tbuckley/cabot-search huggingface dataset:
Metabolic Implications of Body Fat Distribution
Authors: Per Björntorp
Journal: Diabetes Care (1991)

Insulin resistance is the cornerstone for the development of non-insulin-dependent diabetes mellitus (NIDDM). Free fatty acids (FFAs) cause insulin resistance in muscle and liver and increase hepatic gluconeogenesis and lipoprotein production and perhaps decrease hepatic clearance of insulin. It is suggested that the depressing effect of insulin on circulating FFA concentration is dependent on the fraction derived from visceral adipocytes, which have a low responsiveness to the antilipolytic effect of insulin. Elevated secretion of cortisol and/or testosterone induces insulin resistance in muscle. This also seems to be the case for low testosterone concentrations in men. In addition, cortisol increases hepatic gluconeogenesis. Cortisol and testosterone have “permissive” effect on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus have powerful combined effects, resulting in insulin resistance and increased hepatic gluconeogenesis. All these factors promoting insulin resistance are active in abdominal visceral obesity, which is closely associated with insulin resistance, NIDDM, and the “ metabolic syndrome.” In addition, the endocrine aberrations may provide a cause for visceral fat accumulation, probably due to regional differences in steroid-hormone-receptor density. In addition to the increased activity along the adrenocorticosteroid axis, there also seem to be signs of increased activity from the central sympathetic nervous system. These are the established endocrine consequences of hypothalamic arousal in the defeat and defense reactions. There is some evidence that suggests an increased prevalence of psychosocial stress factors is associated with visceral distribution of body fat. Therefore, it is hypothesized that such factors might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease.
Activation of Peroxisome Proliferator-Activated Receptor δ Stimulates the Proliferation of Human Breast and Prostate Cancer Cell Lines
Authors: Ruth L. Stephen, Mattias C. U. Gustafsson, Morag Jarvis, Roger Tatoud, Barry R. Marshall, Deborah Knight, Ewa Ehrenborg, Adrian L. Harris, C. Roland Wolf, Colin N. A. Palmer
Journal: Cancer Research (2004)

Abstract The nuclear receptor peroxisome proliferator-activated receptor δ [PPARδ/β (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARδ by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARδ selective agonists. Activation of PPARδ with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARδ agonist, GW501516. Conditional expression of PPARδ in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARδ in the proliferative response to this drug. Activation of PPARδ in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor α (VEGFα) and its receptor, FLT-1, thus, suggesting that PPARδ may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFα and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARδ can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARδ antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis resembling alcoholic human disease
Authors: Fernando Siller, Silvia Salgado, Jesus Garcia, Jose M. Vera, Alejandra Miranda, Guillermo Grijalva, Javier Galvez, Estuardo Aguilar-Cordova, Juan Armendariz-Borunda
Journal: Journal of Hepatology (2002)
Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure
Authors: Damien Logeart, Gabriel Thabut, Patrick Jourdain, Christophe Chavelas, Pascale Beyne, Florence Beauvais, Erik Bouvier, Alain Cohen Solal
Journal: Journal of the American College of Cardiology (2004)
Thyroxine Suppressive Therapy in Patients with Nodular Thyroid Disease
Authors: Hossein Gharib
Journal: Annals of Internal Medicine (1998)

Purpose: To review evidence about thyroxine suppressive therapy in patients with thyroid nodules, including the clinical importance and natural history of nodules and the effects and potential side effects of thyroxine therapy. Data Sources: English-language articles published from 1986 to December 1996 were identified through searches of the MEDLINE database, selected bibliographies, and personal files. Data Extraction: Randomized, controlled trials and non-randomized trials of thyroxine suppressive therapy for solitary and predominantly solid thyroid nodules were reviewed. In most studies, nodule cytology was evaluated by fine-needle aspiration biopsy. Therapy was considered suppressive if suppression was documented by thyroid-stimulating hormone-releasing hormone tests or sensitive thyroid-stimulating hormone assays. Response was defined as a decrease of 50% or more in nodule size or volume; most recent studies measured nodule size by ultrasonography. Data Synthesis: The evidence suggests that thyroxine suppressive therapy fails to shrink most nodules: Only 10% to 20% of nodules responded to this treatment. Fineneedle aspiration biopsy is more reliable in distinguishing benign from malignant nodules. Recent studies suggest that spontaneous decrease in size with complete disappearance of thyroid nodules is not uncommon. No data show that thyroxine therapy arrests further growth in most existing nodules or prevents the emergence of new nodules. Postoperative thyroxine therapy does not seem to prevent recurrence of thyroid nodules except in patients with a history of radiation therapy. Potential adverse effects of long-term suppressive therapy include osteoporosis and heart disease. Conclusions: Patients with cytologically benign nodules are best followed without thyroxine treatment. Most benign nodules remain stable in size and remain benign when monitored for a long time. For nodules that increase in size, biopsy should be done again or surgery should be performed.
Long-Term Treatment of Glucagon-Like Peptide-1 Analog Exendin-4 Ameliorates Diabetic Nephropathy through Improving Metabolic Anomalies in db/db Mice
Authors: Cheol Whee Park, Hyeong Wook Kim, Seung Hyun Ko, Ji Hee Lim, Gyeong Ryul Ryu, Hyun Wha Chung, Sang Woo Han, Seog Jun Shin, Byung Kee Bang, Matthew D. Breyer, Yoon Sik Chang
Journal: Journal of the American Society of Nephrology (2007)

