tbuckley/cabot-search huggingface dataset:
07.11 Contribution of mthfr gene variants in lupus related subclinical atherosclerosis
Authors: Maira Giannelou, Andrianos Nezos, Kyriaki Maselou, Nikolaos Drakoulis, Dimitrios Ioakeimidis, Michael Koutsilieris, Haralampos M Moutsopoulos, Clio P Mavragani
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of functional polymorphisms of the gene encoding for the enzyme 5,10- methylenetetrahydrofolate reductase (MTHFRC677T and MTHFRA1298C) to atherosclerotic disease characterising SLE patients. <h3>Materials and methods</h3> 138 consecutive SLE patients, according to the American College of Rheumatology (ACR) classification criteria were included in the study. All patients underwent ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque. Clinical, haematological, serological, immunological characteristics, therapeutic regimens and classical risk factors for cardiovascular disease were recorded. Peripheral DNA samples from all SLE patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (C677T and A1298C). Data were analysed using univariate and multivariate models (SPSS 21.0) and SNPstats software. <h3>Results</h3> While no difference in the prevalence of MTHFR677TT and MTHFR1298CC genotypes were detected between SLE patients and HC (19% vs 18.4% and 9.6% vs 11.9%, respectively, p-values&gt;0.05 for both comparisons), MTHFR677TT variant was detected more frequently in SLE patients with plaque formation and high IMT scores compared to those without (26.8% vs 11.9%, p-value=0.004% and 29% vs 15%, p-value=0.02, respectively). A similar trend-though non significant- was observed between MTHFR1298CC variant with plaque formation/heightened IMT scores. The presence of either MTHFR1298CC or 677TT was identified as independent risk factor for both the formation of atherosclerotic plaque and high IMT scores [OR (95%) CI: 4.8 (1.00–23.7) and OR (95%) CI: 3.6 (1.00–13.8) respectively], following adjustment for potential cofounders. <h3>Conclusions</h3> The independent association between the homozygous state for either MTHFR677TT or MTHFR1298CC genetic variants and subclinical atherosclerosis implies genetic influences as potential contributors to the increased burden of atherosclerotic disease characterising SLE.
Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance
Authors: Melania Gaggini, Fabrizia Carli, Chiara Rosso, Emma Buzzigoli, Milena Marietti, Veronica Della Latta, Demetrio Ciociaro, Maria Lorena Abate, Roberto Gambino, Maurizio Cassader, Elisabetta Bugianesi, Amalia Gastaldelli
Journal: Hepatology (2017)

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD‐NO) compared to those with obesity (NAFLD‐Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD‐NO and 15 NAFLD‐Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep‐IR; Hep‐IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD‐Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD‐NO subjects compared to CTs. Glutamate, tyrosine, and the GSG‐index were correlated with Hep‐IR. The GSG‐index correlated with liver enzymes, in particular, gamma‐glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG‐index, while only the new GSG‐index was able to discriminate fibrosis F3‐4 from F0‐2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG‐index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145‐158).
Surgery avoided by the use of over-the-scope clips for severe duodenal complications associated with endoscopic mucosal resection
Authors: Noriko Nishiyama, Hirohito Mori, Hideki Kobara, Shintaro Fujihara, Nobuya Kobayashi, Tatsuo Yachida, Tsutomu Masaki
Journal: Endoscopy (2017)

During endoscopic treatment for duodenal neoplasm, hazardous complications such as perforation and bleeding sometimes occur owing to the anatomical characteristics of the duodenum [1] [2] [3]. Although surgical repair has been traditionally required for these complications, the procedure is invasive and complicated [4]. A currently available over-the-scope clip (OTSC; Ovesco Endoscopy, Tübingen, Germany) has provided excellent outcomes for gastrointestinal refractory bleeding and full-thickness defects [5]. Here, we describe a notable case in which iatrogenic duodenal complications could be managed with OTSCs.
Time, Psoriasis Area and Severity Index and Dermatology Life Quality Index of patients with psoriasis who drop out of clinical trials on etanercept because of lack of efficacy: a pooled analysis from 10 clinical trials
Authors: A. Nast, M. Dilleen, W. Liyanage, L. Aikman, P. Szczypa, C. Dressler
Journal: British Journal of Dermatology (2017)

