac hypertrophy: RhoAing a lipid raft down a protective p38 MAPK signalling stream?
Authors: C. J. Pemberton
Journal: Cardiovascular Research (2007)

The 16-kDa peptide leptin has multiple physiological actions that affect satiety, energy expenditure, reproduction, immunity, and the cardiovascular system. These actions are mediated via the Ob-R receptor system, which has six isoforms (a–f) and are distributed widely throughout the body. The major contributor to circulating concentrations of leptin (∼5–15 ng/mL in lean humans) is adipose tissue secretion, and as such, leptin has been vigorously studied as part of the physiological adipose tissue hormonal signalling pathway controlling appetite, energy balance, and obesity.1 However, over recent years it has become clear that leptin is not exclusively produced by adipocytes and that organs such as the heart have their own endogenous leptin signalling systems. Thus, cardiomyocytes synthesise and secrete leptin and also express two main isoforms of the Ob-R (Ob-Ra and Ob-Rb) in a tissue- and gender-specific manner.2 Furthermore, the heart is a target for circulating leptin, which reduces cardiac contractility and promotes myocyte hypertrophy in vitro .3–5 In contrast, a certain degree of ambiguity exists as to whether leptin induces cardiac hypertrophy in vivo and what this might mean physiologically. It is known from experimental and clinical studies that circulating leptin concentrations are elevated after myocardial infarction and in heart failure and are associated with decreased cardiac contractility, independent of the presence of obesity.6,7 However, there also appears to be what is known as an ‘obesity paradox’ in heart failure patients with a high BMI, in … 

Correspondence author. Tel: +643 364 0887; fax: +643 364 0818. E-mail address : chris.pemberton{at}chmeds.ac.nz
Obstructive sleep apnea syndrome and cardiovascular diseases risk in patients with COPD
Authors: O.S. Khmel, L.A. Glinyana, A.A. Molchanov, V.V. Rodionova
Journal: European Respiratory Journal (2012)

Purpose: to define the correlation between obstructive sleep apnea syndrome (OSAS) and increasing of cardiovascular risk in patients with chronic obstructive pulmonary diseases (COPD).

Design:There were examined 33 patients in the age of 63,93±1,59 years with COPD stage 2 (85%) and stage 3 (15%). Duration of disease was: 10-14 years – 22 patients (67%) and 15-24 years–11 patients (33%). 60% of patients were smoking, index of smoking - 14,7±0,48 pack-years. Control group included 10 practically healthy persons. Methods: Holter monitor test with rheopneumography, spirometry, X-ray examination, six-minute walk test, calculation of cardiovascular risk according to the scale SCORE (Systematic Coronary Risk Evaluation). Patients received basic therapy according to the recommendations of GOLD, 2009. Results: 62% of patients had OSAS of mild stage and 38% - had OSAS of moderate stage (p<0,05). Duration of apnea cases varied from 259,0-1240,0 sec. 82% of patients had from 90 to 13990 cases of cardiac rhythm disturbances within 24 hours. Extremity index of heart rate (EIHR) varied during sleep - 2,1456±0,19. There were revealed correlations between duration of apnea cases and cardiovascular diseases risk (r=0,7136; p<0,05), number of heart rhythm disorders (r=0,7373; p<0,05), general cholesterol (r=0,7269; p<0,05). There was correlation between EIHR during sleep and OSAS (r=0,77; p<0,05). Patients had evidently increased risk for fatal complications according to the scale SCORE (r=0,8139; p<0,05): high risk level in 12,5% and very high - in 75% of cases. Conclusions: Patients with both COPD and OSAS have evidently increased risk for fatal complications.
Cardiac-Specific Ablation of G-Protein Receptor Kinase 2 Redefines Its Roles in Heart Development and β-Adrenergic Signaling
Authors: Scot J. Matkovich, Abhinav Diwan, Justin L. Klanke, Daniel J. Hammer, Yehia Marreez, Amy M. Odley, Eric W. Brunskill, Walter J. Koch, Robert J. Schwartz, Gerald W. Dorn
Journal: Circulation Research (2006)

