tbuckley/cabot-search huggingface dataset:
HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene
Authors: Caroline Quillent, Estelle Oberlin, Joséphine Braun, Dominique Rousset, Gustavo Gonzalez-Canali, Patricia Métais, Luc Montagnier, Jean-Louis Virelizier, Fernando Arenzana-Seisdedos, Alberto Beretta
Journal: The Lancet (1998)
STUDIES ON THE MODE OF ACTION OF DIPHTHERIA TOXIN
Authors: R. J. Collier, A. M. Pappenheimer
Journal: The Journal of Experimental Medicine (1964)

It has been demonstrated that low concentrations of highly purified diphtheria toxin specifically inhibit incorporation of labeled amino acids into polypeptides in extracts from HeLa cells and from rabbit reticulocytes. No inhibition of incorporation occurs in the absence of a specific cofactor. This cofactor has been identified as nicotinamide adenine dinucleotide (NAD). It has been shown that it is one of the steps involving transfer of amino acids from soluble ribonucleic acid to the growing polypeptide chain that is affected by the toxin in the presence of NAD.
Ischemic postconditioning protects remodeled myocardium via the PI3K–PKB/Akt reperfusion injury salvage kinase pathway
Authors: M ZHU, J FENG, E LUCCHINETTI, G FISCHER, L XU, T PEDRAZZINI, M SCHAUB, M ZAUGG
Journal: Cardiovascular Research (2006)

Objective: We tested whether ischemic postconditioning (IPostC) is protective in remodeled myocardium. Methods: Post-myocardial infarct (MI)-remodeled hearts after permanent coronary artery ligation and one kidney one clip (1K1C) hypertensive hearts of male Wistar rats were exposed to 40 min of ischemia followed by 90 min of reperfusion. IPostC was induced by six cycles of 10 s reperfusion interspersed by 10 s of no-flow ischemia. Activation of reperfusion injury salvage kinases was measured using Western blotting and in vitro kinase activity assays. Results: IPostC prevented myocardial damage in both MI-remodeled and 1K1C hearts, as measured by decreased infarct size and lactate dehydrogenase release, and improved function. The reduction in infarct size and the recovery of left ventricular contractility achieved by IPostC was less in 1K1C hearts, but was unchanged in MI-remodeled hearts when compared to healthy hearts. In contrast, the recovery of inotropy was unaffected in 1K1C hearts, but was less in MI-remodeled hearts. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway with LY294002 abolished the protective effects of IPostC on both disease models and healthy hearts. Western blot analysis in conjunction with in vitro kinase activity assays identified protein kinase B (PKB)/Akt but not p42/p44 extracellular-signal regulated kinase 1/2 (ERK1/2) as the predominant kinase in IPostC-mediated cardioprotection in remodeled hearts. IPostC increased phosphorylation of the PKB/Akt downstream targets eNOS, GSK3β, and p70S6K in remodeled hearts. Conclusion: Our results offer evidence that IPostC mediates cardioprotection in the remodeled rat myocardium primarily via activation of the PI3K–PKB/Akt reperfusion injury salvage kinase pathway.
Novel cancer drivers: mining the kinome
Authors: Andrew V Biankin, Sean M Grimmond
Journal: Genome Medicine (2013)

Large-scale cancer genome studies are unveiling significant complexity and heterogeneity even in histopathologically indistinguishable cancers. Differentiating 'driver' mutations that are functionally relevant from 'passenger' mutations is a major challenge in cancer genomics. While recurrent mutations in a gene provides supporting evidence of 'driver' status, novel computational methods and model systems are greatly improving our ability to identify genes important in carcinogenesis. Reimand and Bader have recently shown that driver gene discovery in discrete gene classes (in this case the kinome) is possible across multiple cancer types and has the potential to yield new druggable targets and clinically relevant leads.
Thyroid-antithyroid treatment of hyperthyroidism
Authors: L. Waztofsky
Journal: JAMA (1971)

