tbuckley/cabot-search huggingface dataset:
Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes
Authors: Matthew Taylor, Sharon Graw, Gianfranco Sinagra, Carl Barnes, Dobromir Slavov, Francesca Brun, Bruno Pinamonti, Ernesto E. Salcedo, William Sauer, Stylianos Pyxaras, Brian Anderson, Bernd Simon, Julius Bogomolovas, Siegfried Labeit, Henk Granzier, Luisa Mestroni
Journal: Circulation (2011)

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin ( TTN ) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.
Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
Authors: Indrajit Das, Chin Wen Png, Iulia Oancea, Sumaira Z. Hasnain, Rohan Lourie, Martina Proctor, Rajaraman D. Eri, Yong Sheng, Denis I. Crane, Timothy H. Florin, Michael A. McGuckin
Journal: The Journal of Experimental Medicine (2013)

Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca2+ or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX’s suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER.
A POPULATION OF LYMPHOCYTES BEARING A MEMBRANE RECEPTOR FOR ANTIGEN-ANTIBODY-COMPLEMENT COMPLEXES
Authors: Celso Bianco, Richard Patrick, Victor Nussenzweig
Journal: The Journal of Experimental Medicine (1970)

A population of lymphoid cells from several animal species, including man, was identified through a membrane receptor which binds sheep red blood cells treated with antibody and complement. When cells from different lymphoid organs were incubated with EAC at 37 degrees C, only part of the lymphocytes (named CRL) bound EAC and formed rosettes, and this interaction was shown to be C3-dependent. Mouse lymphoid cells could be specifically depleted of CRL by allowing them first to interact with EAC and then submitting the mixture to ultracentrifugation in a gradient of BSA. After ultracentrifugation, a population of cells containing 95% or more of non-CRL were recovered from the upper layers of the gradient. In addition to their different abilities to bind EAC, CRL and non-CRL from mouse lymphoid organs could be distinguished by the following properties: (a) CRL adhered preferentially to nylon wool at 37 degrees C in the presence of mouse serum. (b) After differential flotation in a gradient of BSA, a significantly higher proportion of CRL were recovered from the upper layers of the gradient. (c) The population of CRL contained most of the lymphocytes bearing immunoglobulin determinants on their membranes. (d) The distribution of CRL was quite different among lymphocytes obtained from various lymphoid organs, and they were never found in the thymus. (e) The membrane receptor for EAC was not detected in plaque-forming cells of mice which had been previously immunized with burro red cells. CRL and non-CRL could not be distinguished by their life span, as they were found in similar proportions among long-lived and short-lived lymphocytes from mouse peripheral lymph nodes. The function of this receptor on the membrane of certain lymphoid cells may be related to (a) the trapping and localization of antigen in lymphoid organs or (b) the localization of lymphoid cells in inflammatory sites.
Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts.
Authors: H F Clemo, L Belardinelli
Journal: Circulation Research (1986)

Adenosine as well as hypoxia and ischemia are known to cause atrioventricular conduction block. To test the hypothesis that adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay in isolated perfused guinea pig hearts, we characterized a) the time courses of hypoxia-induced adenosine release and delay in atrioventricular conduction, b) the relationships between oxygen tension, adenosine concentration in the effluent, and atria-to-His-bundle interval, and c) the adenosine receptor mediating the negative dromotropic effect of hypoxia. Oxygen tension and effluent adenosine levels were linearly related with a correlation coefficient (r) of -0.85 and a slope of -6.3 +/- 0.37 pmol/min/g/torr. Likewise, oxygen tension and atria-to-His-bundle interval prolongation were linearly related with r = -0.85 and a slope of -0.180 +/- 0.013 msec/torr. The EC50 of effluent adenosine in causing atria-to-His-bundle prolongation was 0.26 +/- 0.02 microM. Adenosine deaminase, an enzyme that deaminates adenosine to inosine and is limited to the extracellular space, significantly attenuated (61%) the atria-to-His-bundle interval prolongation caused by hypoxia. This prolongation was further reduced (81%) by a combination of adenosine deaminase and theophylline, an adenosine receptor blocker. Adenosine deaminase also reduced (by 95%) the atria-to-His-bundle interval prolongation in normoxic recipient hearts caused by the effluent of hypoxic donor hearts. Several adenosine antagonists, i.e., theophylline, 8-phenyltheophylline, and 8-(p-sulfophenyl)theophylline antagonized in a dose-dependent manner the negative dromotropic effect of exogenous adenosine and hypoxia. Schild analysis of the antagonism of hypoxia-induced atria-to-His-bundle interval prolongation by 8-(p-sulfophenyl)theophylline yielded the following pA2 values: 5.30 +/- 0.25 and 5.28 +/- 0.31 using oxygen tension and effluent adenosine vs. AH interval prolongation, respectively. 8-(p-Sulfophenyl)theophylline also antagonized to an equal extent atria-to-His-bundle interval prolongations of similar magnitude caused either by adenosine or hypoxia. We conclude that 1) adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay, and 2) the adenosine receptor that mediates the negative dromotropic effect of hypoxia is similar to that of exogenous adenosine.
HTLV-I/II seropositivity and death from AIDS among HIV-1 seropositive intravenous drug users
Authors: J.B. Page, S. Lai, D.D. Chitwood, N.G. Klimas, P.C. Smith, M.A. Fletcher
Journal: The Lancet (1990)

