tbuckley/cabot-search huggingface dataset:
Role of Genetic Testing in Inherited Cardiovascular Disease
Authors: Allison L. Cirino, Stephanie Harris, Neal K. Lakdawala, Michelle Michels, Iacopo Olivotto, Sharlene M. Day, Dominic J. Abrams, Philippe Charron, Colleen Caleshu, Christopher Semsarian, Jodie Ingles, Harry Rakowski, Daniel P. Judge, Carolyn Y. Ho
Journal: JAMA Cardiology (2017)

Genetic testing is a valuable tool for managing inherited cardiovascular disease in patients and families, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies and inherited arrhythmias. By identifying the molecular etiology of disease, genetic testing can improve diagnostic accuracy and refine family management. However, unique features associated with genetic testing affect the interpretation and application of results and differentiate it from traditional laboratory-based diagnostics. Clinicians and patients must have accurate and realistic expectations about the yield of genetic testing and its role in management. Familiarity with the rationale, implications, benefits, and limitations of genetic testing is essential to achieve the best possible outcomes.Successfully incorporating genetic testing into clinical practice requires (1) recognizing when inherited cardiovascular disease may be present, (2) identifying appropriate individuals in the family for testing, (3) selecting the appropriate genetic test, (4) understanding the complexities of result interpretation, and (5) effectively communicating the results and implications to the patient and family. Obtaining a detailed family history is critical to identify families who will benefit from genetic testing, determine the best strategy, and interpret results. Instead of focusing on an individual patient, genetic testing requires consideration of the family as a unit. Consolidation of care in centers with a high level of expertise is recommended. Clinicians without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicans in specialized multidisciplinary clinics.Genetic testing provides a foundation for transitioning to more precise and individualized management. By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management. Successful integration of genetic testing into clinical practice requires understanding of the complexities of testing and effective communication of the implications to patients and families.
生体材料支援間葉系間質細胞療法は結腸放射線誘発損傷を軽減する【Powered by NICT】
Authors: Moussa Lara, Pattappa Girish, Doix Bastien, Benselama Sarra-Louiza, Demarquay Christelle, Benderitter Marc, Semont Alexandra, Tamarat Radia, Guicheux Jerome, Weiss Pierre, Rethore Gildas, Mathieu Noeelle
Journal: Biomaterials (2017)
<scp>CD</scp>11b+Gr‐1<sup>dim</sup> Tolerogenic Dendritic Cell–Like Cells Are Expanded in Interstitial Lung Disease in <scp>SKG</scp> Mice
Authors: Sho Sendo, Jun Saegusa, Takaichi Okano, Soshi Takahashi, Kengo Akashi, Akio Morinobu
Journal: Arthritis & Rheumatology (2017)