To the Editor.—  Selenkow in a recent letter ( 214 :2198,1970) chides Green ( 213 :1652, 1970) for his choice of Dr. John Eager Howard as a supporting reference for the use of thyroid-antithyroid combination therapy in hyperthyroidism ( 202 : 706-709, 1967). In fairness to Dr. Green, his statement simply referred to other physicians who routinely give thyroid with PTU [propylthiouracil], and was clearly not intended to annotate the literature. Likewise, one should not allude to Howard's statement out of context, in that the informal discussion of the quoted lecture was intended neither to be encyclopedic, nor to take credit for the initial advocacy of such a treatment program.  Further, I must take issue with Selenkow's recommendation of this combined therapy in all patients selected for antithyroid treatment. This is still an area of controversy even among eminent thyroidologists, and it may be grossly misleading to the practicing physician for someone of Selenkow's
Osteopontin Is a Critical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules
Authors: Jeffrey A. Wesson, Richard J. Johnson, Marrilda Mazzali, Anne M. Beshensky, Susan Stietz, Ceci Giachelli, Lucy Liaw, Charles E. Alpers, William G. Couser, Jack G. Kleinman, Jeremy Hughes
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Calcium nephrolithiasis is the most common form of renal stone disease, with calcium oxalate (CaOx) being the predominant constituent of renal stones. Current in vitro evidence implicates osteopontin (OPN) as one of several macromolecular inhibitors of urinary crystallization with potentially important actions at several stages of CaOx crystal formation and retention. To determine the importance of OPN in vivo, hyperoxaluria was induced in mice targeted for the deletion of the OPN gene together with wild-type control mice. Both groups were given 1% ethylene glycol, an oxalate precursor, in their drinking water for up to 4 wk. At 4 wk, OPN-deficient mice demonstrated significant intratubular deposits of CaOx crystals, whereas wild-type mice were completely unaffected. Retained crystals in tissue sections were positively identified as CaOx monohydrate by both polarized optical microscopy and x-ray powder diffraction analysis. Furthermore, hyperoxaluria in the OPN wild-type mice was associated with a significant 2- to 4-fold upregulation of renal OPN expression by immunocytochemistry, lending further support to a renoprotective role for OPN. These data indicate that OPN plays a critical renoprotective role in vivo as an inhibitor of CaOx crystal formation and retention in renal tubules. E-mail: [email protected]
Changes in Medical Errors after Implementation of a Handoff Program
Authors: Amy J. Starmer, Nancy D. Spector, Rajendu Srivastava, Daniel C. West, Glenn Rosenbluth, April D. Allen, Elizabeth L. Noble, Lisa L. Tse, Anuj K. Dalal, Carol A. Keohane, Stuart R. Lipsitz, Jeffrey M. Rothschild, Matthew F. Wien, Catherine S. Yoon, Katherine R. Zigmont, Karen M. Wilson, Jennifer K. O’Toole, Lauren G. Solan, Megan Aylor, Zia Bismilla, Maitreya Coffey, Sanjay Mahant, Rebecca L. Blankenburg, Lauren A. Destino, Jennifer L. Everhart, Shilpa J. Patel, James F. Bale, Jaime B. Spackman, Adam T. Stevenson, Sharon Calaman, F. Sessions Cole, Dorene F. Balmer, Jennifer H. Hepps, Joseph O. Lopreiato, Clifton E. Yu, Theodore C. Sectish, Christopher P. Landrigan
Journal: New England Journal of Medicine (2014)

Miscommunications are a leading cause of serious medical errors. Data from multicenter studies assessing programs designed to improve handoff of information about patient care are lacking.We conducted a prospective intervention study of a resident handoff-improvement program in nine hospitals, measuring rates of medical errors, preventable adverse events, and miscommunications, as well as resident workflow. The intervention included a mnemonic to standardize oral and written handoffs, handoff and communication training, a faculty development and observation program, and a sustainability campaign. Error rates were measured through active surveillance. Handoffs were assessed by means of evaluation of printed handoff documents and audio recordings. Workflow was assessed through time-motion observations. The primary outcome had two components: medical errors and preventable adverse events.In 10,740 patient admissions, the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P<0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P<0.001). The rate of nonpreventable adverse events did not change significantly (3.0 and 2.8 events per 100 admissions, P=0.79). Site-level analyses showed significant error reductions at six of nine sites. Across sites, significant increases were observed in the inclusion of all prespecified key elements in written documents and oral communication during handoff (nine written and five oral elements; P<0.001 for all 14 comparisons). There were no significant changes from the preintervention period to the postintervention period in the duration of oral handoffs (2.4 and 2.5 minutes per patient, respectively; P=0.55) or in resident workflow, including patient-family contact and computer time.Implementation of the handoff program was associated with reductions in medical errors and in preventable adverse events and with improvements in communication, without a negative effect on workflow. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and others.).
Cell Cycle Regulator ING4 Is a Suppressor of Melanoma Angiogenesis That Is Regulated by the Metastasis Suppressor BRMS1
Authors: Jun Li, Gang Li
Journal: Cancer Research (2010)

