tbuckley/cabot-search huggingface dataset:
Emerging role of PKA/eNOS pathway in therapeutic angiogenesis for ischaemic tissue diseases
Authors: Shyamal C. Bir, Yan Xiong, Christopher G. Kevil, Jincai Luo
Journal: Cardiovascular Research (2012)

Although an abundant amount of research has been devoted to the study of angiogenesis, its precise mechanisms are incompletely understood. Numerous clinical trials focused on therapeutic angiogenesis for the treatment of tissue ischaemia have not been as successful as those of preclinical studies. Thus, additional studies are needed to better understand critical molecular mechanisms regulating ischaemic neovascularization to identify novel therapeutic agents. Nitric oxide (NO) plays a central role in ischaemic neovascularization through the generation of cyclic guanosine monophosphate (cGMP) and the activation of several other signalling responses. Accumulated evidence suggests that endothelial protein kinase A/endothelial NO synthase (PKA/eNOS) signalling may play an important role in ischaemic disorders by promoting neovascularization. This review highlights recent advances in the role of the PKA/eNOS and NO-cGMP-kinase cascade pathway in ischaemic neovascularization. We also discuss molecular relationships of PKA/eNOS with other angiogenic pathways and explore the possibility of activation of the NO/nitrite endocrine system as potential therapeutic targets for ischaemic angiogenesis.
Yin Yang 1 and farnesoid X receptor: a balancing act in non-alcoholic fatty liver disease?
Authors: Vanessa Legry, Frank G Schaap, Bénédicte Delire, Yves Horsmans, Isabelle A Leclercq
Journal: Gut (2013)

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. It comprises a spectrum ranging from bland steatosis or NAFL to non-alcoholic steatohepatitis (NASH) with or without fibrosis. There is a general consensus that patients with NAFLD have a very slow disease progression (if any). By contrast, patients with NASH can exhibit histological progression and can develop fibrosis, cirrhosis and hepatocellular carcinoma. Parenchymal inflammation is an important determinant of the severity and progression of the disease.

Increased fatty acid flux to the liver, from dietary absorption and from the adipose tissue, owing to insulin resistance, is a main contributor to increased hepatic lipid content. In addition, increased de novo lipogenesis, impaired mitochondrial fatty acid oxidation or decreased export of very low density lipoprotein triglyceride all play a part. Ligand-activated nuclear receptors control several key steps in lipid metabolism as well as inflammation and fibrogenesis and thus are potentially crucial players in NAFLD/NASH pathogenesis.1 One of those nuclear receptors is the bile salt sensor farnesoid X receptor (FXR). Besides regulating cholesterol and bile salt homeostasis, FXR is a key regulator of hepatic lipid metabolism. FXR, via induction of a short heterodimer partner, represses de novo lipogenesis. It induces peroxisome proliferator activated receptor (PPAR)α, and thus stimulates fatty acid β oxidation. The role of FXR is emphasised by the development of hepatosteatosis and hyperlipidaemia in FXR−/− mice.2 ,3 …
Vaccination of COPD patients with a pneumococcus type 6B tetanus toxoid conjugate vaccine
Authors: S. Jonsson, G. Vidarsson, H. Valdimarsson, G. Schiffman, R. Schneerson, I. Jonsdottir
Journal: European Respiratory Journal (2002)

This paper examines how pneumococcal type 6B polysaccharide conjugated to tetanus toxoid (Pn6B-TT) compares to a 23 valent pneumococcal vaccine (pneumococcal polysaccharide (PPS)-23) with respect to immunogenicity and serum opsonic activity in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD aged 55–75 yrs were vaccinated with Pn6B-TT (n=10) or with PPS-23 (n=9). Healthy young adults (HA) were vaccinated with Pn6B-TT as controls. Total antibodies to serotype 6B polysaccharide were measured by radioimmunoassay and immunoglobulin (Ig)G antibodies by enzyme-linked immunosorbent assay. Opsonic activity was measured by a phagocytosis assay using human neutrophils as effector cells. The patient groups were comparable by age, smoking history, lung function and use of steroids. COPD patients vaccinated with Pn6B-TT or PPS-23 showed an increase in IgG antibodies and a nonsignificant increase in opsonic activity. This was similar to the increase in IgG and opsonic activity seen in HA. There was a significant correlation between antibody levels and opsonic activity in COPD patients vaccinated both with Pn6B-TT and PPS-23. Pneumococcal antibodies have been shown to confer protection from infection. The results of the present study indicate that protective immunity can be expected in elderly chronic obstructive pulmonary disease patients vaccinated with conjugate vaccines.
Message about hormone replacement therapy is unclear
Authors: J M. Dixon
Journal: BMJ (2002)

