tbuckley/cabot-search huggingface dataset:
Unusual presentation of familial Mediterranean fever: role of genetic diagnosis
Authors: R. Nir-Paz
Journal: Annals of the Rheumatic Diseases (2000)

To describe the role of molecular analysis in the diagnosis of an unusual presentation of familial Mediterranean fever (FMF).Two patients presenting with prolonged fever without signs and symptoms of serositis are described. FMF was diagnosed by genetic analysis, which disclosed that both patients were homozygous for the M694V mutation of the Mediterranean fever (MEFV) gene.Molecular analysis of FMF should complement the investigation of patients with fever of unknown origin. This test enables a definite diagnosis of the disease and may promote the diagnosis and treatment of patients with an unusual or incomplete clinical picture of FMF.
CsRn1, a Novel Active Retrotransposon in a Parasitic Trematode, Clonorchis sinensis, Discloses a New Phylogenetic Clade of Ty3/gypsy-like LTR Retrotransposons
Authors: Y A Bae, S Y Moon, Y Kong, S Y Cho, M G Rhyu
Journal: Molecular Biology and Evolution (2001)

We screened the genome of a trematode, Clonorchis sinensis, in order to identify novel retrotransposons and thereby provide additional information on retrotransposons for comprehensive phylogenetic study. Considering the vast potential of retrotransposons to generate genetically variable regions among individual genomes, randomly amplified polymorphic DNAs (RAPDs) detected by arbitrarily primed polymerase chain reactions were selected as candidates for retrotransposon-related sequences. From RAPD analysis, we isolated and characterized a novel retrotransposon in C. sinensis as the first member of uncorrupted long-terminal-repeat (LTR) retrotransposons in phylum Platyhelminthes. The retrotransposon, which was named Clonorchis sinensis Retrotransposon 1 (CsRn1), showed a genomewide distribution and had a copy number of more than 100 per haploid genome. CsRn1 encoded an uninterrupted open reading frame (ORF) of 1,304 amino acids, and the deduced ORF exhibited similarities to the pol proteins of Ty3/gypsy-like LTR retrotransposons. The mobile activity of master copies was predicted by sequence analysis and confirmed by the presence of mRNA transcripts. Phylogenetic analysis of Ty3/gypsy-like LTR retrotransposons detected a new clade comprising CsRn1, Kabuki of Bombyx mori, and an uncharacterized element of Drosophila melanogaster. With its high repetitiveness and preserved mobile activity, it is proposed that CsRn1 may play a significant role in the genomic evolution of C. sinensis.
Bortezomib attenuates murine collagen-induced arthritis
Authors: S-W Lee, J-H Kim, Y-B Park, S-K Lee
Journal: Annals of the Rheumatic Diseases (2008)

Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated.Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored.Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment.These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.
In Vivo Cardiac Electrophysiology Studies in the Mouse
Authors: Charles I. Berul, Mark J. Aronovitz, Paul J. Wang, Michael E. Mendelsohn
Journal: Circulation (1996)

Background This report describes a novel in vivo mouse epicardial cardiac electrophysiology study based on clinical protocols used to evaluate cardiac conduction in human patients. The technique allows extensive electrophysiological evaluation, including the response to pacing, programmed stimulation, and pharmacological agents. Methods and Results Surface six-lead ECG data from 18 C57BL/6J mice are presented. Normal cardiac conduction properties for 14 of 18 mice that underwent the procedure are summarized, including determination of sinus node recovery times, AV conduction properties, and atrial, AV, and ventricular effective refractory periods. A subset of six mice was studied after the administration of either procainamide (n=3) or quinidine (n=3). All animals in the procainamide group developed either second-degree or complete AV block spontaneously. The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation. Conclusions This mouse electrophysiology method allows rapid assessment of the conduction properties of the murine heart. The ability to analyze cardiac conduction in normal and transgenic mice provides a powerful tool for examining molecular electrophysiological mechanisms in normal physiology and disease states.
Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma
Authors: G. Reid, M.E. Pel, M.B. Kirschner, Y.Y. Cheng, N. Mugridge, J. Weiss, M. Williams, C. Wright, J.J.B. Edelman, M.P. Vallely, B.C. McCaughan, S. Klebe, H. Brahmbhatt, J.A. MacDiarmid, N. van Zandwijk
Journal: Annals of Oncology (2013)
Depression--the hidden symptom in advanced cancer
Authors: M. Lloyd-Williams
Journal: Journal of the Royal Society of Medicine (2003)

Psychiatric disorders are more prevalent in patients with cancer than in the general population.1,2 About 30% of such patients will be experiencing an 'adjustment reaction' and 20% will qualify for a formal psychiatric diagnosis, most commonly depression.3 For a quarter of all patients admitted to a palliative care unit, depression will be a significant symptom.4 Even in the general population the prevalence of depression is 6-10%, and those with a preexisting psychiatric disorder will be at special risk.5

