tbuckley/cabot-search huggingface dataset:
Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy
Authors: Michaela Yuen, Sarah A. Sandaradura, James J. Dowling, Alla S. Kostyukova, Natalia Moroz, Kate G. Quinlan, Vilma-Lotta Lehtokari, Gianina Ravenscroft, Emily J. Todd, Ozge Ceyhan-Birsoy, David S. Gokhin, Jérome Maluenda, Monkol Lek, Flora Nolent, Christopher T. Pappas, Stefanie M. Novak, Adele D’Amico, Edoardo Malfatti, Brett P. Thomas, Stacey B. Gabriel, Namrata Gupta, Mark J. Daly, Biljana Ilkovski, Peter J. Houweling, Ann E. Davidson, Lindsay C. Swanson, Catherine A. Brownstein, Vandana A. Gupta, Livija Medne, Patrick Shannon, Nicole Martin, David P. Bick, Anders Flisberg, Eva Holmberg, Peter Van den Bergh, Pablo Lapunzina, Leigh B. Waddell, Darcée D. Sloboda, Enrico Bertini, David Chitayat, William R. Telfer, Annie Laquerrière, Carol C. Gregorio, Coen A.C. Ottenheijm, Carsten G. Bönnemann, Katarina Pelin, Alan H. Beggs, Yukiko K. Hayashi, Norma B. Romero, Nigel G. Laing, Ichizo Nishino, Carina Wallgren-Pettersson, Judith Melki, Velia M. Fowler, Daniel G. MacArthur, Kathryn N. North, Nigel F. Clarke
Journal: Journal of Clinical Investigation (2014)

Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
Pretreatment with Rituximab Does Not Inhibit the Human Immune Response against the Immunogenic Protein LMB-1
Authors: Raffit Hassan, Juanita Williams-Gould, Thelma Watson, Lee Pai-Scherf, Ira Pastan
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Rituximab, a humanized monoclonal antibody directed to the CD20 antigen present on B lymphocytes, could potentially abrogate the humoral immune response to murine monoclonal antibodies or immunotoxins by depleting antibody-producing B cells. Experimental Design: A Phase II study of LMB-1, an immunotoxin targeting the Lewis Y tumor antigen, in combination with rituximab was conducted to test the hypothesis that rituximab could abolish or diminish the development of human antibodies to LMB-1. Five patients were treated in this study and received 375 mg/m2 rituximab on days 1 and 7 followed by 45 μg/kg/day LMB-1 on days 10, 12, and 14. The development of human antibodies against LMB-1 was detected using a serum neutralization and ELISA. Results: All five of the patients had a total suppression of circulating CD20/CD19 B-cell population before the administration of the first dose of the immunotoxin. Before rituximab treatment, the mean percentage of CD20/CD19-positive B cells in the five treated patients was 19.8% (range, 4.5–29.8%) of the total peripheral lymphocytes. After two doses of rituximab, CD20/CD19-positive B lymphocytes constituted ≤0.1% of the total peripheral lymphocytes. Despite absent circulating antibody-producing B cells, before and during LMB-1 treatment, all of the patients developed neutralizing antibodies to the immunotoxin by day 21 of drug administration, which prevented retreatment. Conclusions: Even though rituximab caused complete depletion of circulating CD20/CD19-positive B cells, it had no effect in suppressing the human antibody response to LMB-1 and may be of limited utility in suppressing human antibody responses to other immunogenic proteins.
Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
Authors: Cindy S. Ma, Nathan J. Hare, Kim E. Nichols, Loic Dupré, Grazia Andolfi, Maria-Grazia Roncarolo, Stephen Adelstein, Philip D. Hodgkin, Stuart G. Tangye
Journal: Journal of Clinical Investigation (2005)

X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule-associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4(+) T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4(+) T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4(+) T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.
Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Authors: Frank I. Marcus, William J. McKenna, Duane Sherrill, Cristina Basso, Barbara Bauce, David A. Bluemke, Hugh Calkins, Domenico Corrado, Moniek G.P.J. Cox, James P. Daubert, Guy Fontaine, Kathleen Gear, Richard Hauer, Andrea Nava, Michael H. Picard, Nikos Protonotarios, Jeffrey E. Saffitz, Danita M. Yoerger Sanborn, Jonathan S. Steinberg, Harikrishna Tandri, Gaetano Thiene, Jeffrey A. Towbin, Adalena Tsatsopoulou, Thomas Wichter, Wojciech Zareba
Journal: Circulation (2010)