Abstract ING4 has been previously shown to play important roles in regulating apoptosis, cell cycle progress, cell migration, and invasion. In this study, we investigated the impact of ING4 on melanoma angiogenesis. ING4 overexpression strongly suppressed the growth of human umbilical vein endothelial cells (HUVEC) and their ability to form tubular structure in vitro. We also found that ING4 inhibits interleukin-6 (IL-6) at both mRNA and protein levels through suppressing NF-κB activity. Knockdown of endogenous ING4 resulted in enhanced HUVEC growth and IL-6 expression. Our in vivo studies using nude mice confirmed that ING4 inhibited blood vessel formation and the recruitment of CD31-positive cells in matrigel plugs. Furthermore, we found that expression of ING4 was induced by BRMS1, a metastasis suppressor that inhibits melanoma angiogenesis through inhibiting NF-κB activity and IL-6 level as well. Further experiments showed that ING4 knockdown abrogated the suppressive effect of BRMS1 on HUVEC growth, whereas ING4 overexpression inhibited BRMS1 knockdown-induced angiogenesis, indicating that ING4 is a downstream target of BRMS1 in regulating tumor angiogenesis. Collectively, our findings indicate that ING4 is induced by BRMS1 and that it inhibits melanoma angiogenesis by suppressing NF-κB activity and IL-6 expression. Restoration of ING4 function offers a potential new strategy for the treatment of human melanoma. Cancer Res; 70(24); 10445–53. ©2010 AACR.
Religious and Spiritual Issues in Psychiatric Diagnosis: A Research Agenda for DSM-Vedited by PeteetJohn R., M.D., LuFrancis G., M.D., and NarrowWilliam E., M.D., M.P.H. Washington, DC, American Psychiatric Publishing, 2011, 297 pp., $67.00.
Authors: Frederick J. Stoddard
Journal: American Journal of Psychiatry (2012)
Interferon-β Reduces Proteinuria in Experimental Glomerulonephritis
Authors: Simon C. Satchell, Olena Buchatska, Sarah B. Khan, Gurjeet Bhangal, Candida H. Tasman, Moin A. Saleem, Darren P. Baker, Roy R. Lobb, Jennifer Smith, H. Terence Cook, Peter W. Mathieson, Charles D. Pusey
Journal: Journal of the American Society of Nephrology (2007)

Interferon-beta (IFN-beta) is a multifunctional cytokine with immunomodulatory properties. We examined the effect of IFN-beta in three separate rat models of glomerular injury and in cultured human glomerular endothelial cells and podocytes. In nephrotoxic nephritis in WKY rats, recombinant rat IFN-beta started either at induction or after establishment of disease significantly reduced 24-h proteinuria by up to 73% and 51%, respectively, but did not affect serum creatinine. There was a slight reduction in numbers of glomerular macrophages, but no difference in glomerular or tubulointerstitial scarring. In Thy-1 nephritis in Lewis rats, IFN-beta started at induction of disease reduced proteinuria by up to 66% with no effect on numbers of glomerular macrophages, but a reduced number of proliferating cells. In puromycin nephropathy in Wistar rats, IFN-beta started at induction of disease reduced proteinuria by up to 93%, but had no effect on glomerular histology. In cultured cells, human IFN-beta-1a had a dramatic effect on barrier properties, increasing electrical resistance across monolayers of either glomerular endothelial cells or podocytes and decreasing trans-monolayer passage of albumin. In conclusion, these results show that IFN-beta reduces proteinuria in three different rat models of glomerular injury and that its anti-proteinuric action may result from direct effects on cells that comprise the glomerular filtration barrier. These data indicate that IFN-beta may have potential as a therapeutic agent in proteinuric renal disease.
Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial
Authors: N. Dalbeth, S. Wong, G. D. Gamble, A. Horne, B. Mason, B. Pool, L. Fairbanks, F. M. McQueen, J. Cornish, I. R. Reid, K. Palmano
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> Recent observational studies have highlighted the beneficial role of dairy ingestion in gout prevention. The aims of this study were to determine the acute effects of milk ingestion on serum urate concentrations and examine the mechanisms of these effects. <h3>Methods</h3> This was a short-term randomised controlled crossover trial of milk in 16 healthy male volunteers. The following products were tested (each 80 g protein): soy control, early season skim milk, late season skim milk (containing high concentrations of orotic acid, a naturally occurring uricosuric agent) and ultrafiltrated MPC 85 skim milk. Each participant received a single dose of each product in random order. Serum and urine were obtained immediately before and then hourly over a 3 h period after ingestion of each study product. <h3>Results</h3> Ingestion of the soy control led to an increase in serum urate concentrations by approximately 10%. In contrast, ingestion of all milks led to a decrease in serum urate concentrations by approximately 10% (p&lt;0.0001). All products (including soy) rapidly increased the fractional excretion of uric acid (FEUA). Late season milk led to a greater increase in FEUA than MPC 85 (p=0.02) and early season milk (p=0.052). There were no differences over time in serum oxypurines or purine-containing nucleosides. However, all products increased the fractional excretion of xanthine. <h3>Conclusions</h3> Intact milk has an acute urate-lowering effect. These data provide further rationale for long-term intervention studies to determine whether such dietary interventions have an adjunctive role in the management of individuals with hyperuricaemia and gout.
Anti-myeloperoxidase antibodies in patients with rheumatoid arthritis: prevalence, clinical correlates, and IgG subclass.
Authors: G Cambridge, M Williams, B Leaker, M Corbett, C.R. Smith
Journal: Annals of the Rheumatic Diseases (1994)

