tbuckley/cabot-search huggingface dataset:
Response: Cricoarytenoid arthritis presenting as croup
Authors: Jonathan L Marks, Sandeep Mukherjee, Richard G Hull
Journal: Journal of the Royal Society of Medicine (2010)

Following your recent case report ‘Cricoarytenoid arthritis presenting as croup’1 we felt it important to highlight some important points that arise.

First, there is an issue of nomenclature. The report of quotidian fever, rash and polyarthritis is clearly a description of systemic onset juvenile idiopathic arthritis (JIA). While this condition has previously been termed juvenile rheumatoid arthritis (JRA) in North America and juvenile chronic arthritis (JCA), there has been a move away from these terms to JIA not least to emphasize that JIA is a condition quite pathophysiologically distinct from rheumatoid arthritis (RA). JIA encompasses the three sub-subsets of JCA previously used to classify patients on the basis of their clinical features and number of joints involved: systemic-onset; pauci-articular-onset; and polyarticular-onset.2,3 The change of classification is important to allow research into the causes, pathogenesis, epidemiology and outcomes of childhood arthritides. In this report we would suggest that it is more important to associate cricoarytenoid arthritis with other cases documented in association with childhood arthritis.

While recognizing that cricoarytenoid arthritis is a rare association with JIA, we feel that more common causes of croup may have been overlooked in the case described. First, it is well-documented that non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen can cause laryngeal oedema that may present respiratory distress.4 Second, patients with active autoimmune conditions such as JIA are essentially immunosuppressed, and given that croup is most commonly caused by infection this should have prompted a more thorough evaluation and earlier involvement of the ENT specialists during the first admission with respiratory distress.

We suspect that, in this case, earlier ENT involvement would have identified the cricoarytenoid arthritis thereby altering the management of her JIA and possibly preventing subsequent readmission in extremis.
Jane Skok: Choreography of allelic exclusion
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

Antibody diversity is generated during B cell development by the rearrangement of variable (V), diversity (D), and joining (J) segments of immunoglobulin (Ig) genes. Both alleles of each Ig locus can initiate rearrangement, but only one allele successfully rearranges. As soon as this occurs, the other allele is prevented from following suit. This mechanism, known as allelic exclusion, guarantees that each B cell produces antibodies specific for just one antigen. In her laboratory at New York University (NYU), Jane Skok studies how exclusion is established.




Figure 1





Jane Skok




Skok's initial foray into research involved dissecting the genetics of the complement cascade with Ellen Solomon at Cancer Research UK (1). But immediately after earning her Ph.D., Skok left science to care for her ill child. When she returned nearly a decade later, she had to start from scratch. After getting up to speed with a Master's in immunology, she joined Amanda Fisher's lab, where she gravitated toward B cells and the question of allelic exclusion.

Skok has since helped define some of the steps that make exclusion possible. She discovered that the excluded Ig allele gets sent to repressive DNA domains near the centromere, whereas the productive allele remains within accessible domains (2–4). She later focused on one of the more curious aspects of allelic exclusion. During rearrangement, the Ig locus contracts, allowing V, D, and J segments to get close to each other and join up. Skok found that the successful rearrangement of one allele triggers locus relaxation, thereby stopping rearrangement of the other allele (5). She is now hunting for the proteins and pathways that direct the contortion and movement of Ig loci.
Preventing Exercise-Related Cardiovascular Events
Authors: Barry A. Franklin
Journal: Circulation (2014)