Objective SKG mice develop interstitial lung disease ( ILD ) resembling rheumatoid arthritis–associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung‐infiltrating cells in SKG mice with ILD . Methods We assessed the severity of zymosan A (ZyA)–induced ILD in SKG mice histologically, and we examined lung‐infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid‐derived suppressor cells ( MDSC s) were cultured in vitro with granulocyte–macrophage colony‐stimulating factor ( GM ‐ CSF ) and interleukin‐4. The proliferation of 5,6‐carboxyfluorescein diacetate N ‐succinimidyl ester–labeled naive T cells cocultured with isolated CD 11b+Gr‐1 dim cells and MDSC s was evaluated by flow cytometry. CD 11b+Gr‐1 dim cells were adoptively transferred to ZyA‐treated SKG mice. Results MDSC s, Th17 cells, and group 1 and 3 innate lymphoid cells ( ILC 1s and ILC 3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD 11b+Gr‐1 dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD 11b+Gr‐1 dim cells expressed CD 11c. CD 11b+Gr‐1 dim cells were induced from monocytic MDSC s with GM ‐ CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD 11b+Gr‐1 dim cells have never been described previously, and we termed them CD 11b+Gr‐1 dim tolerogenic dendritic cell ( DC )–like cells. Th17 cells, ILC 1s, and ILC 3s in the inflamed lung produced GM ‐ CSF , which may have expanded CD 11b+Gr‐1 dim tolerogenic DC –like cells in vivo. Furthermore, adoptive transfer of CD 11b+Gr‐1 dim tolerogenic DC –like cells significantly suppressed progression of ILD in SKG mice. Conclusion We identified unique suppressive myeloid cells that were differentiated from monocytic MDSC s in SKG mice with ILD , and we termed them CD 11b+Gr‐1 dim tolerogenic DC –like cells.
工学内皮細胞化心筋と心臓に対するaチップのためのバイオプリンティング3次元ミクロ繊維足場【Powered by NICT】
Authors: Zhang Yu Shrike, Arneri Andrea, Bersini Simone, Shin Su-Ryon, Zhu Kai, Goli-Malekabadi Zahra, Aleman Julio, Colosi Cristina, Busignani Fabio, Dell’Erba Valeria, Bishop Colin, Shupe Thomas, Demarchi Danilo, Moretti Matteo, Rasponi Marco, Dokmeci Mehmet Remzi, Atala Anthony, Khademhosseini Ali
Journal: Biomaterials (2016)
07.13 A case of sting-associated vasculopathy with onset in infancy (savi) in a young adult male with a novel tmem173 gene mutation
Authors: Evangelia Zampeli, Aglaia G Vakrakou, Anastasios E Germenis, Clio P Mavragani, Haralampos M Moutsopoulos, Menelaos N Manoussakis
Journal: Annals of the Rheumatic Diseases (2017)

<h3></h3> The type-I interferonopathies comprise a recently recognised group of diseases characterised by an up-regulation of type-I interferon signalling. Autosomal dominant mutations in <i>TMEM173</i> gene, which encodes the stimulator of interferon genes (STING), have been described in children presenting with cutaneous vasculopathy and pulmonary inflammation, lately termed STING-associated vasculopathy with onset in infancy (SAVI). Herein, we present a case of a 18-years old male patient, who has suffered from cutaneous vasculopathy since early infancy and recently diagnosed severe interstitial lung disease, wherein a novel <i>TMEM173</i> gene mutation was identified, most probably representing a not yet reported causative genetic defect for SAVI. The patient presented with fever, diffuse livedo reticularis, resorption of distal phalanges, nail dystrophy and scarred ears. He has been suffering since early infancy from intermittent febrile episodes, livedo reticularis, Raynaud's phenomenon and cutaneous vasculopathy affecting the ears, the nose, the fingers and the toes. The patient has also severe interstitial lung disease (markedly affected pulmonary function tests along with diffuse honeycombing, reticular opacities and patchy ground-glass on high-resolution chest CT scan). Since infancy, repeated laboratory examinations were revealing elevated acute phase reactants with negative cultures for microbes. Despite receiving sequentially or in combination, all immunosuppressive agents the disease was