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-beta1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator-activated receptor alpha and GLP-1 receptor-positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial
Authors: Edward B Garon, Tudor-Eliade Ciuleanu, Oscar Arrieta, Kumar Prabhash, Konstantinos N Syrigos, Tuncay Goksel, Keunchil Park, Vera Gorbunova, Ruben Dario Kowalyszyn, Joanna Pikiel, Grzegorz Czyzewicz, Sergey V Orlov, Conrad R Lewanski, Michael Thomas, Paolo Bidoli, Shaker Dakhil, Steven Gans, Joo-Hang Kim, Alexandru Grigorescu, Nina Karaseva, Martin Reck, Federico Cappuzzo, Ekaterine Alexandris, Andreas Sashegyi, Sergey Yurasov, Maurice Pérol
Journal: The Lancet (2014)
Pharmacological Evidence for the Importance of Catecholamines in Cardiac Rhythmicity
Authors: JAY ROBERTS, WALTER MODELL
Journal: Circulation Research (1961)

Dogs with complete heart block were used to explore the dependence of the intrinsic rhythmicity of the heart on catecholamine activity. By the use of reserpine, hexamethonium, and surgical sympathectomy, it was demonstrated that, while reduction in catecholamine activity slows both the atrial and the ventricular rates, the ventricular pace maker was always affected to a greater degree. The effect of a combination of reserpine and hexamethonium on the ventricle was greater than when either agent was administered alone, suggesting that the greater the sympathetic blockade, the greater the depression in pacemaker rhythmicity. Since the course of its action on the heart paralleled that of catecholamine depletion, it seems probable that the effect of reserpine on rhythmicity was due to its catecholamine depleting action. It was thought unlikely that prolonged hypotension contributed to the reserpine action on the heart. It is indicated that disturbances in electrolyte balance and blood pH did not play a role in the effects observed.
Ursodeoxycholic Acid in the Treatment of Primary Biliary Cirrhosis: First Controlled Data
Authors: Marie Borum, Hans Fromm
Journal: Hepatology (1990)

We studied the effect of ursodeoxycholic acid on 18 women and 2 men with primary biliary cirrhosis, mainly stages I and II. After a 3–mo observation period, patients were randomized to a 9–mo treatment period with ursodeoxycholic acid, 10 mg/kg · day, or placebo. Two patients on placebo left the study. In all patients on ursodeoxycholic acid, mean values of serum glutamate dehydrogenase, aspartate and alanine aminotransferases, alkaline phosphatase, and γ–glutamyl transpeptidase fell significantly by 48%–79% after 18-24 wk; 7 of 10 showed a mean decrease of 35% in immunoglobulin M after 24 wk. Prothrombin time, serum bilirubin, albumin, the antipyrine breath test, and plasma disappearance of indocyanine green were normal initially and did not change. Total serum bile acid concentrations increased; ursodeoxycholic acid became the predominant bile acid. No significant improvement occurred in the placebo group. Hepatic histology improved in 6 patients of the ursodeoxycholic acid group but deteriorated in 4 patients receiving placebo. In studies with erythrocyte membranes, changes in electron spin resonance revealed that ursodeoxycholic acid was less toxic than chenodeoxycholic or deoxycholic acid, and coaddition of ursodeoxycholic acid prevented their toxic effect.
Familial Aggregation of Suicidal Behavior: A Family Study of Male Suicide Completers From the General Population
Authors: Caroline D. Kim, Monique Seguin, Nadia Therrien, Geneviève Riopel, Nadia Chawky, Alain D. Lesage, G. Turecki
Journal: American Journal of Psychiatry (2005)