G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non–G-protein signaling pathways. GRK2 is unique among members of the GRK family in that its genetic ablation causes embryonic lethality. Cardiac abnormalities in GRK2 null embryos implicated GRK2 in cardiac development but prevented studies of the knockout phenotype in adult hearts. Here, we created GRK2-loxP –targeted mice and used Cre recombination to generate germline and cardiac-specific GRK2 knockouts. GRK2 deletion in the preimplantation embryo with EIIa-Cre (germline null) resulted in developmental retardation and embryonic lethality between embryonic day 10.5 (E10.5) and E11.5. At E9.5, cardiac myocyte specification and cardiac looping were normal, but ventricular development was delayed. Cardiomyocyte-specific ablation of GRK2 in the embryo with Nkx2.5- driven Cre (cardiac-specific GRK2 knockout) produced viable mice with normal heart structure, function, and cardiac gene expression. Cardiac-specific GRK2 knockout mice exhibited enhanced inotropic sensitivity to the β-adrenergic receptor agonist isoproterenol, with impairment of normal inotropic and lusitropic tachyphylaxis, and exhibited accelerated development of catecholamine toxicity with chronic isoproterenol treatment. These findings show that cardiomyocyte autonomous GRK2 is not essential for myocardial development after cardiac specification, suggesting that embryonic developmental abnormalities may be attributable to extracardiac effects of GRK2 ablation. In the adult heart, cardiac GRK2 is a major factor regulating inotropic and lusitropic tachyphylaxis to β-adrenergic agonist, which likely contributes to its protective effects in catecholamine cardiomyopathy.
Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors
Authors: Paul Haluska, Michael Menefee, Elizabeth R. Plimack, Jonathan Rosenberg, Donald Northfelt, Theresa LaVallee, Li Shi, Xiang-Qing Yu, Patricia Burke, Jaiqi Huang, Jaye Viner, Jennifer McDevitt, Patricia LoRusso
Journal: Clinical Cancer Research (2014)

This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity.In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response.The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis.
Analysis of the insertion/deletion related polymorphism within T cell antigen receptor variable genes in primary Sjogren's syndrome
Authors: C A Lawson
Journal: Annals of the Rheumatic Diseases (2004)

To analyse T cell receptor beta variable (TCRBV) gene polymorphisms (insertion/deletion related polymorphism (IDRP) and BV6S7) in primary Sjögren's syndrome (PSS).Genomic DNA was extracted from blood samples from patients fulfilling the modified European criteria for PSS (n = 61). Healthy control blood samples were obtained from the Blood Transfusion Service (n = 121). As a disease control group, samples from patients with systemic lupus erythematosus (n = 42) were analysed. BV6S7 was genotyped using an established PCR/RFLP method. The IDRP was determined by comparison of the intensity of PCR product bands from within BV9S2 and an internal control region (BV9S1), to ascertain whether 0, 1, or 2 copies of the insertion were present.There was a decrease (p = 0.018) in the proportion of PSS patients with the deleted/deleted genotype. There was no association with specific BV6S7 alleles or genotypes with either the PSS group or the hypergammaglobulinaemic subgroup. There were no significant differences in haplotype frequencies after Bonferroni correction.A reduced proportion of patients with PSS have the deleted/deleted genotype. Eighty nine per cent of PSS patients have at least one extra germline copy of BV13S2*1. This may relate to previous observations of increased BV13 specific T cells and mRNA in the salivary glands.
Interaction Between Dietary Lipids and Physical Inactivity on Insulin Sensitivity and on Intramyocellular Lipids in Healthy Men
Authors: Rodrigue Stettler, Michael Ith, Kevin J. Acheson, Jacques Décombaz, Chris Boesch, Luc Tappy, Christophe Binnert
Journal: Diabetes Care (2005)