In a prospective study of street-recruited intravenous drug users (IVDUs) in Miami, Florida, USA, 107 (46·5%) of 230 IVDUs were infected with HIV-1. Of these HIV-1 seropositive individuals, 23 were also infected with human T-lymphotropic virus type I or II (HTLV-I/II). To test the hypothesis that HTLV-I/II infection has an effect on the survival of HIV-1 seropositive IVDUs, various baseline clinical and laboratory HIV-1 related indices in HTLV-I/II positive and negative groups were compared. Life table analysis and Cox's proportional hazards model were used to estimate the potential effect of HTLV-I/II infection on the survival patterns of people infected with HIV-1. IVDUs infected with both viruses were three times more likely to die from AIDS during follow-up than were those infected with HIV-1 only. This finding suggests that HTLV-I/II seropositivity may adversely affect the clinical outcome of HIV-1 seropositive patients.
Expression of c-MYC under the control of GATA-1 regulatory sequences causes erythroleukemia in transgenic mice.
Authors: R C Skoda, S F Tsai, S H Orkin, P Leder
Journal: The Journal of Experimental Medicine (1995)

To study oncogenesis in the erythroid lineage, we have generated transgenic mice carrying the human c-MYC proto-oncogene under the control of mouse GATA-1 regulatory sequences. Six transgenic lines expressed the transgene and displayed a clear oncogenic phenotype. Of these, five developed an early onset, rapidly progressive erythroleukemia that resulted in death of the founder animals 30-50 d after birth. Transgenic progeny of the sixth founder, while also expressing the transgene, remained asymptomatic for more than 8 mo, whereupon members of this line began to develop late onset erythroleukemia. The primary leukemic cells were transplantable into nude mice and syngeneic hosts. Cell lines were established from five of the six leukemic animals and these lines, designated erythroleukemia/c-MYC (EMY), displayed proerythroblast morphology and expressed markers characteristic of the erythroid lineage, including the erythropoietin receptor and beta-globin. Moreover, they also manifested a limited potential to differentiate in response to erythropoietin. Studies in the surviving transgenic line indicated that, contrary to our expectations, the transgene was not expressed in the mast cell lineage. That, coupled with the exclusive occurrence of erythroleukemia in all the transgenic lines, suggests that the GATA-1 promoter construct we have used includes regulatory sequences necessary for in vivo erythroid expression only. Additional sequences would appear to be required for expression in mast cells. Further, our results show that c-MYC can efficiently transform erythroid precursors if expressed at a vulnerable stage of their development.
Quinine induced lupus-like syndrome and cardiolipin antibodies.
Authors: D Rosa-Re, F Garcia, J Gascon, J Angrill, R Cervera
Journal: Annals of the Rheumatic Diseases (1996)

Binding profiles of cardiolipin- binding antibodies in SLE and infectious diseases.JrAutoimmun 199 1; 4: 819-30.Age of onset in successive generations of patients with a spondyloarthropathy Juvenile spondyloarthropathy JSPA) is as yet not a fully defined disorder,' but can be considered as the juvenile form of the adult spondyloarthropathy (SPA).Preliminary criteria for the latter have been proposed,2 the tip of the iceberg being ankylosing spondylitis.These criteria are also applicable for JSPA.3The clinical presentation ofJSPA may differ from adult onset SPA,4 but eventually a considerable percentage of patients with JSPA will develop a clinical picture indistinguishable from adult SPA.Ankylosing spondylitis has a strong asso- ciation with the presence of the HLA-B27 antigen.5The risk for a first degree HLA-B27 positive relative of a patient with ankylosing spondylitis developing that disease is about 20%.6The higher prevalence of SPA in parents of children with early onset pauciarticular juvenile chronic arthritis than in the general population was reported previously.7 Possibly, the prevalence of SPA among parents with a child with JSPA might also be higher than in the general population.We report that there is a tendency towards an earlier onset of SPA in the next generation.Seven index patients were seen in the paediatric rheumatology clinic and presented with JSPA according to the European Spondyloarthropathy Study Group (ESSG) criteria,2 around the age of 10 (table ).The age of onset in the children varied from 5 to
Effect of varying amino acid levels on protein metabolism in nephrotic rats during total parenteral nutrition.
Authors: A Kawashima, K Chiku, M Kawashima, K Nitta, W Yumura, N Sugino, H Nihei, Y Natori
Journal: Journal of the American Society of Nephrology (1997)