BackgroundPatient‐reported outcomes in psoriasis studies are assessed at specific study time points. If a treatment has not become effective by a certain time point, it may increase the likelihood of patients being dissatisfied and leaving a clinical study.
インシュリンの経口デリバリーに対するデキストラン‐b‐ポリ(乳酸‐グリコール酸)共重合体ポリマソーム:in vitroとin vivo評価
Authors: Alibolandi Mona, Alabdollah Fatemeh, Sadeghi Fatemeh, Mohammadi Marzieh, Abnous Khalil, Ramezani Mohammad, Hadizadeh Farzin
Journal: Journal of Controlled Release (2016)
Role and Regulation of Glucose Metabolism in Proliferating Cells
Authors: D A Hume, M J Weidemann
Journal: JNCI Journal of the National Cancer Institute (1979)

The history of the interest in glucose metabolism in malignantly transformed cells dates back to the pioneering studies of Warburg. These studies led to the statement, in 1956: “The era in which the fermentation of cancer cells, or its importance, could be debated is over and no-one today can doubt that we understand the origin of cancer cells if we know how their large fermentation originates, or to express it more fully, if we know how the damaged respiration and the excessive fermentation of cancer cells originates.” Even at this time, doubts were expressed about the respiratory deficiency of tumor cells.
HOW MUCH RUGBY IS TOO MUCH? A SEVEN-SEASON PROSPECTIVE COHORT STUDY OF MATCH EXPOSURE IN PROFESSIONAL RUGBY UNION PLAYERS
Authors: Sean Williams, Grant Trewartha, Simon Kemp, John Brooks, Colin Fuller, Aileen Taylor, Matt Cross, Gavin Shaddick, Keith Stokes
Journal: British Journal of Sports Medicine (2017)

Background Player welfare concerns have been raised by a number of professional Rugby Union stakeholders regarding the match exposure demands faced by players. Objective To investigate the influence that acute and chronic match exposures have upon injury risk. Design A seven-season (2006/7–2012/13) prospective cohort design was used to record time-loss injuries (&gt;24 h) and match exposure. Setting English Premiership Professional Rugby Union. Participants 1253 professional players. Assessment of Risk Factors A player's 12-month match exposure (number of matches a player was involved in for ≥20 mins in the preceding 12 months) and month match exposure (number of full-game equivalent matches in preceding 30 days) were assessed as ‘chronic’ and ‘acute’ risk factors, respectively. Main Outcome Measurements A nested-frailty model was applied to calculate adjusted hazard ratios (HR) for the assessed risk factors. Thresholds for beneficial and harmful effects were 0.90 and 1.11, respectively. Results 12-month match exposure was associated with injury in a non-linear fashion, with players who had been involved in less than ≈15 or greater than ≈35 matches (for ≥20 mins) over the preceding 12-month period being more susceptible to injury. Monthly match exposure was linearly associated with injury (HR: 1.14 per 2-SD increase, 90% CI: 1.08–1.20; likely harmful), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposure (&gt;28 matches). Conclusions A player's accumulated and recent match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workload and monitoring the responses of players involved in: 1) a high number of matches in the previous year; 2) a low number of matches in the previous year; 3) a low-moderate number of matches in the previous year but have played intensively in the recent past. These findings could inform match workload planning in professional Rugby Union.
Severe Reduction of Free ADAMTS13, Unbound to Von Willebrand Factor, in Plasma Milieu Is a Unique Feature of HELLP Syndrome
Authors: Yoko Yoshida, Ayami Isonishi, Toshiyuki Sado, Masaki Hayakawa, Hideo Yagi, Hiroshi Kobayashi, Yoshihiro Fujimura, Masanori Matsumoto
Journal: Blood (2016)
悪性消化管間質腫瘍(GIST)の日本人(Jpn)患者(Pts)でのST1571の第II相臨床試験:B1201試験の治療成績
Authors: Doi T, Nishida T, Hirota S, Sugiyama T, Yamao K, Koseki M, Okamura T, Shirao K, Ohtsu A
Journal: Journal of Clinical Oncology (2004)
Allergens displayed on virus‐like particles are highly immunogenic but fail to activate human mast cells
Authors: P. Engeroff, F. Caviezel, F. Storni, F. Thoms, M. Vogel, M. F. Bachmann
Journal: Allergy (2017)