To determine the prevalence and clinical associations of autoantibodies to myeloperoxidase (MPO) in an unselected series of well-characterised outpatients with rheumatoid arthritis (RA) and to compare the distribution of IgG subclasses of anti-MPO antibodies in these patients with that in patients with systemic vasculitis. A study was made of 97 patients with RA, who have been seen regularly in this department for up to 20 years, and 29 patients with anti-neutrophil cytoplasmic antibody (ANCA) positive systemic vasculitis. Anti-MPO antibodies were detected using a direct-binding enzyme-linked immunosorbent assay (ELISA) with MPO from human granulocytes as antigen. The IgG subclass of anti-MPO antibodies was determined by ELISA using isotype specific monoclonal antibodies. Anti-MPO antibodies were detected in 12% of patients with RA. Six sera contained IgG anti-MPO antibodies only, 1 IgM only and 5 antibodies of both classes. In the patients with RA the predominant subclasses were IgG1 and IgG3: only 2 sera contained detectable IgG4 antibodies. This was in contrast to patients with vasculitis, in whom most sera contained IgG1, IgG3 and IgG4 anti-MPO antibodies. Anti-MPO antibodies in sera from both patient groups bound only to the native protein. None of the patients studied with RA had evidence of vasculitis affecting the nerves or kidney: three patients (1 positive for anti-MPO antibodies and 2 negative) had cutaneous vasculitis. In the patients with RA, positivity for anti-MPO antibodies was associated with nodules and number of active joints. Three patients with anti-MPO antibodies, and none without, had pulmonary fibrosis. Twelve per cent of a group of unselected outpatients with RA, but without evidence of major systemic vasculitis, had anti-MPO antibodies in their serum. Positivity for anti-MPO antibodies was more common in patients with nodular disease and lung involvement but not in patients with cutaneous vasculitis. IgG4 sub-class anti-MPO antibodies were present in 90% of sera from patients with ANCA-positive vasculitis and only 2/11 (18%) of anti-MPO antibody containing sera from patients with RA.
Cellular models of hibernating myocardium: implications for future research
Authors: G Hughes
Journal: Cardiovascular Research (2001)

See article by Dispersyn et al. [1] (pages 230–240) in this issue. 

In the current issue of Cardiovascular Research , Dispersyn and colleagues [1] describe a novel in vitro model of cardiomyocyte de-differentiation similar to that seen in hibernating myocardium. By co-culturing adult rabbit cardiomyocytes with cardiac fibroblasts, ultrastructural changes including sarcomere depletion and disalignment, appearance of aberrantly shaped mini-mitochondria, and progressive dispersion of nuclear heterochromatin were seen within the cardiomyocytes beginning several days after their establishment of cell–cell apposition with fibroblasts. These ultrastructural findings are nearly identical to those seen in both large animals [2] and humans [3] with hibernating myocardium with the one exception being that the cultured cells did not demonstrate a significant increase in glycogen content within the regions of sarcomere loss, a change typically considered among the hallmarks of hibernating myocardium [4]. In addition to the ultrastructural alterations, Dispersyn and colleagues also demonstrated changes in the pattern of expression of the structural proteins titin, desmin, cardiotin, α-actinin, and α-smooth muscle actin characteristic of de-differentiation and similar to that described previously in myocardial tissue from patients with chronic hibernating myocardium [4]. As outlined below, this and other in vitro cellular models may prove helpful in identifying those mechanisms involved in the development and progression of the hibernating phenotype as well as therapeutic strategies aimed at halting the progression and speeding reversal following revascularization.