progressing. The possibility of a type-I interferonopathy was raised and genetic analysis was performed, which revealed a heterozygous mutation in exon 6 of TMEM173 gene (p.Cys206Gly, c.616T&gt;G, with estimated frequency &lt;0.0008236%, considered probably damaging by bioinformatic tools; PolyPhen score 0.986). The occurrence of type-I interferon signature was also verified in the patient's peripheral whole blood cells, as compared to age-matched healthy controls and compared to his parents and male sibling. We present this SAVI case for raising awareness aiming at early and accurate diagnosis of this new disease entity and because the mutation found in this patient is a newly identified mutation and not been todate registered in the relevant databases (dbSNP, NCBI, ENSEMBL).
02.25 Mir125 mediates angiogenic mechanisms in psoriatic arthritis
Authors: Sarah Wade, Nils Ohnesorge, Stephaine Merrigan, Monika Biniecka, Trudy McGarry, Brendan Kennedy, Douglas Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Introduction</h3> Psoriatic arthritis (PsA) is characterised by an early vascular phase which is essential in perpetuating pannus growth, immune responses and disease progression. Whilst established therapies, including methotrexate, anti-TNFs and Vitamin3D analogues, have demonstrated anti-angiogenic properties a greater molecular understanding is required to further harness these beneficial effects. Herein we propose microRNA, miR-125, has a fundamental role in orchestrating joint angiogenesis as characterised by <i>ex-vivo</i> associations, <i>in-vitro</i> assays and novel <i>in-vivo</i> zebrafish models. <h3>Aims</h3> To elucidate the molecular role of miR-125 in regulating synovial angiogenesis and in response to therapy in PsA. <h3>Methods</h3> MiRNA levels were quantified in synovial tissue (ST), synovial fluid (SF) and PBMC by RT-PCR and compared to clinical markers. Immunohistochemical analysis of vascular markers, VEGF, ANG2 and factor VIII were compared with microRNA expression. Matrigel tube formation and migration assays were performed to elucidate the angiogenic functions of miR-125 in endothelial cells (HMVEC) and fibroblast like synoviocytes (FLS). HMVECs were cultured in hypoxic tPO<sub>2</sub> levels similar to joint conditions. GFP-tagged zebrafish embryos treated with anti-125 morpholinos, or vitaminD3 analogue, calcitrol, were monitored for angiogenic development. <h3>Results</h3> MiR-125 was significantly decreased in PsA ST compared to OA. Similarly, miR-125 expression was lower SFMCs compared to PBMC, suggesting that miR-125 is decreased at the site of inflammation. Synovial expression of miR-125 was inversely associated with both increased macroscopic and microscopic vascularity, and in HMVEC miR-125 expression decreased in response to hypoxia. Decreased expression of miR-125a in HMVEC and FLS displayed increased tube formation and/or migrational mechanisms. Zebrafish with decreased miR-125 displayed increased vascular sprouts. In contrast, Calcitriol significantly reduced vascular development and increased the expression of miR-125, promoting miR-125 as a potential mechanism for orchestrating angiogenic development <i>in vivo</i> and in response to pharmaceutical agents. <h3>Conclusion</h3> Our data demonstrates decreased expression of miR-125 in PsA and <i>in-vivo</i> models was strongly associated with pro-angiogenic mechanisms. Correcting these deficiencies, either by conventional pharmacological or as novel drug targets, may provide therapeutic benefit, especially in early disease.
Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location
Authors: Michael Karremann, Gerrit H Gielen, Marion Hoffmann, Maria Wiese, Niclas Colditz, Monika Warmuth-Metz, Brigitte Bison, Alexander Claviez, Dannis G van Vuurden, André O von Bueren, Marco Gessi, Ingrid Kühnle, Volkmar H Hans, Martin Benesch, Dominik Sturm, Rolf-Dieter Kortmann, Andreas Waha, Torsten Pietsch, Christof M Kramm
Journal: Neuro-Oncology (2017)