3][4] To address these concerns, public health strategies commonly incorporate the goal of safely increasing physical activity levels in the populations of industrialized societies.Accordingly, the number of health/fitness facilities and members is expected to increase exponentially over the next decade.Current market research indicates that the fastest-growing user subsets are those aged 35 to 54 years and those ≥55 years of age.These data, coupled with the recent finding that regular exercise prevents cellular senescence, have led an increasing number of adults, many of whom have known or occult chronic disease, to the conclusion that "more exercise is better."Marathon running, for example, has increased in popularity over the past 3 decades, with participation increasing from 25 000 runners in 1976 to ≈2 million in 2010.Thus, we have a population paradox in which there is an expansion in the number of habitually sedentary individuals paralleling a concomitant increase in those taking part in unprecedented hours of vigorous exercise.
2009 ACCF/AHA Focused Update on Perioperative Beta Blockade Incorporated Into the ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery
Authors: Lee A. Fleisher, Joshua A. Beckman, Kenneth A. Brown, Hugh Calkins, Elliot L. Chaikof, Kirsten E. Fleischmann, William K. Freeman, James B. Froehlich, Edward K. Kasper, Judy R. Kersten, Barbara Riegel, John F. Robb
Journal: Journal of the American College of Cardiology (2009)
An Ethical Analysis of Mandatory Influenza Vaccination of Health Care Personnel: Implementing Fairly and Balancing Benefits and Burdens
Authors: Armand H. Matheny Antommaria
Journal: The American Journal of Bioethics (2013)

Health care institutions have paid increasing attention to preventing nosocomial transmission of influenza through vaccination of health care personnel. While multifaceted voluntary interventions have increased vaccination rates, proponents of mandatory programs contend the rates remain unacceptably low. Conventional bioethical analyses of mandatory programs are inadequate; they fail to account for the obligations of nonprofessional personnel or to justify the weights assigned to different ethical principles. Using an ethics framework for public health permits a fuller analysis. The framework's focus on fairness accentuates the potential differences between the risk of transmitting infection and employment status, and the need to equitably evaluate exemptions. The framework's emphasis on balancing benefits and burdens highlights the need to justify a specific goal and questions the need to exclude all nonmedical exemptions. While mandatory vaccination programs are justifiable, greater attention should be paid to their implementation.
Phase I Study of Adenoviral Delivery of the HSV-tk Gene and Ganciclovir Administration in Patients with Recurrent Malignant Brain Tumors
Authors: Todd W. Trask, Rebecca P. Trask, Estuardo Aguilar-Cordova, H.David Shine, Philip R. Wyde, J.Clay Goodman, Winifred J. Hamilton, Augusto Rojas-Martinez, Shu-Hsia Chen, Savio L.C. Woo, Robert G. Grossman
Journal: Molecular Therapy (2000)

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 × 109, 2 × 1010, 2 × 1011, or 2 × 1012 vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses ≤2 × 1011 VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 × 1012 VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.
REIC/Dkk-3 induces cell death in human malignant glioma
Authors: Yoshifumi Mizobuchi, Kazuhito Matsuzaki, Kazuyuki Kuwayama, Keiko Kitazato, Hideo Mure, Teruyoshi Kageji, Shinji Nagahiro
Journal: Neuro-Oncology (2008)

The progression of glioma to more malignant phenotypes results from the stepwise accumulation of genetic alterations and the consequent disruption of the apoptotic pathway and augmentation of survival signaling. REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of the growth of several human cancers; however, to date it has not been identified in brain tumors. We compared the gene and protein expression of REIC/Dkk-3 in human malignant glioma and normal brain tissues using quantitative real-time PCR, Western blotting, and immunohistochemistry. We also performed small interfering REIC/Dkk-3 (siREIC/Dkk-3) knockdown and REIC/Dkk-3 overexpression experiments to examine the role of REIC/Dkk-3 in human malignant glioma cells in vitro. In brain tissue from patients with malignant glioma, the gene and protein expression of REIC/Dkk-3 was lower than in normal brain tissue and was related to the malignancy grade. In the primary glioblastoma cell line, REIC/Dkk-3 transfection led to apoptosis owing to the activation of phosphorylated JUN, caspase-9, and caspase-3 and the reduction of beta-catenin; in REIC/Dkk-3 knockdown experiments, cell growth was augmented. Our results suggest that REIC/Dkk-3 regulates the growth and survival of these cells in a caspase-dependent and -independent way via modification of the Wnt signaling pathway. Our work is the first documentation that the gene and protein expression of REIC/Dkk-3 is down-regulated in human malignant glioma. Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy.
Pathways of Antigen Processing
Authors: Janice S. Blum, Pamela A. Wearsch, Peter Cresswell
Journal: Annual Review of Immunology (2013)