In an attempt to determine appropriate diet in nephrotic syndrome, nephrotic rats, induced by puromycin aminonucleoside, were nourished by total parenteral nutrition fluid containing the same energy, but three different levels (1.65, 3.3, and 6.6%) of amino acids for 7 d. The fractional rate of total protein synthesis in the liver was determined by injecting a flooding dose of [3H]phenylalanine. The proportion of newly synthesized proteins retained and exported by the liver was estimated by injecting a tracer dose of [14C]leucine and then measuring the protein radioactivity remaining in the liver and present in the plasma after secretion was completed. Nephrotic animals synthesized more protein than control animals. Although the absolute synthesis rates of total protein in liver were increased with increasing amino acid administration, the absolute rates of synthesis of albumin were higher in the 3.3% group than in the other groups in nephrotic rats. However, kidney protein synthesis in nephrotic rats was higher in the 1.65% group than in the 3.3% group. Interestingly, the 3.3% group revealed the smallest urinary excretion of total protein and albumin. In addition, in the 3.3% group, plasma concentrations of total protein and albumin were higher, and plasma concentrations of total cholesterol and triglyceride were lower than in other groups. It was concluded that the 3.3% group, corresponding to a normal protein diet, has the greatest salutary effect on urinary protein excretion, followed by protein and lipid metabolism, in nephrotic rats. Not only protein intake but also the energy:protein ratio are important for diet therapy in nephrotic animals. The technique of total parenteral nutrition may be useful in defining the factors involved in glomerular permeability or permselectivity and intracellular protein metabolism.
Intravenous nitroglycerin for prevention of pancreatitis after therapeutic endoscopic retrograde cholangiography: a randomized, double-blind, placebo-controlled multicenter trial
Authors: M. Beauchant, P. Ingrand, J. Favriel, J. Dupuychaffray, P. Capony, H. Moindrot, M. Barthet, J. Escourrou, C. Plane, T. Barrioz, L. Lacoste, I. Ingrand
Journal: Endoscopy (2008)

See also: Commentaire de travail de M. Beauchant et al., pp. 631Endoscopy 2008; 40(08): 796-796DOI: 10.1055/s-0032-1306857
Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE)
Authors: Ole Raaschou-Nielsen, Zorana J Andersen, Rob Beelen, Evangelia Samoli, Massimo Stafoggia, Gudrun Weinmayr, Barbara Hoffmann, Paul Fischer, Mark J Nieuwenhuijsen, Bert Brunekreef, Wei W Xun, Klea Katsouyanni, Konstantina Dimakopoulou, Johan Sommar, Bertil Forsberg, Lars Modig, Anna Oudin, Bente Oftedal, Per E Schwarze, Per Nafstad, Ulf De Faire, Nancy L Pedersen, Claes-Göran Östenson, Laura Fratiglioni, Johanna Penell, Michal Korek, Göran Pershagen, Kirsten T Eriksen, Mette Sørensen, Anne Tjønneland, Thomas Ellermann, Marloes Eeftens, Petra H Peeters, Kees Meliefste, Meng Wang, Bas Bueno-de-Mesquita, Timothy J Key, Kees de Hoogh, Hans Concin, Gabriele Nagel, Alice Vilier, Sara Grioni, Vittorio Krogh, Ming-Yi Tsai, Fulvio Ricceri, Carlotta Sacerdote, Claudia Galassi, Enrica Migliore, Andrea Ranzi, Giulia Cesaroni, Chiara Badaloni, Francesco Forastiere, Ibon Tamayo, Pilar Amiano, Miren Dorronsoro, Antonia Trichopoulou, Christina Bamia, Paolo Vineis, Gerard Hoek
Journal: The Lancet Oncology (2013)
HIGH-ENERGY FEMORAL SHAFT FRACTURES IN CABLE WAKEBOARDING AND REVIEW OF THE LITERATURE. CASE REPORT
Authors: Henrik Bäcker, Gábor Vásárhelyi, Gergely Pánics
Journal: British Journal of Sports Medicine (2013)