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.
Surveillance of Dutch Patients With Li-Fraumeni Syndrome
Authors: Marielle W. G. Ruijs, Claudette E. Loo, Colette A. J. M. van Buchem, Eveline M. A. Bleiker, Gabe S. Sonke
Journal: JAMA Oncology (2017)

This cohort study of patients with Li-Fraumeni syndrome assesses the diagnostic yield and false-positive rate of an annual surveillance program including whole-body magnetic resonance imaging in patients identified as carriers of TP53 gene mutations.
Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis
Authors: Luciana C. Veiras, Adriana C.C. Girardi, Joshua Curry, Lei Pei, Donna L. Ralph, An Tran, Regiane C. Castelo-Branco, Nuria Pastor-Soler, Cristina T. Arranz, Alan S.L. Yu, Alicia A. McDonough
Journal: Journal of the American Society of Nephrology (2017)

Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na + /H + exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na + /Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na + /Cl − cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na + channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K + concentration. A K + -rich meal increased the urinary K + concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K + secretion and set plasma K + at a lower level.
Perioperative hemodynamics and outcomes of patients on metyrosine undergoing resection of pheochromocytoma or paraganglioma
Authors: James J. Butz, Toby N. Weingarten, Alexandre N. Cavalcante, Irina Bancos, William F. Young, Travis J. McKenzie, Darrell R. Schroeder, David P. Martin, Juraj Sprung
Journal: International Journal of Surgery (2017)
Myocardial Redox State Predicts Post-Operative Atrial Fibrillation in Cardiac Surgery
Authors: M Demosthenous, C Antoniades, S Reilly, M Margaritis, R Jayaram, D Tousoulis, A S Antonopoulos, K M Channon, C Stefanadis, B Casadei
Journal: Circulation (2011)
TP53 Mutations and Outcome in Patients with Myelodysplastic Syndromes (MDS)
Authors: Karam Al-Issa, Mikkael A. Sekeres, Alek d Nielsen, Babal Jha, Bartlomiej P Przychodzen, Mai Aly, Hetty E. Carraway, Anjali S. Advani, Bhumika Patel, Michael J. Clemente, Sudipto Mukherjee, Aaron T. Gerds, Jaroslaw P Maciejewski, Aziz Nazha
Journal: Blood (2016)
Abstract 243: The Role of Reactive Oxygen Species in Hyperglycemia-Induced Attenuation of Anesthetic Preconditioning in Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Scott Canfield, Danielle Twaroski, Xiaowen Bai, Chika Kikuchi, Zeljko J Bosnjak
Journal: Circulation Research (2012)

Anesthetic Preconditioning (APC) protects the myocardium from ischemia/reperfusion injury. The cardioprotective effects of APC is diminished or even eliminated in individuals with diabetes mellitus and/or hyperglycemia. The development of patient-specific induced pluripotent stem cells and their differentiation capability has provided us with an in vitro model to study the inefficiency of APC in these individuals.To investigate the underlying mechanisms involved in the attenuation of APC in both diabetic individuals and in hyperglycemia we utilized cardiomyocytes derived from Type 2 diabetic patient and healthy individual iPSCs, (T2DM-iPSCs and N-iPSCs, respectively). Contracting cardiomyocytes were dissociated and selected by the expression of green fluorescent protein under the transcriptional control of myosin light chain-2v. Cardiomyocytes were exposed to varying glucose concentrations (5, 11, and 25 mM). Lactate dehydrogenase (LDH) release was measured using a colorimetric cytotoxicity assay kit and read spectrophotometrically. Mitochondrial membrane potential and reactive oxygen species (ROS) generation were measured with confocal microscopy. APC reduced oxidative stress-induced lactate dehydrogenase (LDH) release in cardiomyocytes derived from both N-iPSCs- and T2DM-iPSCs in 5 and 11 mM glucose concentrations, but not in 25 mM glucose. Baseline membrane potential was similar between non-diabetic- and Type 2 diabetic-derived cardiomyocytes; however 25 mM glucose hyperpolarized the mitochondrial membrane potential. T2DM-iPSC-derived cardiomyocytes had an increase in ROS baseline levels compared to N-iPSC-derived cardiomyocytes. Additionally, high glucose concentrations increased oxidative stress-induced ROS production compared to lower glucose conditions in both cell lines. Our preliminary data shows that high glucose generates excessive ROS and hyperpolarizes the mitochondrial membrane and may contribute to the inefficiency of diabetic and/or hyperglycemic individuals to be anesthetically preconditioned. By utilizing human iPSC-derived cardiomyocytes we can begin to understand the inability of hyperglycemic and diabetic individuals to be anesthetically preconditioned.
THE RELATIONSHIP BETWEEN TACKLE COACHING METHODS AND PLAYERS' TACKLE TRAINING ATTITUDES AND BEHAVIOURS
Authors: Sharief Hendricks, Lindsay Starling, Ben Jones, Kevin Till, Mike Lambert
Journal: British Journal of Sports Medicine (2017)