More than 40 years have passed since Hinton drew attention to the issue of mental distress in the dying6 yet surveys still point to much unrecognized suffering;7 as much as 80% of the psychological and psychiatric morbidity of patients with cancer goes unrecognized and untreated. One reason is that many patients choose not to disclose their symptoms—perhaps because they feel it is a waste of the professional's time or because they think they are in some way blameworthy.8 But another factor may be that medical and nursing staff lack confidence in diagnosing depression in these circumstances.9 In this article I review the methods that can help in detection of depression and the options for intervention when it is identified.
Parasite-host interaction in malaria: genetic clues and copy number variation
Authors: Imad Faik, Elisandra de Carvalho, Jürgen FJ Kun
Journal: Genome Medicine (2009)

In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction.
Induction of resistance to antibody-mediated cytotoxicity. H-2, Ia, and Ig antigens are independent entities in the membrane of mouse lymphocytes.
Authors: V Hauptfeld, M Hauptfeld, J Klein
Journal: The Journal of Experimental Medicine (1975)

Mouse spleen or thymus lymphocytes incubated with monospecific H-2 or Ia alloantisera and then coated with a xenogeneic antimouse Ig serum become specifically resistant to the alloantiserum (and complement) they have been incubated with. This so called "lysostrip method" was used to investigate the molecular interrelationships of antigens in the mouse lymphocyte membrane. The results of this investigation confirm that H-2K and H-2D antigens are carried by two distinct populations of molecules. They provide evidence that the Ia antigens move in the membrane independently of both H2-K and H-2D antigens; and finally they demonstrate absence of any physical linkage between Ig receptors in B cells, on the one hand, and Ia, H-2K, and H-2D molecules on the other hand.
DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3
Authors: Benjamin J. Thompson, Rahul Bhansali, Lauren Diebold, Daniel E. Cook, Lindsay Stolzenburg, Anne-Sophie Casagrande, Thierry Besson, Bertrand Leblond, Laurent Désiré, Sébastien Malinge, John D. Crispino
Journal: The Journal of Experimental Medicine (2015)

Pre–B and pre–T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells’ proliferation, but little is known about its posttranslational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition in mice, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a nonphosphorylatable Cyclin D3 T283A mutant recapitulated these defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or loss. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development.
Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD
Authors: JC Celedon, FE Speizer, JM Drazen, ST Weiss, EJ Campbell, VJ Carey, JJ Reilly, L Ginns, EK Silverman
Journal: European Respiratory Journal (1999)

Bronchodilator responsiveness has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1). Therefore, bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were assessed in 184 adult first-degree relatives of probands with severe early-onset chronic obstructive pulmonary disease (COPD) and a control group. Greater bronchodilator responsiveness was found among current smokers or exsmokers who were first-degree relatives of early-onset COPD probands than in currently or exsmoking controls, expressed as increase in FEV1 as a percentage of baseline (5.8+/-8.1 versus 2.9+/-5.1%, p<0.01), absolute increase in FEV1 from baseline (120+/-130 versus 60+/-110 mL, p<0.05), and increase in FEV1 as a percentage of the predicted value (3.6:4.1 versus 2.2+/-3.9%, p<0.05). However, elevated total serum IgE levels were not found in first-degree relatives of early-onset COPD probands compared with control subjects. The increased bronchodilator responsiveness among currently smoking/exsmoking first-degree relatives of early-onset COPD probands suggests that these individuals may have enhanced susceptibility to the detrimental effects of cigarette smoking.
MPs condemn Serco for substandard out of hours service in Cornwall
Authors: A. O'Dowd
Journal: BMJ (2013)

A private firm providing a GP out of hours service in Cornwall has been described as bullying and inhibiting staff from whistleblowing when things started to go wrong.

In a highly critical report published on 11 July by the parliamentary public accounts select committee, MPs accused Serco of bullying employees, providing a short staffed and substandard service, and manipulating data to hide the truth.1

Out of hours GP services in Cornwall are provided by Serco for NHS Kernow, the clinical commissioning group for Cornwall and the Isles of Scilly, as part of a five year contract worth £32m (€37m; $47m).

Serco has been the subject of various critical reports about its service from the NHS regulator the …
Young Age at Diagnosis Correlates With Worse Prognosis and Defines a Subset of Breast Cancers With Shared Patterns of Gene Expression
Authors: Carey K. Anders, David S. Hsu, Gloria Broadwater, Chaitanya R. Acharya, John A. Foekens, Yi Zhang, Yixin Wang, P. Kelly Marcom, Jeffrey R. Marks, Phillip G. Febbo, Joseph R. Nevins, Anil Potti, Kimberly L. Blackwell
Journal: Journal of Clinical Oncology (2008)

Purpose Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined. Patients and Methods Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: ≤ 45 years, n = 200; older: ≥ 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed. Results Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P &lt; .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERα mRNA (P &lt; .0001), ERβ (P = .02), and progesterone receptor (PR) expression (P &lt; .0001), but higher HER-2 (P &lt; .0001) and epidermal growth factor receptor (EGFR) expression (P &lt; .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERβ and higher EGFR mRNA expression were significant predictors of inferior DFS. Conclusion This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.
Introduction to Aortic Stenosis
Authors: Blase A. Carabello
Journal: Circulation Research (2013)