Background— In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims—the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. Methods and Results— Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. Conclusions— The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00024505.
A screening clinic for relatives of patients with colorectal cancer in a district general hospital.
Authors: S Carpenter, M Broughton, C G Marks
Journal: Gut (1995)

A family cancer screening clinic was set up to screen and counsel subjects at above average risk of developing colorectal cancer. Criteria for referral were one first degree relative under 50 years or two of any age with colorectal cancer. Pedigree information was used to estimate lifetime risks of developing colorectal cancer and offer appropriate screening: colonoscopy for high risks (greater than 1 in 10), faecal occult blood testing for lower risks. One hundred and eleven subjects from 76 families were seen over four years. Forty two families gave a pedigree consistent with dominantly inherited non-polyposis colorectal cancer syndrome (HNPCC). Three subjects from one family were found to have familial adenomatous polyposis. Ninety two colonoscopies yielded 21 patients with polyps (12 had tubular adenomas, including one with early malignant invasion). Thirty three per cent (four of 12) of the tubular adenomas were beyond the reach of a flexible sigmoidoscope. Three hundred and forty two further high risk relatives were identified from the family history.
C5 deficiency and C5a or C5aR blockade protects against cerebral malaria
Authors: Samir N. Patel, Joanne Berghout, Fiona E. Lovegrove, Kodjo Ayi, Andrea Conroy, Lena Serghides, Gundula Min-oo, D. Channe Gowda, J. Vidya Sarma, Daniel Rittirsch, Peter A. Ward, W. Conrad Liles, Philippe Gros, Kevin C. Kain
Journal: The Journal of Experimental Medicine (2008)

Experimental infection of mice with Plasmodium berghei ANKA (PbA) provides a powerful model to define genetic determinants that regulate the development of cerebral malaria (CM). Based on the hypothesis that excessive activation of the complement system may confer susceptibility to CM, we investigated the role of C5/C5a in the development of CM. We show a spectrum of susceptibility to PbA in a panel of inbred mice; all CM-susceptible mice examined were found to be C5 sufficient, whereas all C5-deficient strains were resistant to CM. Transfer of the C5-defective allele from an A/J (CM resistant) onto a C57BL/6 (CM-susceptible) genetic background in a congenic strain conferred increased resistance to CM; conversely, transfer of the C5-sufficient allele from the C57BL/6 onto the A/J background recapitulated the CM-susceptible phenotype. The role of C5 was further explored in B10.D2 mice, which are identical for all loci other than C5. C5-deficient B10.D2 mice were protected from CM, whereas C5-sufficient B10.D2 mice were susceptible. Antibody blockade of C5a or C5a receptor (C5aR) rescued susceptible mice from CM. In vitro studies showed that C5a-potentiated cytokine secretion induced by the malaria product P. falciparum glycosylphosphatidylinositol and C5aR blockade abrogated these amplified responses. These data provide evidence implicating C5/C5a in the pathogenesis of CM.
Ripley’s Believe It or Not
Authors: Leonard J. Hoenig, Walter H. C. Burgdorf
Journal: JAMA Dermatology (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Elevated plasma protein C levels correlate with the presence of fatty liver (NASH and NAFLD)
Authors: N Assy
Journal: Gut (2005)

The clinical implications of non-alcoholic fatty liver disease (NAFLD) are derived mostly from its common occurrence in the general population and the potential of the condition to progress to fibrosis and cirrhosis.1 Markers that help in making an early diagnosis and treatment are warranted. Protein C is a vitamin K dependent glycoprotein that functions as a circulating anticoagulant through proteolytic cleavage and inactivation of the coagulation factors Va and VIIIa.2 Whether or not protein C levels increase in patients with NAFLDs has not been assessed.

We measured protein C …
THE PREVALENCE OF INJURY PREVENTION PROGRAM USE BY HIGH SCHOOL TEAMS
Authors: M Norcross, S Johnson, M Hoffman
Journal: British Journal of Sports Medicine (2014)