Background The tackle event in rugby is a technical and physical contest between opposing players. A player's ability to tolerate and contest during a tackle is a prerequisite for safe participation and success in rugby. The attitude and behaviour of players towards safety have been identified as risk factors for injury. How a skill is coached may influence the player's attitude and actions when executing the skill in training and match play. Objective The purpose of this study was to investigate the relationship between tackle coaching methods and players' tackle training attitudes and behaviours. Design Cross-sectional Survey. Setting High Schools. Participants 164 Under-19 rugby male players. Assessment of Risk Factors Questionnaire using a 5-point Likert scale for importance (attitude), quantity (behaviour) and frequency (behaviour). Main Outcome Measurements Associations between tackle coaching methods and players' tackle training attitudes and behaviours using the χ 2 test and Cramer's V. Results The more time spent on coaching proper technique to prevent injuries, the higher players rated the importance of injury prevention (28% somewhat important-very important, χ 2 (16)=29.13, p&lt;0.05, Cramer's V=0.21, moderate). Verbal instruction from the coach, whether to the individual player (29% somewhat important-very important, χ 2 (16)=30.41, p&lt;0.05, Cramer's V=0.22, moderate) or team (34% somewhat important-very important, χ 2 (16)=34.04, p&lt;0.01, Cramer's V=0.23, moderate) was positively associated with how important players rated injury prevention. Conclusions This is the first study to report on the relationship between tackle coaching methods and players' tackle training attitudes and behaviours. When coaches offered verbal instruction and spent more time coaching proper technique to prevent injuries, players tended to have a more positive attitude toward injury prevention when training the tackle.
02.15 Disease activity measured by das28 in a cohort of 260 patients with rheumatoid arthritis. Are the presence of anti citrullinated peptide antibodies related with trh activity of the disease?
Authors: Raquel Hernández, Julia Uceda, Sergio Antonio Rodriguez, Carmen Almeida, Jose Luis Marenco
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid artritis (RA) is a systemic autoimmune disease of unknown and multifactorial aetiology, whoseprevalence is around 1% of the adult population. Anti citrullinated peptide antibodies (ACPA) are the most specific serological markers of RA, with a specificity of 98%–99% in some studies. The presence of autoantibodies such as rheumatoid factor (RF) and ACPA is related to more severe structural damage and joint destruction during disease progression. <h3>Objectives</h3> To assess whether the presence of ACPA is associated with higher levels of disease activity score (DAS 28) in a sample of patients with RA. <h3>Methods</h3> We performed a descriptive study of a cohort of patients from Valme Hospital diagnosed with RA. Patients were identified from an electronic database. Demographic data, inmunological profile (presence of RF and/or ACPA),treatment (DMARDs or biological therapy) and disease activity measured by DAS 28 were collected transversely. <h3>Results</h3> Two hundred and sixty RA patients were included, current average age of 58.5 years, 72% were women, 48% were receiving biological therapy. Regarding serological markers, 61% were ACPA positive, 65% were RF positive and 54.3% were ACPA and RF positive. Mean DAS28 was 2.6 for RF and ACPA negative patients, compared to 2.8 for patients that showed positivity for one or both autoantibodies, without statistically significant difference. With respect to the subgroup of patients receiving biological treatment (n=122), no significant difference of the mean value of DAS28 was seen (regarding to the presence/absence of ACPA): DAS28 2,53 for ACPA positive versus 2.52 for ACPA negative. <h3>Conclusions</h3> The presence of ACPA in RA patients has been traditionally considered a predictor of radiographic progression and higher clinical activity. But recently, new studies suggest that, although ACPA positivity does maintain relationship with structural damage, there is no association with the severity of clinical activity measured by DAS28.<sup>1</sup> In line with with these results, in our population of RA we found no relationship between the presence of ACPA and/or RF and disease activity, but it should be noted that the present is a cross-sectional study, so further prospective studies will be needed to elucidate this point. <h3>Reference</h3> M Kaushik R. Anti-Cyclic Citrullinated Peptide Antibodies as a Predictor of Clinical and Radiological Disease Severity in Rheumatoid Arthritis. <i>Curr Rheumatol Rev</i>2015 Jan 13.
Abstract 20417: Muscle Derived New Cell Population Has Therapeutic Potentials Through Paracrine Effects in Cell-sheet Transplantation in a Rat Ischemic Cardiomyopathy Model
Authors: Hiroko Iseoka, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Shigeo Masuda, Yoshiki Sawa
Journal: Circulation (2016)

Background: Transplantation of autologous skeletal myoblast (SMB) cell-sheets has been shown to produce therapeutic effects via paracrine effects in ischemic cardiomyopathy (ICM). Although purity o...