T cell recognition of antigen-presenting cells depends on their expression of a spectrum of peptides bound to major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Conversion of antigens from pathogens or transformed cells into MHC-I- and MHC-II-bound peptides is critical for mounting protective T cell responses, and similar processing of self proteins is necessary to establish and maintain tolerance. Cells use a variety of mechanisms to acquire protein antigens, from translation in the cytosol to variations on the theme of endocytosis, and to degrade them once acquired. In this review, we highlight the aspects of MHC-I and MHC-II biosynthesis and assembly that have evolved to intersect these pathways and sample the peptides that are produced.
Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study
Authors: Marina Cuchel, Emma A Meagher, Hendrik du Toit Theron, Dirk J Blom, A David Marais, Robert A Hegele, Maurizio R Averna, Cesare R Sirtori, Prediman K Shah, Daniel Gaudet, Claudia Stefanutti, Giovanni B Vigna, Anna ME Du Plessis, Kathleen J Propert, William J Sasiela, LeAnne T Bloedon, Daniel J Rader
Journal: The Lancet (2012)
Iron deficiency anaemia and perianastomotic ulceration as a late complication of ileal resection in infancy
Authors: P Abdullannan, J W L Puntis
Journal: Gut (2007)

I was interested to read the “editor’s quiz: GI snapshot” of iron deficiency anaemia in an adult who had been operated on for ileal atresia as a newborn infant ( Gut 2007; 56 :43). While the heading for this item was “iron deficiency anaemia …
Disseminated histoplasmosis in diabetes.
Authors: B R Tulloch, A Jariwalla
Journal: BMJ (1977)

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094), a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess 1) antiproliferative and 2) anti-inflammatory actions and 3) the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these three biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro, and GT-094 was seen to induce phase 2 enzymes via the antioxidant responsive element. In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal, and combinations of nitrates with acetylsalicylic acid were inactive.
Genetic, Clinical, and Radiographic Delineation of Hallervorden–Spatz Syndrome
Authors: Susan J. Hayflick, Shawn K. Westaway, Barbara Levinson, Bing Zhou, Monique A. Johnson, Katherine H.L. Ching, Jane Gitschier
Journal: New England Journal of Medicine (2003)

Hallervorden-Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase-associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden-Spatz syndrome with and without mutations in PANK2.One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations.All patients with classic Hallervorden-Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations.PANK2 mutations are associated with all cases of classic Hallervorden-Spatz syndrome and one third of cases of atypical disease. A specific MRI pattern distinguishes patients with PANK2 mutations. Predicted levels of pantothenate kinase 2 protein correlate with the severity of disease.
Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins
Authors: Lianchun Wang, Jillian R. Brown, Ajit Varki, Jeffrey D. Esko
Journal: Journal of Clinical Investigation (2002)

Heparin has been used clinically as an anticoagulant and antithrombotic agent for over 60 years. Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin. Unfractionated heparin and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl LewisX and of cell adhesion to immobilized selectins or thrombin-activated endothelial cells. Compared with unfractionated heparin, the modified heparinoids had inhibitory activity in this general order: over–O-sulfated heparin > heparin > 2-O,3-O-desulfated ≥ N-desulfated/N-acetylated heparin ≥ carboxyl-reduced heparin ≥ N-,2-O,3-O-desulfated heparin >> 6-O-desulfated heparin. The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity. Mice deficient in P- or L-selectins showed impaired inflammation, which could be further reduced by heparin. However, heparin had no additional effect in mice deficient in both P- and L-selectins. We conclude that (a) heparin's anti-inflammatory effects are mainly mediated by blocking P- and L-selectin–initiated cell adhesion; (b) the sulfate groups at C6 on the glucosamine residues play a critical role in selectin inhibition; and (c) some non-anticoagulant forms of heparin retain anti-inflammatory activity. Such analogs may prove useful as therapeutically effective inhibitors of inflammation.
MPs challenge Serco over its trustworthiness to run public services
Authors: A. O'Dowd
Journal: BMJ (2013)

MPs have challenged the company at the centre of a GP out of hours service scandal over its trustworthiness to continue to provide the public service.