Aortic stenosis is perhaps the most common of all valvular heart diseases in the developed nations of the world. Once primarily caused by rheumatic fever, the most common pathogenesis today is an active inflammatory process with some features that are similar to atherosclerosis. Because of this shift, the age at onset of severe obstruction has changed from the sixth decade 50 years ago to the eighth decade in most individuals today. The onset of symptoms remains a key determinant of outcome, although the later age at onset may make it difficult to discern if aortic stenosis or other age-related comorbidities is the cause of the symptoms. Once symptoms of aortic stenosis develop, life expectancy is shortened to ≈3 years unless the mechanical obstruction to left ventricular outflow is relieved by aortic valve replacement. Traditionally performed during cardiac surgery, aortic valve replacement now may be performed safely and effectively using transcatheter techniques, potentially revolutionizing the approach to this potentially fatal disease.
Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies
Authors: Cari M. Kitahara, Alan J. Flint, Amy Berrington de Gonzalez, Leslie Bernstein, Michelle Brotzman, Robert J. MacInnis, Steven C. Moore, Kim Robien, Philip S. Rosenberg, Pramil N. Singh, Elisabete Weiderpass, Hans Olov Adami, Hoda Anton-Culver, Rachel Ballard-Barbash, Julie E. Buring, D. Michal Freedman, Gary E. Fraser, Laura E. Beane Freeman, Susan M. Gapstur, John Michael Gaziano, Graham G. Giles, Niclas Håkansson, Jane A. Hoppin, Frank B. Hu, Karen Koenig, Martha S. Linet, Yikyung Park, Alpa V. Patel, Mark P. Purdue, Catherine Schairer, Howard D. Sesso, Kala Visvanathan, Emily White, Alicja Wolk, Anne Zeleniuch-Jacquotte, Patricia Hartge
Journal: PLoS Medicine (2014)

In a pooled analysis of 20 prospective studies, Cari Kitahara and colleagues find that class III obesity (BMI of 40–59) is associated with excess rates of total mortality, particularly due to heart disease, cancer, and diabetes. Please see later in the article for the Editors' Summary
Response to Letters Regarding Article, “High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease”
Authors: Philip Haaf, Beatrice Drexler, Tobias Reichlin, Raphael Twerenbold, Miriam Reiter, Julia Meissner, Nora Schaub, Claudia Stelzig, Michael Freese, Amely Heinzelmann, Christophe Meune, Cathrin Balmelli, Heike Freidank, Katrin Winkler, Kris Denhaerynck, Willibald Hochholzer, Stefan Osswald, Christian Mueller
Journal: Circulation (2013)
A critical role for regulatory T cell–mediated control of inflammation in the absence of commensal microbiota
Authors: Takatoshi Chinen, Pavel Y. Volchkov, Alexander V. Chervonsky, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2010)

Suppression mediated by regulatory T cells (T reg cells) represents a unique, cell-extrinsic mechanism of in-trans negative regulation that restrains multiple types of immune cells. The loss of T reg cells leads to fatal, highly aggressive, and widespread immune-mediated lesions. This severe autoimmunity may be driven by commensal microbiota, the largest source of non-self ligands activating the innate and adaptive immune systems. Alternatively, T reg cells may primarily restrain T cells with a diverse self–major histocompatibility complex (MHC)–restricted T cell receptor repertoire independently of commensal microbiota. In this study, we demonstrate that in germ-free (GF) mice, ablation of the otherwise fully functional T reg cells resulted in a systemic autoimmune lympho- and myeloproliferative syndrome and tissue inflammation comparable with those in T reg cell–ablated conventional mice. Importantly, there were two exceptions: in GF mice deprived of T reg cells, the inflammation in the small intestine was delayed, whereas exocrine pancreatitis was markedly accelerated compared with T reg cell–ablated conventional mice. These findings suggest that the main function of T reg cells is restraint of self-MHC–restricted T cell responsiveness, which, regardless of the presence of commensal microbiota, poses a threat of autoimmunity.
Quantitative Control of Adaptive Cardiac Hypertrophy by Acetyltransferase p300
Authors: Jian Qin Wei, Lina A. Shehadeh, James M. Mitrani, Monica Pessanha, Tatiana I. Slepak, Keith A. Webster, Nanette H. Bishopric
Journal: Circulation (2008)

Acetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown.Pressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5- to 3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload-induced hypertrophy by approximately 50% and rescued the hypertrophic phenotype of p300 overexpressers. Increased p300 expression had no effect on total histone deacetylase activity but was associated with proportional increases in p300 acetyltransferase activity and acetylation of the p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300 transgenic hearts were highly enriched for MEF2 binding sites.Small increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2 and upstream of signals promoting phosphorylation or nuclear export of histone deacetylases. We propose that induction of myocardial p300 content is a primary rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.
Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
Authors: Chera L Maarouf, Ian D Daugs, Salvatore Spina, Ruben Vidal, Tyler A Kokjohn, R Lyle Patton, Walter M Kalback, Dean C Luehrs, Douglas G Walker, Eduardo M Castaño, Thomas G Beach, Bernardino Ghetti, Alex E Roher
Journal: Molecular Neurodegeneration (2008)

Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA.We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations.These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.