Background The use of injury prevention programs (IPPs) during organized warm-up activities is encouraged to reduce lower extremity injury risk. However, the prevalence of structured IPP use by high school teams in Oregon is unknown. Objective 1) Describe the warm-up practices of Oregon high school teams; and 2) evaluate if these behaviors are influenced by team access to a medical professional (Athletic Trainer-AT) at the school. Design Cross-sectional survey. Setting High school. Participants Athletic directors from all 287 Oregon School Activity Association schools were asked to forward survey invitations to their head girls' and boys' basketball, soccer, and volleyball coaches. Coaches reported information about 276 teams. Interventions Independent variable was team access to an AT. Main outcome measurements Team use of: 1) any organized warm-up at least three times per week; 2) a scientifically proven IPP; and 3) activities from the five categories common to efficacious IPPs. Results Student-athletes on 248/276 (89.9%) teams performed an organized warm-up, but only 27/248 (10.9%) teams used a structured IPP; and just 6/248 (2.4%) used a proven IPP as designed. Teams reported using 3.7±1.2 of the five categories common to IPPs (Flexibility=96%, Balance=48%, Strengthening=79%, Plyometrics=62%, Agility=88%). Access to an AT (AT:129 teams, No AT:147 teams) did not influence organized warm-up use ( X 2 =0.189, P=.664), the types of activities performed ( X 2 =0.014–0.842, P=.359-.907), or the distribution of the total number of IPP categories performed (Mann-Whitney U =0.354, P=.723). Conclusions The use of IPPs in Oregon high schools is extremely rare. However, irrespective of access to an AT, most teams perform an organized warm-up using activities from several categories common to IPPs. Modification of current IPPs and/or the method for IPP delivery to address factors currently limiting program adoption is likely necessary to improve implementation effectiveness.
Spider Angiomas Appearing during Treatment with Trihexyphenidyl
Authors: C. Lawrence Holt
Journal: New England Journal of Medicine (1953)

TRIHEXYPHENIDYL ([1-piperidyl]-1-phenyl-1-cyclohexyl-1-propanol hydrochloride)† is a relatively effective compound for treating the tremors and muscle rigidity of Parkinson's disease whether due to previous encephalitis or cerebral arteriosclerosis.1 2 3 4 Untoward reactions include dry mouth, nausea, dizziness, blurring of vision, nervousness, tinnitus, generalized pruritus, vomiting, mental confusion, memory impairment and excitement.2 , 5 , 6 Pharmacologic studies on laboratory animals reveal that prolonged administration creates no significant alterations in blood sugar levels, phenolsulfonephthalein excretion tests for kidney function and bromsulfalein tests for liver function.7 Hepatic and renal disorders are reported as not representing contraindications to the use of the drug.4 Personal observations of a group of patients treated . . .
Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN
Authors: Cory L. Ahonen, Christie L. Doxsee, Sean M. McGurran, Tony R. Riter, William F. Wade, Richard J. Barth, John P. Vasilakos, Randolph J. Noelle, Ross M. Kedl
Journal: The Journal of Experimental Medicine (2004)

Toll-like receptors are important in the activation of innate immunity, and CD40 is a molecule critical for many T and B cell responses. Whereas agonists for either pathway have been used as vaccine adjuvants, we show that a combination of Toll-like receptor (TLR)7 and CD40 agonists synergize to stimulate CD8+ T cell responses 10–20-fold greater than the use of either agonist alone. Antigen-specific CD8+ T cells elicited from combination CD40/TLR7 treatment demonstrated both lytic activities and interferon (IFN)γ production and an enhanced secondary response to antigenic challenge. Agonists for TLRs 2/6, 3, 4, and 9 also synergized with CD40 stimulation, demonstrating that synergy with the CD40 pathway is a property of TLR-derived stimuli in general. The CD8+ T cell expansion induced by CD40/TLR7 triggering was independent of CD4+ T cells, IFNγ, and IL-12 but dependent on B7-mediated costimulation and surprisingly on type I IFN. These studies provide the rational basis for the use of TLR and CD40 agonists together as essential adjuvants to optimize vaccines designed to elicit protective or therapeutic immunity.
Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1β in the synovium
Authors: Jean-Pierre Pelletier, Mohit Kapoor, Hassan Fahmi, Daniel Lajeunesse, Alexia Blesius, Juliette Maillet, Johanne Martel-Pelletier
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To explore the disease-modifying effect, under therapeutic conditions, of strontium ranelate (SrRan) on the progression of joint structural changes and on the major pathophysiological pathways in an experimental osteoarthritis dog model. <h3>Methods</h3> Dogs underwent sectioning of the anterior cruciate ligament, and 4 weeks after surgery received oral treatment of SrRan 25, 50 or 75 mg/kg per day, or placebo for 12 weeks. Methods included macroscopy, picrosirius red staining, histology, subchondral bone histomorphometry, quantitative PCR, and ELISA for CTX-II level in serum. Strontium plasma and synovial fluid levels were also measured. <h3>Results</h3> At steady state, strontium blood exposures were within the clinical therapeutic range of osteoarthritis patients and correlated with strontium concentrations in synovial fluid. SrRan treatment significantly reduced the osteoarthritis cartilage lesions at all doses tested (p≤0.05). Significantly better preservation of the collagen network was also found in SrRan-treated dogs at 50 and 75 mg/kg per day (p=0.03). The osteoarthritis subchondral bone thickening observed in osteoarthritis-placebo dogs was significantly reduced by SrRan at 50 mg/kg per day (p=0.02). The increased gene expression levels of MMP-1, MMP-13 and cathepsin K in osteoarthritis cartilage were all significantly reduced by SrRan at 75 mg/kg per day (p≤0.03) as were, in osteoarthritis synovium, IL-1β at 50 and 75 mg/kg per day (p=0.05) and MMP-3 at all doses tested (p≤0.02). The serum level of CTX-II was reduced (p≤0.04) by SrRan at 16 weeks in dogs treated with 50 and 75 mg/kg per day. <h3>Conclusions</h3> This study is the first to demonstrate in vivo in an animal model that SrRan reduced the progression of osteoarthritis structural changes. The inhibition of several key proteases as well as IL-1β may have contributed to the beneficial effect of SrRan.
Multiple Hepatic Receptors Cooperate to Eliminate Secretory Mucins Aberrantly Entering the Bloodstream: Are Circulating Cancer Mucins the “Tip of the Iceberg”?
Authors: Mark G. Wahrenbrock, Ajit Varki
Journal: Cancer Research (2006)

