tbuckley/cabot-search huggingface dataset:
Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction
Authors: Sabine Klaassen, Susanne Probst, Erwin Oechslin, Brenda Gerull, Gregor Krings, Pia Schuler, Matthias Greutmann, David Hürlimann, Mustafa Yegitbasi, Lucia Pons, Michael Gramlich, Jörg-Detlef Drenckhahn, Arnd Heuser, Felix Berger, Rolf Jenni, Ludwig Thierfelder
Journal: Circulation (2008)

Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction.Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site.We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.
Plasma free fatty acid in liver disease
Authors: A. Mortiaux, A. M. Dawson
Journal: Gut (1961)

The plasma free fatty acid level was raised in the majority of 131 patients with a variety of liver disorders, and included both those with severe liver cell damage and those with relatively good liver cell function and obstructive jaundice. This raised level is probably due to an increased mobilization of depot fat, for glucose, which inhibits peripheral liberation of free fatty acids, caused a fall in the plasma level and obliteration of the femoral venous-arterial difference in patients with liver disease comparable with that in normal persons. In addition, the plasma free fatty acid flux was measured using palmitate-1-C<sup>14</sup> and was found to be increased in patients with liver disease.
Epinephrine Administration for Cases of Anaphylaxis in a US School Setting: Results from the EpiPen4Schools Survey
Authors: Margaret Wooddell, Diana Goss, Kelly Hollis, K. Millar, Suyapa Silvia, Peter Siegel, Mary Elizabeth Bennett, Ray A. Wolf, Susan Hogue, Martha V. White
Journal: Journal of Allergy and Clinical Immunology (2015)
Low Neutral Endopeptidase Levels in Bronchoalveolar Lavage Fluid of Lung Cancer Patients
Authors: ANDREA J. COHEN, WILBUR A. FRANKLIN, CATHY MAGILL, JULIE SORENSON, YORK E. MILLER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Neutral endopeptidase (NEP) is a cell surface enzyme found in normal human lung and which hydrolyzes small bioactive peptides, some of which act as growth factors for normal and malignant airway epithelial cells. Expression of NEP varies widely in human lung tissue from different individuals. NEP is often expressed at low or undetectable levels in both small-cell and non-small–cell lung cancer, and inhibits the growth of lung cancer cell lines. Variation in the expression of NEP could be a factor in susceptibility to lung cancer. We hypothesized that NEP could be measured in bronchoalveolar lavage fluid (BALF) and that airway levels of NEP would be low in lung cancer patients as compared with normal controls. We measured NEP and total protein in cell-free BALF supernatant, and expressed the respective concentrations as a ratio. NEP levels showed wide variation in BALF of healthy volunteers. Most patients with lung cancer had no NEP detectable in BALF. The mean NEP/total protein ratio was significantly lower in patients with lung cancer (0.87 ± 0.7 ng NEP/mg protein) than in normal healthy subjects (14.0 ± 4.3, p < 0.0003). We conclude that NEP levels are highly variable in BALF of normal volunteers, and are low or undetectable in most BALF specimens from patients with lung cancer. Low NEP levels in the airways may be a factor in the pathogenesis of carcinoma of the lung.
Azone analogues: classification, design, and transdermal penetration principles
Authors: Josef Jampilek, Katerina Brychtova
Journal: Medicinal Research Reviews (2010)

Abstract The development in the field of pharmaceutical dosage forms results in the discovery of additional highly sophisticated drug delivery systems that allow maintaining a constant level of the active substance in an organism. Transdermal therapeutic systems are an excellent alternative to conventional pharmaceutical dosage forms. However, the application of transdermal drug delivery faces the problem of insufficient or no penetration of active pharmaceutical substances through the skin. This review article describes the possible fundamental mechanisms of penetration through the skin barrier and refers to the classification of skin penetration enhancers. Azone‐like enhancers are considered in detail and classified according to their structure on the basis of medicinal chemistry approaches. The article also provides a review of original transdermal penetration enhancers prepared in our laboratory and discusses the relationship between the chemical structure of the described Azone analogues and their penetration activity (SAR/QSAR).
Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus
Authors: K M Walsh
Journal: Gut (2001)