OBJECTIVE—To assess the effect of a possible interaction between dietary fat and physical inactivity on whole-body insulin sensitivity and intramyocellular lipids (IMCLs). RESEARCH DESIGN AND METHODS—Eight healthy male volunteers were studied on two occasions. After 2 days of an equilibrated diet and moderate physical activity, participants remained inactive (bed rest) for 60 h and consumed either a high–saturated fat (45% fat, of which ∼60% was saturated fat [BR-HF]) or a high-carbohydrate (70% carbohydrate [BR-HCHO]) diet. To evaluate the effect of a high-fat diet alone, six of the eight volunteers were restudied after a 2-day equilibrated diet followed by 60 h on a high–saturated fat diet and controlled physical activity (PA-HF). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and IMCL concentrations by 1H-magnetic resonance spectroscopy. RESULTS—Insulin-mediated glucose disposal was decreased by BR-HF condition (−24 ± 6%, P &amp;lt; 0.05) but did not change with BR-HCHO (+19 ± 10%, NS). BR-HF and BR-HCHO increased IMCL levels (+32 ± 7%, P &amp;lt; 0.05 and +17 ± 8%, P &amp;lt; 0.0011, respectively). Although the increase in IMCL levels with PA-HF (+31 ± 19%, P = 0.12) was similar to that during BR-HF, insulin-mediated glucose disposal (−7 ± 9%, NS) was not decreased. CONCLUSIONS—These data indicate that physical inactivity and a high–saturated fat diet may interact to reduce whole-body insulin sensitivity. IMCL content was influenced by dietary lipid and physical inactivity but was not directly associated with insulin resistance.
Magnesium Intake in Relation to Systemic Inflammation, Insulin Resistance, and the Incidence of Diabetes
Authors: Dae Jung Kim, Pengcheng Xun, Kiang Liu, Catherine Loria, Kuninobu Yokota, David R. Jacobs, Ka He
Journal: Diabetes Care (2010)

OBJECTIVE To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation, and insulin resistance among young American adults. RESEARCH DESIGN AND METHODS A total of 4,497 Americans, aged 18–30 years, who had no diabetes at baseline, were prospectively examined for incident diabetes based on quintiles of magnesium intake. We also investigated the associations between magnesium intake and inflammatory markers, i.e., high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS During the 20-year follow-up, 330 incident cases of diabetes were identified. Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders. The multivariable-adjusted hazard ratio of diabetes for participants in the highest quintile of magnesium intake was 0.53 (95% CI, 0.32–0.86; Ptrend &amp;lt; 0.01) compared with those in the lowest quintile. Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR, and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR. CONCLUSIONS Magnesium intake was inversely longitudinally associated with incidence of diabetes in young American adults. This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.
Open lung biopsy in patients with diffuse pulmonary shadowing.
Authors: G E Venn, P H Kay, C J Midwood, P Goldstraw
Journal: Thorax (1985)

The radiological appearances of diffuse pulmonary shadowing are not specific and frequently histological examination is necessary to provide a diagnosis or assess the activity of the disease. From July 1979 to May 1983 open lung biopsy was performed in 101 patients through a limited submammary incision. Twenty seven patients had undergone prior invasive investigations and 27 were taking corticosteroids at the time of biopsy. In 92 patients the histological appearances after open lung biopsy were sufficiently specific to permit diagnosis. Respiratory tract infection occurred in six patients and in eight there was some superficial infection of the wound. These complications were more frequent in patients taking corticosteroids but the difference was not statistically significant. The chest drain was removed usually on the first postoperative day. In three critically ill patients an air leak occurred after removal of the drain, requiring formal surgical re-exploration and drainage in two cases and a brief period of intercostal drainage in the third. Four patients in the series died. All had severe pre-existing lung disease; in three open lung biopsy was performed in the late stages of severe, rapidly progressive lung disease eluding diagnosis; the fourth patient, who had massive pulmonary fibrosis from asbestos lung disease, developed a respiratory tract infection and died from progressive respiratory failure. Open lung biopsy can be performed with minimal morbidity and a high diagnostic yield. The approach used in this series provides a safe and reliable operation with good cosmetic results.
A Theory for the Quantification of Transcapillary Exchange in the Presence of Shunt Flow
Authors: Shu Chien
Journal: Circulation Research (1971)