EDITOR—Two contrasting leading articles followed publication of the randomised trial of the women's health initiative study of hormone replacement therapy. 1 2

Stevenson and Whitehead in the BMJ said that the increased risk of breast cancer in the study was small, but they did not mention that during the study 42% of women taking active drug and 38% receiving placebo stopped the assigned treatment.1

In contrast, Fletcher and Colditz reported in JAMA that the intention to treat analysis may have underestimated the …
Expression of Profilin, an Actin-Binding Protein, in Rat Experimental Glomerulonephritis and Its Upregulation by Basic Fibroblast Growth Factor in Cultured Rat Mesangial Cells
Authors: MASAHITO TAMURA, HIROSHI TANAKA, AKIRA YASHIRO, AKIHIKO OSAJIMA, MASAHIRO OKAZAKI, HIDEAKI KUDO, YOSHIAKI DOI, SUNAO FUJIMOTO, KEN HIGASHI, YASUHIDE NAKASHIMA, HIDEYASU HIRANO
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Profilin binds to actin monomer to regulate actin polymerization, and to phosphatidylinositol 4,5-biphosphate to inhibit hydrolysis by phospholipase Cγ1. This study investigated the expression of profilin in rat anti-Thy-1.1 mesangial proliferative glomerulonephritis (GN) and examined the effect of growth factors on its expression in cultured rat mesangial cells. Profilin mRNA was constitutively expressed in isolated glomeruli of untreated rats. However, in glomeruli of anti-Thy-1.1 GN rats, its expression was upregulated beginning on day 1, reaching a peak level on day 4 (3.9-fold versus control glomeruli), and decreased on day 14, as determined by competitive reverse transcription-PCR. Increased expression of profilin protein was confirmed using immunoblotting and immunohistochemistry. Immunoelectron microscopy revealed the presence of profilin in plasma membrane and the rough endoplasmic reticulum of mesangial cells, indicating that profilin was produced in mesangial cells. In cultured rat mesangial cells, expression of profilin mRNA and protein was upregulated by basic fibroblast growth factor but not by platelet-derived growth factor or transforming growth factor-β. Suppression of profilin expression using an antisense oligonucleotide against profilin inhibited [ 3 H]thymidine uptake. These findings indicated the involvement of profilin in anti-Thy-1.1 GN and suggest that the upregulation of profilin might be involved in the progression of anti-Thy-1.1 GN possibly by affecting cell growth.
Monitoring Plasma HIV-1 RNA Levels in Addition to CD4+ Lymphocyte Count Improves Assessment of Antiretroviral Therapeutic Response
Authors: Michael D. Hughes
Journal: Annals of Internal Medicine (1997)

Background: CD4+ lymphocyte counts and plasma HIV-1 RNA levels predict progression of HIV-related disease, but the relative importance of these and other virological factors in defining response to antiretroviral therapy is not yet clear. Objective: To determine the short-term variability of plasma HIV-1 RNA level during stable therapy; the relative importance of pretreatment values and early changes in CD4+ count, HIV-1 RNA levels, and infectious HIV-1 titers in mononuclear cells of peripheral blood and pretreatment syncytium-inducing phenotype of an HIV-1 isolate for prediction of disease progression and decline in CD4+ counts during therapy. Design: Data were collected prospectively in a randomized, clinical trial comparing two combination regimens (ACTG [AIDS Clinical Trials Group] Protocol 241) and pooled across treatments. Setting: 8 AIDS Clinical Trials Units. Patients: 198 adults with HIV-1 infection and no more than 350 CD4+ lymphocytes/mm3 who had received at least 6 months of nucleoside therapy. Interventions: All patients received zidovudine and didanosine; 100 received nevirapine and 98 received placebo. Measurements: CD4+ lymphocyte counts, plasma HIV-1 RNA levels, and infectious HIV-1 titers in cells were measured before and 8 and 48 weeks after study treatment. Assay for the syncytium-inducing viral phenotype was done at baseline. Progression was defined as occurrence of opportunistic infection, malignancy, or death during the 48 weeks after treatment began. Results: The difference between two measurements of HIV-1 RNA levels at baseline was within ± 0.39 log10 copies/mL (2.5-fold) for 90% of 167 patients receiving stable therapy. In a multivariate model, risk for disease progression was reduced by 56% (95% CI, 8% to 79% [P = 0.028]) for every 10-fold lower HIV-1 RNA level at baseline, by 52% (CI, 6% increase to 79% reduction [P = 0.071]) for every 10-fold reduction in HIV-1 RNA level at 8 weeks after treatment initiation, and by 67% (CI, 42% to 81% [P < 0.001]) for every 2-fold higher CD4+ count at baseline. These risk factors and syncytium-inducing viral phenotype at baseline, but not infectious HIV-1 titers in circulating cells, were associated with change in CD4+ counts over 48 weeks. Conclusions: For an individual patient, a change in plasma HIV-1 RNA level of 2.5-fold or more probably indicates a true biological change. Monitoring HIV-1 RNA levels and CD4+ lymphocytes before a change in antiretroviral treatment and monitoring HIV-1 RNA levels shortly thereafter improves prediction of disease progression and decline in CD4+ counts for 1 year compared with monitoring CD4+ counts or HIV-1 RNA levels alone. Additional monitoring of infectious HIV-1 titers in mononuclear cells of peripheral blood is not useful.
Observations on the onset of Torsade de Pointes arrhythmias in the acquired long QT syndrome
Authors: M Vos
Journal: Cardiovascular Research (2000)