This study compared suicidality in families of adult male suicide completers and community comparison subjects.Two hundred forty-seven relatives of 25 male suicide completers and 171 relatives of 25 matched comparison subjects were assessed for recurrent risk of suicidal and related behaviors. Analyses were performed on a subgroup of relatives of suicide completers with cluster B personality disorders.Relatives of suicide completers were over 10 times more likely than relatives of comparison subjects to attempt or complete suicide after the authors controlled for psychopathology. Relatives of suicide completers were not more likely to exhibit suicidal ideation but had more severe suicidal ideation than relatives of comparison subjects. These findings were stronger for the suicide completers diagnosed with cluster B personality disorders.Suicide has a familial component independent of psychopathology that may be mediated by a combination of factors, including more severe suicidal ideation and aggressive behavior.
Exploring the Association between Severe Respiratory Syncytial Virus Infection and Asthma
Authors: Simon Francis Thomsen, Sophie van der Sluis, Lone G. Stensballe, Danielle Posthuma, Axel Skytthe, Kirsten O. Kyvik, David L. Duffy, Vibeke Backer, Hans Bisgaard
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Severe respiratory syncytial virus (RSV) infection is associated with asthma but the nature of this association is imperfectly understood.To examine the nature of the association between severe RSV infection and asthma in a population-based sample of twins.Data on hospitalization due to RSV infection was gathered for all twins born in Denmark between 1994 and 2000 (8,280 pairs) and linked to information on asthma obtained from hospital discharge registries and parent-completed questionnaires. Genetic variance components models and direction of causation models were fitted to the observed data.RSV hospitalization and asthma were positively associated (r = 0.43), and genetic determinants for the two disorders overlapped completely. Modeling the direction of causation between RSV hospitalization and asthma showed that a model in which asthma "causes" RSV hospitalization fitted the data significantly better (P = 0.39 for deterioration in model fit) than a model in which RSV hospitalization "causes" asthma (P < 0.001 for deterioration in model fit), even when sex, birth weight, and maternal smoking during pregnancy were accounted for.RSV infection that is severe enough to warrant hospitalization does not cause asthma but is an indicator of the genetic predisposition to asthma.
Features of wild-type human SOD1 limit interactions with misfolded aggregates of mouse G86R Sod1
Authors: David A Qualls, Mercedes Prudencio, Brittany LT Roberts, Keith Crosby, Hilda Brown, David R Borchelt
Journal: Molecular Neurodegeneration (2013)

Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is well established that mutations in SOD1, associated with fALS, heighten the propensity of the protein to misfold and aggregate. Although aggregation appears to be a factor in the toxicity of mutant SOD1s, the precise nature of this toxicity has not been elucidated. A number of other studies have now firmly established that raising the levels of wild-type (WT) human SOD1 (hSOD1) proteins can in some manner augment the toxicity of mutant hSOD1 proteins. However, a recent study demonstrated that raising the levels of WT-hSOD1 did not affect disease in mice that harbor a mouse Sod1 gene (mSod1) encoding a well characterized fALS mutation (G86R). In the present study, we sought a potential explanation for the differing effects with WT-hSOD1 on the toxicity of mutant hSOD1 versus mutant mSod1. In the cell culture models used here, we observe poor interactions between WT-hSOD1 and misfolded G86R-mSod1, possibly explaining why over-expression of WT-hSOD1 does not synergize with mutant mSod1 to accelerate the course of the disease in mice.
Experimental rhinovirus challenges in adults with mild asthma: Response to infection in relation to IgE
Authors: Juan C. Zambrano, Holliday T. Carper, Gary P. Rakes, James Patrie, Deborah D. Murphy, Thomas A.E. Platts-Mills, Frederick G. Hayden, Jack M. Gwaltney, Tina K. Hatley, Angela M. Owens, Peter W. Heymann
Journal: Journal of Allergy and Clinical Immunology (2003)
NO RECOVERY OF DRUG-ELUTING STENT USE IN CLINICAL PRACTICE IN EUROPE AFTER THE COLLAPSE FOLLOWING THE INITIAL REPORTS OF IMPAIRED OUTCOMES IN SEPTEMBER 2006: RESULTS OF THE EURO HEART SURVEY PCI-REGISTRY
Authors: Anselm K. Gitt, Matthias Hochadel, Timm Bauer, Uwe Zeymer, Ralf Zahn, Franz Weidinger, Ricardo Seabra-Gomes, Christian Hamm
Journal: Journal of the American College of Cardiology (2011)
Development of the mammalian lymphatic vasculature
Authors: Ying Yang, Guillermo Oliver
Journal: Journal of Clinical Investigation (2014)