Fibrosing cholestatic hepatitis (FCH) is a severe clinical and histological variant of hepatitis B virus (HBV) infection seen most commonly in the HBV infected allograft after liver transplantation. Without treatment, FCH is fatal, rapidly and universally. Remission has been reported with lamivudine but is associated with evolving resistance to lamivudine. Adefovir dipivoxil has recently been reported to be a potent and highly effective inhibitor of HBV replication in both wild-type and lamivudine resistant HBV infection. We report a case of FCH 15 months after liver transplantation for HBV related cirrhosis despite therapy with lamivudine and hepatitis B immunoglobulin (HBIg). Within two weeks of commencing treatment with adefovir dipivoxil 10 mg once daily, the patient had made a remarkable recovery with resolution of jaundice and normalisation of liver biochemistry. HBV DNA and hepatitis B e antigen were lost from serum subsequently and liver histology had improved at four months. This case report suggests firstly, that advanced FCH can be reversed and secondly, that addition of adefovir dipivoxil to lamivudine and HBIg may be an effective antiviral strategy.
L1CAM in Early-Stage Type I Endometrial Cancer: Results of a Large Multicenter Evaluation
Authors: Alain G. Zeimet, Daniel Reimer, Monica Huszar, Boris Winterhoff, Ulla Puistola, Samira Abdel Azim, Elisabeth Müller-Holzner, Alon Ben-Arie, Léon C. van Kempen, Edgar Petru, Stephan Jahn, Yvette P. Geels, Leon F. Massuger, Frédéric Amant, Stephan Polterauer, Elisa Lappi-Blanco, Johan Bulten, Alexandra Meuter, Staci Tanouye, Peter Oppelt, Monika Stroh-Weigert, Alexander Reinthaller, Andrea Mariani, Werner Hackl, Michael Netzer, Uwe Schirmer, Ignace Vergote, Peter Altevogt, Christian Marth, Mina Fogel
Journal: JNCI Journal of the National Cancer Institute (2013)

Despite the excellent prognosis of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome.We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death.Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89).To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.
Incorporation of <sup>14</sup> C-Labeled Acetate into Lipid by Isolated Foam Cells and by Atherosclerotic Arterial Intima
Authors: ALLAN J. DAY, GWENDOLINE K. WILKINSON
Journal: Circulation Research (1967)

The synthesis of lipid by rabbit atherosclerotic intima incubated in vitro has been investigated and compared with that of foam cells isolated from intimal lesions. In the atherosclerotic arterial intima, 14 C-labeled acetate is readily incorporated into the lipid fraction, most of the label being found in the phos-pholipid and cholesterol ester fatty acid fractions. Minimal incorporation into triglyceride, fatty acid, and cholesterol occurred. The major phospholipid synthesized was lecithin but significant incorporation into phosphatidyl inositol, phosphatidyl ethanolamine, and sphingomyelin also took place. The fatty acids synthesized were predominantly saturated in the phospholipid fraction. More monounsaturated fatty acids were present in the cholesterol ester fatty acids, but in both moieties little polyunsaturated fatty acids were labeled by the acetate. Isolated foam cells were also shown to incorporate 14 C-labeled acetate into both phospholipid and cholesterol ester fatty acids. The foam cells, however, incorporated a significantly higher proportion of acetate into cholesterol ester than did the whole intima. The fatty acids synthesized by the foam cells were more polyunsaturated in both the phospholipid and the cholesterol ester fraction than was the case with the whole intima. The relevance of these findings to the origin of lipid in the atherosclerotic lesion is discussed.
Effect of mass media campaign to reduce socioeconomic differences in women's awareness and behaviour concerning use of folic acid: cross sectional study
Authors: H E K de Walle, K M van der Pal, L T W d. J.-v. den Berg, W Jeeninga, J S A G Schouten, C M de Rover, S E Buitendijk, M C Cornel
Journal: BMJ (1999)