A new report into what happened in Cornwall where private company Serco provides out of hours GP services for NHS Kernow Clinical Commissioning Group was discussed by MPs on the parliamentary public accounts committee at an evidence session on 20 November.

Representatives from four private companies, which provide services to the public sector, appeared before the committee as part of its inquiry into the delivery of public services by private contractors.

In July the committee published a critical report into the service Serco provides in Cornwall in which …
A Decade of Rituximab: Improving Survival Outcomes in Non-Hodgkin's Lymphoma
Authors: Arturo Molina
Journal: Annual Review of Medicine (2008)

The anti-CD20 monoclonal antibody rituximab, first approved for clinical use in 1997, has changed the standard of care for many patients with non-Hodgkin's lymphoma (NHL). Recent data from large randomized clinical trials confirm that the addition of rituximab to standard chemotherapy regimens (chemoimmunotherapy) improves both response rates and survival outcomes in patients with follicular NHL and diffuse large B cell lymphoma (DLBCL), the two most common subtypes of NHL. Population-based analyses have found substantial improvements in NHL survival over the past decade; studies indicate that rituximab has favorably altered the long-term prognosis of follicular NHL and DLBCL patients. This review discusses the clinical development of rituximab-based therapies for patients with low-grade or follicular NHL and newly diagnosed DLBCL, highlighting recent key randomized trials with a focus on survival outcomes.
Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant
Authors: Odile Oberlin, Annie Rey, Anne Sophie Desfachelles, Thierry Philip, Dominique Plantaz, Claudine Schmitt, Emmanuel Plouvier, Odile Lejars, Hervé Rubie, Philippe Terrier, Jean Michon
Journal: Journal of Clinical Oncology (2006)

To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan.Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT.Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement.Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.
Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome
Authors: Yoichi Takeuchi, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Chitose Suzuki, Takehiro Suzuki, Takayasu Kobayashi, Yoichi Suzuki, Tomohiro Nakayama, Yasuhiro Takeshima, Norma Vazquez, Sadayoshi Ito, Gerardo Gamba, Takaaki Abe
Journal: Journal of the American Society of Nephrology (2014)

A variety of genetic backgrounds cause the loss of function of thiazide-sensitive sodium chloride cotransporter, encoded by SLC12A3, responsible for the phenotypes in Gitelman syndrome. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. Specifically, mutations in exonic splicing enhancer (ESE) sequences can promote exon skipping. Here, we used a bioinformatics program to analyze 88 missense mutations in the SLC12A3 gene and identify candidate mutations that may induce exon skipping. The three candidate mutations that reduced ESE scores the most were further investigated by minigene assay, and two (p.A356V and p.M672I) caused abnormal splicing in vitro. Furthermore, we identified the p.M672I (c.2016G>A) mutation in a patient with Gitelman syndrome and found that this single nucleotide mutation causes exclusion of exon 16 in the SLC12A3 mRNA transcript. Functional analyses revealed that the protein encoded by the aberrant SLC12A3 transcript does not transport sodium. These results suggest that aberrant exon skipping is one previously unrecognized mechanism by which missense mutations in SLC12A3 can lead to Gitelman syndrome.
Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca++-dependent complex of C-reactive protein with very-low–density lipoprotein and is a novel marker of impending disseminated intravascular coagulation
Authors: Cheng Hock Toh, John Samis, Colin Downey, John Walker, Lev Becker, Nicole Brufatto, Liliana Tejidor, Greg Jones, Wim Houdijk, Alan Giles, Marlys Koschinsky, Larry O. Ticknor, Ray Paton, Richard Wenstone, Michael Nesheim
Journal: Blood (2002)