Premature ectopic beats may create a specific sequence of events (e.g. short-long-short) preceding Torsade de Pointes arrhythmias (TdP) in the long QT syndrome. The relevance of this sequence for the initiation of TdP is not clear. In our dog model of TdP, interventricular dispersion (DeltaAPD=left-right ventricular monophasic action potential duration: APD) is associated with TdP, therefore we tested the hypothesis that the ectopic beats contributes to DeltaAPD.In 17 anaesthetized dogs with chronic AV-block, which showed spontaneous TdP after class III medication, APD was analyzed to 1. quantitate the alterations due to (multiple) ectopic beats on the left and right APD (measured with endocardial catheters) and 2. compare the DeltaAPD prior to the occurrence of premature beats (steady state) in dogs with non-sudden onset of TdP (n=10) and sudden onset TdP (n=7). Three phases were distinguished: phase 1: steady state beats prior to ectopic beats, phase II: the beat(s) belonging to the dynamic phase, and phase III: the beat causing TdP. Because the coupling interval of premature beats in this condition often falls within the APD, the DeltaAPD(50) was validated as an alternative for the previously applied DeltaAPD(100) (r=0.51, P<0.01).In steady state (phase I) DeltaAPD(50) is longer in the sudden onset TdP (130+/-35 ms) as in the non-sudden onset TdP (65+/-40 ms). In the non-sudden TdP group the dynamic phase II contribute to the heterogeneity in APD, i.e. LV-APD increases more than RV-APD leading to a DeltaAPD(50) increase to 130+/-100 ms (P<0.01) just preceding TdP (phase III).The synergism between ectopic beats (short-long-short sequence) and DeltaAPD create the circumstances for TdP initiation.
Mu Opioids and Their Receptors: Evolution of a Concept
Authors: Gavril W. Pasternak, Ying-Xian Pan
Journal: Pharmacological Reviews (2013)

Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
Daily air pollution levels and acute asthma in southern Sweden
Authors: B Forsberg, N Stjernberg, R Linne, B Segerstedt, S Wall
Journal: European Respiratory Journal (1998)

This study aimed to investigate the association between daily air pollution levels and the occurrence of acute respiratory signs and symptoms among people with asthma or asthma-like problems. Thirty eight subjects in the southern Swedish city of Landskrona kept a daily diary for 10 weeks. The daily prevalence of symptoms, supplementary bronchodilator use and peak flow deviations were compared with measurements of environmental nitrogen dioxide (NO2), sulphur dioxide, temperature and humidity in the city. The occurrence of severe asthma, both during the day and during the evening, was significantly positively associated with the concurrent 24 h average concentration of NO2, which never exceeded 72 microg x m(-3). A correlation of borderline significance was found between the use of on-demand medication and the NO2 level. However, peak flow deviations were not associated with air pollution or weather conditions, which may be explained by the beneficial effect of bronchodilators used by 28 of the subjects. The results of this study confirm those of some earlier studies and suggest that aggravation of asthma is related to daily variations in air quality, as indicated by relatively low ambient concentrations of nitrogen dioxide. These results also indicate that it may be appropriate to examine severe asthma symptoms separately.
Association between Angiotensin-Converting Enzyme Gene Polymorphisms and Diabetic Nephropathy
Authors: Samy Hadjadj, Lise Tarnow, Carol Forsblom, Gbenga Kazeem, Michel Marre, Per-Henrik Groop, Hans-Henrik Parving, Franc[COMBINING CEDILLA]ois Cambien, David A. Tregouet, Ivo G. Gut, Alexandre The[Combining Acute Accent]va, Dominique Gauguier, Martin Farrall, Roger Cox, Fumihiko Matsuda, Mark Lathrop, Nathalie Hager-Vionnet
Journal: Journal of the American Society of Nephrology (2007)