Wakeboarding is a common water sport which may cause serious injuries. Especially joints are affected like anterior cruciate ligament tears, shoulder dislocations or sprained ankles and have frequently been described. In contrast, because of the largeness, length and strength of the femur, femoral shaft fractures are mainly caused by high-energy trauma in young people 1 in an ordinary population. Among athletic population numerous studies evaluated stress fractures of the femur. According to their results this type of injury is relatively uncommon, and data from the literature suggest that they constitute only 2.8–7% of all sport related stress fractures. 2 There are only few data about high-energy trauma of the femoral shaft in sport although the incidence of acute femoral fractures is quite high in certain sports' like motocross (10%), 3 and alpine skiing among inpatient athletes. Despite multiple reports in various sports of stress fracture of the femur and few publications of direct trauma, to our knowledge there is only one retrospective epidemiological study in wakeboarding, which reports femur fractures without differentiating between vehicle towed and cable wakeboarding. Our purpose is to illustrate two cases of high-energy related femoral shaft fractures in a male recreational cable wakeboarder and to review the pertinent literature.
<i>Mycobacterium marinum</i> Escapes from Phagosomes and Is Propelled by Actin-based Motility
Authors: Luisa M. Stamm, J. Hiroshi Morisaki, Lian-Yong Gao, Robert L. Jeng, Kent L. McDonald, Robyn Roth, Sunao Takeshita, John Heuser, Matthew D. Welch, Eric J. Brown
Journal: The Journal of Experimental Medicine (2003)

Mycobacteria are responsible for a number of human and animal diseases and are classical intracellular pathogens, living inside macrophages rather than as free-living organisms during infection. Numerous intracellular pathogens, including Listeria monocytogenes, Shigella flexneri, and Rickettsia rickettsii, exploit the host cytoskeleton by using actin-based motility for cell to cell spread during infection. Here we show that Mycobacterium marinum, a natural pathogen of fish and frogs and an occasional pathogen of humans, is capable of actively inducing actin polymerization within macrophages. M. marinum that polymerized actin were free in the cytoplasm and propelled by actin-based motility into adjacent cells. Immunofluorescence demonstrated the presence of host cytoskeletal proteins, including the Arp2/3 complex and vasodilator-stimulated phosphoprotein, throughout the actin tails. In contrast, Wiskott-Aldrich syndrome protein localized exclusively at the actin-polymerizing pole of M. marinum. These findings show that M. marinum can escape into the cytoplasm of infected macrophages, where it can recruit host cell cytoskeletal factors to induce actin polymerization leading to direct cell to cell spread.
The Role of Knee Alignment in Disease Progression and Functional Decline in Knee Osteoarthritis
Authors: Leena Sharma
Journal: JAMA (2001)

ContextKnee osteoarthritis (OA) is a leading cause of disability in older persons. Few risk factors for disease progression or functional decline have been identified. Hip-knee-ankle alignment influences load distribution at the knee; varus and valgus alignment increase medial and lateral load, respectively.ObjectiveTo test the hypotheses that (1) varus alignment increases risk of medial knee OA progression during the subsequent 18 months, (2) valgus alignment increases risk of subsequent lateral knee OA progression, (3) greater severity of malalignment is associated with greater subsequent loss of joint space, and (4) greater burden of malalignment is associated with greater subsequent decline in physical function.Design and SettingProspective longitudinal cohort study conducted March 1997 to March 2000 at an academic medical center in Chicago, Ill.ParticipantsA total of 237 persons recruited from the community with primary knee OA, defined by presence of definite tibiofemoral osteophytes and at least some difficulty with knee-requiring activity; 230 (97%) completed the study.Main Outcome MeasuresProgression of OA, defined as a 1-grade increase in severity of joint space narrowing on semiflexed, fluoroscopically confirmed knee radiographs; change in narrowest joint space width; and change in physical function between baseline and 18 months, compared by knee alignment at baseline.ResultsVarus alignment at baseline was associated with a 4-fold increase in the odds of medial progression, adjusting for age, sex, and body mass index (adjusted odds ratio [OR], 4.09; 95% confidence interval [CI], 2.20-7.62). Valgus alignment at baseline was associated with a nearly 5-fold increase in the odds of lateral progression (adjusted OR, 4.89; 95% CI, 2.13-11.20). Severity of varus correlated with greater medial joint space loss during the subsequent 18 months (R = 0.52; 95% CI, 0.40-0.62 in dominant knees), and severity of valgus correlated with greater subsequent lateral joint space loss (R = 0.35; 95% CI, 0.21-0.47 in dominant knees). Having alignment of more than 5° (in either direction) in both knees at baseline was associated with significantly greater functional deterioration during the 18 months than having alignment of 5° or less in both knees, after adjusting for age, sex, body mass index, and pain.ConclusionThis is, to our knowledge, the first demonstration that in primary knee OA varus alignment increases risk of medial OA progression, that valgus alignment increases risk of lateral OA progression, that burden of malalignment predicts decline in physical function, and that these effects can be detected after as little as 18 months of observation.