Subjects never previously tested for hepatitis B virus were less likely to be seropositive (5/22 v 41/62; 2 = 10.66,df = 1, P < 0.005).A similar pattern was seen for hepatitis C virus positivity (7/11 v 70/79; 2 = 3.06, df = 1, P < 0.10).Of the 33 addicts not previously tested for hepatitis B or hepatitis C virus, only 10 accurately perceived their combined status. DiscussionOur finding of 86% seropositivity for hepatitis C virus is consistent with the 67% found among Australian injecting drug users 1 and 75% among UK addicts receiving maintenance treatment. 3 The participants' perceptions of their viral status were often inaccurate: for both hepatitis B and hepatitis C virus, they tended to believe they were negative when they were positive.If untested drug users assume they are positive and act accordingly they pose no threat to public health.If they mistakenly presume negative status, this may have serious public health consequences.Clinicians should encourage testing in all patients who are injecting drug users and use this as a catalyst for interventions.As Crofts et al point out, 1 drug treatment alone is not sufficient in reducing hepatitis seroconversion and clinicians must be more vigorous in encouraging drug users to reduce risk behaviours.We thank the staff and patients involved in the study.Contributors: JS, DB, and EF conceived and initiated the study, for which the data were then collected by DB, EF, AN, and CS.All authors contributed to the analysis and preparation of the article.
Gene Duplication Is Infrequent in the Recent Evolutionary History of RNA Viruses
Authors: Etienne Simon-Loriere, Edward C. Holmes
Journal: Molecular Biology and Evolution (2013)

Gene duplication generates genetic novelty and redundancy and is a major mechanism of evolutionary change in bacteria and eukaryotes. To date, however, gene duplication has been reported only rarely in RNA viruses. Using a conservative BLAST approach we systematically screened for the presence of duplicated (i.e., paralogous) proteins in all RNA viruses for which full genome sequences are publicly available. Strikingly, we found only nine significantly supported cases of gene duplication, two of which are newly described here--in the 25 and 26 kDa proteins of Beet necrotic yellow vein virus (genus Benyvirus) and in the U1 and U2 proteins of Wongabel virus (family Rhabdoviridae). Hence, gene duplication has occurred at a far lower frequency in the recent evolutionary history of RNA viruses than in other organisms. Although the rapidity of RNA virus evolution means that older gene duplication events will be difficult to detect through sequence-based analyses alone, it is likely that specific features of RNA virus biology, and particularly intrinsic constraints on genome size, reduce the likelihood of the fixation and maintenance of duplicated genes.
Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRÉ Investigation
Authors: V P van Halm, M J L Peters, A E Voskuyl, M Boers, W F Lems, M Visser, C D A Stehouwer, A M W Spijkerman, J M Dekker, G Nijpels, R J Heine, L M Bouter, Y M Smulders, B A C Dijkmans, M T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2008)

Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other.The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50-75 years; the CARRE study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRE study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194).The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively).The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.
Cross-talk between HIF and p53 as mediators of molecular responses to physiological and genotoxic stresses
Authors: Joanna Obacz, Silvia Pastorekova, Borek Vojtesek, Roman Hrstka
Journal: Molecular Cancer (2013)

Abstract Abnormal rates of growth together with metastatic potential and lack of susceptibility to cellular signals leading to apoptosis are widely investigated characteristics of tumors that develop via genetic or epigenetic mechanisms. Moreover, in the growing tumor, cells are exposed to insufficient nutrient supply, low oxygen availability (hypoxia) and/or reactive oxygen species. These physiological stresses force them to switch into more adaptable and aggressive phenotypes. This paper summarizes the role of two key mediators of cellular stress responses, namely p53 and HIF, which significantly affect cancer progression and compromise treatment outcomes. Furthermore, it describes cross-talk between these factors.
Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus
Authors: John B. Buse, Henry N. Ginsberg, George L. Bakris, Nathaniel G. Clark, Fernando Costa, Robert Eckel, Vivian Fonseca, Hertzel C. Gerstein, Scott Grundy, Richard W. Nesto, Michael P. Pignone, Jorge Plutzky, Daniel Porte, Rita Redberg, Kimberly F. Stitzel, Neil J. Stone
Journal: Circulation (2006)