Angiotensin 1-converting enzyme gene ( ACE ) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [≥15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C , rs4311-T , Insertion/deletion (I/D or rs1799752)-D , rs4366-G , and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366\_G and rs12449782\_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.
Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice
Authors: J ZHONG, X YU, Y HUANG, L YUNG, C LAU, S LIN
Journal: Cardiovascular Research (2007)

The apelin receptor APJ is a putative receptor protein related to angiotensin (Ang) type 1 receptor. The apelin-APJ system has been implicated in diabetes, but its role in the diabetic vasculature and the mechanisms involved remain unclear. Our aim here was to explore the regulatory role of apelin in the aortic vascular tone in diabetic mice.A Multi Myograph system was used to determine the isometric vessel tone in aortic rings from diabetic db/db and control db/m+ mice. The mRNA, phosphorylation, and protein levels of APJ, Akt, and endothelial nitric oxide synthase (eNOS) were analyzed by reverse transcription-polymerase chain reaction and Western blotting, respectively.There is depressed expression of APJ, enhanced contractile response to Ang II, and reduced relaxation response to acetylcholine in aortas from db/db mice. Apelin treatment strikingly reversed the altered aortic vascular responsiveness to Ang II and acetylcholine in db/db mice, both of which were abolished by the eNOS inhibitor NG-nitro-L-arginine methyl ester. Finally, in db/db mice, considerable increases in phosphorylation of Akt on serine 473 and of eNOS on serine 1177 were found in aortas pretreated with apelin.Apelin treatment modulates the abnormal aortic vascular tone in response to Ang II and acetylcholine by potentiating phosphorylation of Akt and eNOS in diabetic mice, suggesting that the apelin-APJ system might be an important regulator of vascular function in diabetes.
Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
Authors: Frances A. Shepherd, José Rodrigues Pereira, Tudor Ciuleanu, Eng Huat Tan, Vera Hirsh, Sumitra Thongprasert, Daniel Campos, Savitree Maoleekoonpiroj, Michael Smylie, Renato Martins, Maximiliano van Kooten, Mircea Dediu, Brian Findlay, Dongsheng Tu, Dianne Johnston, Andrea Bezjak, Gary Clark, Pedro Santabárbara, Lesley Seymour
Journal: New England Journal of Medicine (2005)

We conducted a randomized, placebo-controlled, double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non–small-cell lung cancer after the failure of first-line or second-line chemotherapy.
Inferring Cortical Function From the Patient's Job: He Made Grass Trimmer, But Could He Have Made Vice President?
Authors: Allen H. Roberts
Journal: JAMA (1989)

<h3>To the Editor.—</h3> May I express my appreciation to you and to Dr Murphy<sup>1</sup>for a fine review of blastomycosis in the June 2 issue ofThe Journal? May I also, however, express concern regarding one of the author's statements? The author states that "[the patient's] job suggested that his level of cortical function had never been high." The patient's job was that of a highway grass trimmer and tidier, a job he had apparently held for two decades. There is no suggestion that he did not trim in a straight line or that he was untidy. I respectfully submit that his job suggests nothing regarding his cortical function. Perhaps the patient would even be saddened by such a thought. I understand the author's meaning, or intent. However, we who are in medicine must take care not to infer patients' mental status from the nature of their work, lest
D<scp>IETARY</scp> C<scp>ONJUGATED</scp> L<scp>INOLEIC</scp> A<scp>CID IN</scp> H<scp>EALTH</scp>: Physiological Effects and Mechanisms of Action
Authors: Martha A. Belury
Journal: Annual Review of Nutrition (2002)

Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health.
The Metabolic Syndrome as a Risk Factor for Chronic Kidney Disease
Authors: Jeffrey R. Schelling, John R. Sedor
Journal: Journal of the American Society of Nephrology (2004)

The metabolic syndrome, also known as syndrome X or insulin resistance syndrome, is characterized by abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and reduced HDL cholesterol. In this issue of the Journal of the American Society of Nephrology , Wisse ([1][1]) describes the
Mindin/Spondin 2 inhibits hepatic steatosis, insulin resistance, and obesity via interaction with peroxisome proliferator-activated receptor α in mice
Authors: Li-Hua Zhu, Aibing Wang, Pengcheng Luo, Xinan Wang, Ding-Sheng Jiang, Wei Deng, Xiaofei Zhang, Tao Wang, Yi Liu, Lu Gao, Shumin Zhang, Xiaodong Zhang, Jie Zhang, Hongliang Li
Journal: Journal of Hepatology (2014)