Abstract Hollow organs lined by columnar epithelial cells normally secrete mucins and their proteolytic fragments vectorially into the lumen. These heterogeneously O-glycosylated molecules are known to aberrantly enter the bloodstream in the setting of epithelial carcinomas and possibly during injury or inflammation. We have recently shown that carcinoma mucin fragments can trigger the rapid formation of platelet-rich microthrombi in vivo. Thus, mechanisms to clear such aberrantly secreted mucins must exist. Indeed, we found that i.v. injected carcinoma mucin fragments had an ∼1 minute half-life in mice, which was primarily due to rapid clearance by hepatic reticuloendothelial cells. Inhibition of known glycan-recognizing hepatic clearance receptors showed involvement of multiple partially overlapping clearance systems. Studies of genetically deficient mice and incomplete competition between different mucins confirmed this result. Thus, multiple hepatic clearance receptors cooperate to eliminate secretory mucins entering the circulation, limiting potential pathology. This may also explain why mucin-type clustered O-glycosylation is rare on plasma proteins. Notably, small subsets of injected carcinoma mucins remained unrecognized by clearance systems, had a much longer half-life, and carried highly sialylated O-glycans. Similar circulating mucins were found in tumor-bearing mice despite lack of saturation of hepatic clearance mechanisms. Thus, circulating cancer mucins currently used as clinical diagnostic markers likely represent only the clearance-resistant “tip of the iceberg.” Such aberrantly circulating mucins could play pathologic roles not only in cancer but also during injury or inflammation of hollow organs and in liver disease. (Cancer Res 2006; 66(4): 2433-41)
Allergic contact dermatitis in children: should pattern of dermatitis determine referral? A retrospective study of 500 children tested between 1995 and 2004 in one U.K. centre
Authors: T.H. Clayton, S.M. Wilkinson, C. Rawcliffe, B. Pollock, S.M. Clark
Journal: British Journal of Dermatology (2005)

Allergic contact dermatitis (ACD) increases with age, and a prevalence of between 13.3% and 24.5% has been reported. Patch testing infants may be particularly difficult, and false-positive reactions may occur.The purpose of this retrospective study was to determine whether the site of primary dermatitis in children could predict a diagnosis of ACD. The current frequency of sensitization in children was also evaluated and the main sensitizing substances among children were verified.Between 1995 and 2004, 500 children were patch tested and entered on to the patch test database at Leeds General Infirmary. Analysis of the database included identifying the presenting patterns of eczema and reviewing the patch test results for each child.Of the children, 133 (27%) had one or more positive patch test result. The effect of age on the likelihood of a positive patch test was highly significant (P < 0.001). Girls were significantly more likely to have a positive patch test compared with boys: odds ratio for a positive test 0.62 (95% confidence interval 0.41-0.95; P = 0.029). Type IV allergy to nickel (33%) was the most frequent finding. Reactions to fragrance mix (18%), cobalt (11%), mercapto chemicals, Myroxylon pereirae and p-phenylenediamine (each 8%) were the next most common. No statistical significance was found in the relationship between the site of primary dermatosis and a positive patch test result.The pattern of presenting dermatitis in children should not determine referral for patch testing. Any child with persistent eczema should be referred for patch testing.