The two vascular systems of our body are the blood and lymphatic vasculature. Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade. In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified. The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived. Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature.
Comparison of circadian variations using FEV1 and peak expiratory flow rates among normal and asthmatic subjects.
Authors: S Troyanov, H Ghezzo, A Cartier, J L Malo
Journal: Thorax (1994)

BACKGROUND--Most studies that describe circadian variations in asthma have used maximum rate of peak expiratory flow (PEF) rather than forced expiratory volume in one second (FEV1) to assess airway calibre. This study was designed to assess circadian variations in PEF and FEV1 measured simultaneously and to compare variations in these measurements in normal and asthmatic subjects in a stable clinical state. METHODS--Twenty nine subjects (nine asthmatic subjects on bronchodilators, 10 on inhaled steroids, and 10 normal controls) were asked to record their PEF and FEV1 with a new portable instrument every two hours during the day and once on waking at night for two weeks. Circadian variations were examined in different ways using arithmetical indices and cosinor analysis. RESULTS--78% of PEF values and 75% of FEV1 values were considered to be reproducible and were included in the analysis. Variations obtained using PEF did not differ from those obtained using FEV1. Significant cosinor variations were found in at least 50% of recording days for most of the subjects and showed the same features as for arithmetical indices. Daily variations in PEF and FEV1 were significantly correlated with airway calibre and PC20 methacholine (r approximately 0.5 to approximately 0.6). CONCLUSIONS--PEF is as satisfactory as FEV1 for describing circadian variations among normal subjects and stable asthmatic subjects.
Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition
Authors: JW Kappler, B Skidmore, J White, P Marrack
Journal: The Journal of Experimental Medicine (1981)

We developed a method for production of antigen-specific, H-2-restricted T cell hybrids. The tumor cell partner in the fusions was itself a T cell hybrid, FS6-14.13.AG2 (or its derivatives), which could be induced to produce the growth factor, interleukin-2 (IL-2), in response to a challenge with concanavalin A, but had no known antigen specificity. The normal T cell partner in the fusions was a population of lymph node T cell blasts that had been highly enriched in antigen-specific, H-2-restricted T cells by in vivo immunization, followed by in vitro challenge with antigen and clonal expansion in IL-2-containing medium. These fusions produced hybrids that grew constitutively in culture. A sizable proportion of the hybrids demonstrated the ability to produce IL-2 in response to a challenge with specific antigen presented by irradiated spleen cells of the appropriate H-2 type. Four cloned antigen/H-2-specific hybrid lines were produced. AO-40.10 responded to chicken ovalbumin (OVA) when presented by I-A(k)-bearing cells. DC1.18.3 responded to the apo form of beef cytochrome c when presented with I-A(d). AODK-10.4 responded to keyhole limpet hemocyanin (KLH) presented with I-A (d). AODK-1.16 also responded to KLH presented by a product of the I region of H-2(d), but the data were consistent with either a product of the I-J-I-E(d) region or a combinatorial molecule with elements from both I-A(d) and I-E(d)/I-C(d). Coincidentally, AO-40.10 was shown to have an unexpected alloreactivity with a product of H-2(b) mapping to the K-I-A region. These hybrids should prove invaluable as sources of monoclonal material for the study of the receptor(s) on T cells with H-2-restricted antigen specificities. We also generated T cell hybrids with two antigen/H-2 specificities by fusing an azaguanine-resistant clone of AO-40.10 to normal T cells with a different antigen/H-2 specificity. Many of the hybrids retained reactivity to OVA plus H-2(a) and to the second antigen/H-2 combination. None reacted to either OVA plus the second H-2 type or to the second antigen plus H-2(a). One of these hybrids was successfully cloned to produce the line AOFK- 11.11.1. It retained the ability to recognize OVA plus I-A(k) inherited from one parent, and KLH plus IA(f) inherited from the other. It did not recognize OVA plus IA(f) or KLH plus I-A(k). These results have some bearing on models describing the nature of T cell receptors for antigen recognized in association with H-2 products. They do not support models in which antigen and H-2 are recognized separately by two independent T cell receptors.