Consensus exists that myocardial hibernation describes chronic, reversible left ventricular dysfunction at rest due to coronary artery disease [4,5]. However, intense controversy surrounds the underlying pathophysiology of the condition, as has been well-publicized in several recent reviews [6–8]. As originally described [9], hibernating myocardium was felt to result from a chronic reduction in myocardial blood flow at rest to the dysfunctional yet viable regions with the affected segments … 

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Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the λ Light Chain Locus in Precursor B Cells in the Mouse
Authors: Gemma M. Dingjan, Sabine Middendorp, Katarina Dahlenborg, Alex Maas, Frank Grosveld, Rudolf W. Hendriks
Journal: The Journal of Experimental Medicine (2001)

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase involved in precursor B (pre-B) cell receptor signaling. Here we demonstrate that Btk-deficient mice have an ∼50% reduction in the frequency of immunoglobulin (Ig) λ light chain expression, already at the immature B cell stage in the bone marrow. Conversely, transgenic mice expressing the activated mutant BtkE41K showed increased λ usage. As the κ/λ ratio is dependent on (a) the level and kinetics of κ and λ locus activation, (b) the life span of pre-B cells, and (c) the extent of receptor editing, we analyzed the role of Btk in these processes. Enforced expression of the Bcl-2 apoptosis inhibitor did not alter the Btk dependence of λ usage. Crossing 3-83μδ autoantibody transgenic mice into Btk-deficient mice showed that Btk is not essential for receptor editing. Also, Btk-deficient surface Ig+ B cells that were generated in vitro in interleukin 7-driven bone marrow cultures manifested reduced λ usage. An intrinsic defect in λ locus recombination was further supported by the finding in Btk-deficient mice of reduced λ usage in the fraction of pre-B cells that express light chains in their cytoplasm. These results implicate Btk in the regulation of the activation of the λ locus for V(D)J recombination in pre-B cells.
Unique receptor dissociation kinetics of the novel endothelin receptor antagonist macitentan
Authors: John Gatfield, Celia Mueller Grandjean, Thomas Sasse, Beat Steiner, Pauline Steiner, Marc Iglarz, Katalin Kauser, Martine Clozel, Oliver Nayler
Journal: European Respiratory Journal (2012)

Association and dissociation rates of G protein-coupled receptor antagonists can influence their in vivo pharmacological activity, such as duration of action, activity in situations of increased agonist concentrations and ultimately clinical efficacy.

Using signaling assays in human pulmonary arterial smooth muscle cells (PASMC), we investigated the endothelin (ET) receptor inhibition kinetics of macitentan, a novel ET receptor antagonist currently in phase 3 clinical trials in pulmonary arterial hypertension, and compared them with the kinetics of bosentan and ambrisentan.

Calcium flux assays showed that macitentan, but not ambrisentan or bosentan, increased in potency (10-fold) upon prolongation of antagonist pre-incubation time from 10 min to 120 min, indicating slow apparent association of macitentan with ET receptors. Macitentan furthermore displayed a slow receptor dissociation rate, as inhibition of ET-1-induced calcium flux persisted for more than 60 min after macitentan wash-out. Conversely, bosentan and ambrisentan did not maintain receptor blockade after washout and displayed a ∼15-fold shorter receptor occupancy half life than macitentan. The slow dissociation kinetics rendered macitentan an efficient antagonist of ET-1-induced IP3 synthesis and ET-1-induced sustained calcium flux across the whole range of ET-1 concentrations tested. In contrast, bosentan and ambrisentan did not display antagonism against high ET-1 concentrations in these assays.

In pulmonary arterial smooth muscle cells, macitentan is a slow-offset competitive antagonist and, unlike ambrisentan and bosentan, capable of efficient receptor blockade in functional assays irrespective of the ET-1 concentration.
Linkage and mutational analysis of the CDAN1 gene reveals genetic heterogeneity in congenital dyserythropoietic anemia type I
Authors: Momin R. Ahmed, Aref Chehal, Laila Zahed, Ali Taher, Joud Haidar, Ali Shamseddine, Anne-Marie O'Hea, Nicola Bienz, Orly Dgany, Nili Avidan, Jacqui S. Beckmann, Hannah Tamary, Douglas Higgs, Paresh Vyas, William G. Wood, Sunitha N. Wickramasinghe
Journal: Blood (2006)