A theory is proposed to treat the transcapillary exchange of diffusion-limited substances in the presence of shunt circulation. With the simultaneous use of a nondiffusible indicator to correct for the distribution of intravascular transit and two diffusible indicators with different diffusion coefficients, the triple-indicator method can be used to assess the behavior of the diffusion-limited indicators in the exchange circuit. Application of this theory to data on perfused skeletal muscle allows the calculation of capillary blood flow, indicator extraction, and capillary diffusion capacity in the exchange circuit. The initial extraction of Na and Rb in the exchange circuit before back diffusion occurs shows a biphasic relation to flow rate. As the overall blood flow is increased to 10-15 ml min -1 100 g -1 , decrease of indicator extraction is associated with an increase of capillary blood flow and a decrease of diffusion capacity in the exchange circuit. The increase of indicator extraction at higher flows is attributable to an increase of diffusion capacity in the exchange circuit. The biphasic changes in capillary diffusion capacity with blood flow has been attributed to the influences of metabolic factors and distending pressure.
Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications
Authors: Valeria Santini, Hagop M. Kantarjian, Jean-Pierre Issa
Journal: Annals of Internal Medicine (2001)

Methylation of DNA is a biochemical modification that can influence gene expression and is involved in inactivating one of the two X chromosomes in women. Evidence that has accumulated in the past 10 years suggests that cancer cells usurp this physiologic mechanism and use it to their benefit by inactivating tumor suppressor genes and related proteins. However, the primary structure of the affected proteins remains intact; reversal of abnormalities in DNA methylation may therefore restore the tumor-suppressive function of these genes and provide a novel approach to cancer therapy. Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development. In this article, the biological rationale for targeting aberrant methylation in cancer therapy is reviewed and completed phase I and II trials of this approach, some of which show promise for treatment of hematologic malignancies, are summarized.
The Influence of Cognitive Impairment and Behavioral Dysregulation on Daily Functioning in the Nursing Home Setting
Authors: Susan K. Schultz, Vicki L. Ellingrod, Carolyn Turvey, David J. Moser, Stephan Arndt
Journal: American Journal of Psychiatry (2003)

The influence of psychiatric symptoms and cognitive impairment on daily living skills was explored in a series of nursing home residents. Three categories of symptoms were examined: behavioral disturbances, depression, and delusions.Nursing home residents (N=69) underwent comprehensive psychiatric evaluations. Relationships among psychiatric symptoms, cognitive function, and daily living skills were assessed by using regression and correlation analyses.Cognitive decline had the greatest effect on functional impairment in a standard least squares model, followed by behavioral disturbances. Psychiatric symptoms correlated positively with each other and with functional impairment, and correlated inversely with cognitive functioning.Cognitive decline appears to confer the greatest burden of functional disability in the nursing home setting. After cognitive effects were accounted for, behavioral dysregulation was also associated with functional impairment. In conclusion, interventions to enhance cognition and ameliorate behavioral disturbances are important areas for future studies in long-term care.
A Comprehensive Public Health Approach to Address the Burden of Renal Disease in Singapore
Authors: Sylvia Paz B. Ramirez
Journal: Journal of the American Society of Nephrology (2003)

With the epidemic rise of ESRD in multiple regions of the world, there is an urgent need to implement programs to address this increasing burden of kidney disease. We illustrate a public health approach using the program of the National Kidney Foundation of Singapore that incorporates stepwise primary, secondary, and tertiary strategies for prevention. Components of the program include an aggressive public education program, routine surveillance for kidney disease and associated chronic diseases, the implementation of a disease management program to improve physician practice patterns, and the provision of comprehensive services in the community through a network of Prevention Centers designed to optimize the care of patients at risk for kidney disease. Finally, an equally important aspect is the clinical and epidemiologic research component, because this will provide clear benchmarks to determine the program's effect on ESRD as well as generate information that can be used to identify future directions for this evolving program.