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.
Airway Inflammation in Smokers and Nonsmokers with Varying Responsiveness to Ozone
Authors: ALFONSO TORRES, MARK J. UTELL, PAUL E. MOROW, KAREN Z. VOTER, JOHN C. WHITIN, CHRISTOPHER COX, R. JOHN LOONEY, DONNA M. SPEERS, YING TSAI, MARK W. FRAMPTON
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Exposure to ozone causes symptoms, changes in lung function, and airway inflammation. We studied whether individuals who differ in lung-function responsiveness to ozone, or in smoking status, also differ in susceptibility to airway inflammation. Healthy subjects were selected on the basis of responsiveness to a classifying exposure to 0.22 ppm ozone for 4 h with exercise (responders, with a decrease in FEV1 > 15%; and non-responders, with a decrease in FEV1 < 5%). Three groups were studied: nonsmoker–nonresponders (n = 12), nonsmoker–responders (n = 13), and smokers (n = 13, 11 nonresponders and two responders). Each subject underwent two exposures to ozone and one to air, separated by at least 3 wk; bronchoalveolar and nasal lavages were performed on three occasions: immediately (early) and 18 h (late) after ozone exposure, and either early or late after air exposure. Recovery of polymorphonuclear leukocytes (PMN) increased progressively in all groups, and by up to 6-fold late after ozone exposure. Interleukin-6 (IL-6) and IL-8 increased early (by up to 10-fold and up to 2-fold, respectively), and correlated with the late increase in PMN. Lymphocytes, mast cells, and eosinophils also increased late after exposure. We conclude that ozone-induced airway inflammation is independent of smoking status or airway responsiveness to ozone.
Nature of the antigenic complex recognized by T lymphocytes II. T-cell activation by direct modification of macrophage histocompatibility antigens.
Authors: D W Thomas, E M Shevach
Journal: The Journal of Experimental Medicine (1977)

In order to analyze the molecular structures involved in T-cell recognition we developed an in vitro primary response against alloantisera bound to histocompatibility antigens in which nonimmune guinea pig T cells can be sensitized and subsequently challenged in tissue culture with antisera-treated macrophages. If macrophages were incubated with alloantisera directed against the I-region-associated (Ia) antigens of the guinea pig major histocompatibility complex (MHC) T cells could be sensitized to the antisera bound to macrophage Ia determinants. Anti-Ia-treated syngeneic macrophages in the first and second cultures elicited specific T-cell activation, as measured by increased DNA synthesis, to the antisera-induced immunogenic determinants. Similarly, antiIa-treated allogeneic macrophages also specifically stimulated T cells to antisera bound to allogeneic Ia determinants while reducing the mixed leukocyte reaction. Antisera to the B.1 antigens of the guinea pig MHC, the homologue of the mouse H-2K or H-2D antigens, also elicited specific T-cell activation that did not cross-react with that produced by the anti-Ia alloantisera. Furthermore, the anti-B.1-induced stimulation appeared to be associated with the Ia antigens of the macrophage used for priming since (2 x 13)F1 T cells sensitized with anti-B.1-treated parental macrophages could be restimulated only with the parental macrophage used for initial sensitization, and not with those of the other parent. Since the parental strain 2 and strain 13 guinea pigs express serologically identical B.1 antigens and differ only by Ia antigens of the MHC, this observation suggests that both B.1 and Ia antigens may be included in the immunogenic complex recognized by T cells. However, we cannot rule out the possibility that this restriction is due to other genetic differences between strain 2 and strain 13 guinea pigs that is unrelated to the I-region. We interpret these findings as showing that macrophage Ia antigens may serve to directly present antigens bound to the Ia molecule, and possibly indirectly aid in the presentation of antigens bound to other membrane components, such as the B.1 antigens.