The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased protective IgG responses compared to free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity.We differentiated human mast cells in vitro from blood-derived stem cell progenitors and sensitized the cells with a monoclonal Fel d 1-specific IgE. We compared the capability of Fel d 1 to induce mast cell activation in its free form versus displayed on VLPs and we performed allergen binding studies by surface plasmon resonance as well as flow cytometry.We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d 1 displayed on VLPs fails to induce mast cell activation. We demonstrate that this inability to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation.These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.
08.40 Evaluation of structural damage evolution in rheumatoid arthritis (ra) with optimisedoptimized doses of biological therapies (bt)
Authors: Julia Uceda Montañez, Raquel Hernández Sánchez, L Marenco de la Fuente Jose
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> RA is the most common chronic inflammatory arthropathy. About 30% of patients are treated with BT. The optimisation of BT doses in patients in clinical remission of the disease is a strategy used in clinical practice. The best method for assessing structural damage in daily clinical practice is the SENS method (simplified form of the Van der Heijde method). The main endpoint was evaluate the evolution of the structural damage of the disease in a cohort of patients with RA in follow-up in Rheumatology Unit, of Valme University Hospital, receiving optimised doses of BT, according to the BT dose optimisation protocol elaborated in our unity. <h3>Materials and methods</h3> Observational, descriptive, longitudinal and retrospective study in a cohort of 32 patients diagnosed with RA (ACR 1987), who are treated at reduced doses of TB. A description of the baseline characteristics was made. The evolution of structural damage was measured using the SENS method on hand radiographs. The evaluation was done at different moments of the evolution: before the reduction, at the end of the reduction and in the current visit of collection of results. <h3>Result</h3> 62.5% are women, mean age at diagnosis of 42.6 years. The duration of RA at the start of BT was 98.63 months and the biological treatment time at the beginning of the optimisation was 160.66 months The 75% of the sample was FR positive and 56.7% ACPA positive. The 59.4% were with etanercept. The mean of SENS score in hands before the optimisation was 8.78. The mean of SENS score in patients who continued optimised at time of analysis was 10.67. There were no statistically significant differences. <h3>Conclusions</h3> All the patients in our study were in clinical remission of the disease at the beginning of the dose reduction of TB. The results of our study suggest that optimised doses of BT in patients in clinical remission maintains the patient without significant progression of structural damage.
Almost nine in 10 obstetric units have unfilled rotas, finds audit
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Nearly nine in 10 obstetric units said that they have had problems filling registrar rotas in recent months, an audit of services in England, Scotland, and Wales has found.

Lesley Regan, president of the Royal College of Obstetricians and Gynaecologists, described the rota gaps as “particularly worrying.” She said that they would worsen over time and put the care of mothers and babies at risk.

The National Maternity and Perinatal Audit gathered information from all 155 trusts and boards in Britain between January and March this year to identify good practice and areas that needed improvement. Its first report, published on 10 August, looked at the delivery of maternity and neonatal care, including the availability of services and facilities, and staffing.

It found …
03.26 Early mouse interferon-alpha1 overexpression in vivo triggers an expansion of highly suppressive regulatory t lymphocytes protecting against experimental arthritis
Authors: Matthieu Ribon, Katarzyna Matyja, Roxane Hervé, Delphine Lemeiter, Ken Tsumiyama, Shunichi Shiozawa, Marie-Christophe Boissier, Natacha Bessis, Patrice Decker
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Type I interferons (IFN-I) can be both anti- and pro-inflammatory. Their role is controversial in rheumatoid arthritis (RA) and experimental models. A not-understood IFN-I signature has been reported in RA patients. In mice, IFN-I enhance/inhibit arthritis according to IFN subtype and arthritis models/kinetics. We have evaluated the effects of early IFN-α production in collagen-induced arthritis (CIA) which mimics RA. <h3>Materials and methods</h3> CIA was induced by 2 immunizations with collagen/CFA. Disease development was studied in conditional transgenic mice over-expressing mouse IFN-α1 (Tet-off system) and in IFN-α1-negative littermates. Arthritis was followed by clinical evaluation. Inflammation/bone destruction were estimated by histology. Plasma cytokines/anti-collagen antibodies were measured by Luminex/ELISA. Lymphocyte sub-populations were analysed by flow cytometry. Bone marrow cells were cultured with M-CSF/RANKL to study osteoclasts. CD4<sup>+</sup>CD25<sup>+</sup> regulatory T cells (Treg) and CD4<sup>+</sup>CD25<sup>-</sup> effector T cells (Teff) were purified by magnetic sorting. ATPase activity was determined <i>in vitro</i> by a luminescent assay. Treg inhibition of Teff proliferation was measured by flow cytometry in co-cultures. The <i>in vivo</i> therapeutic capacity of purified Treg was estimated by adoptive transfer. <h3>Results</h3> Induction of mouse IFN-α1 production before the first or between the two immunizations resulted in CIA protection, in contrast to IFN-α1 induction after both immunizations. Both immunised IFN-α1<sup>-</sup> and IFN-α1<sup>+</sup> mice produced anti-collagen antibodies, however the latter produced less. IFN-α1<sup>+</sup> mice produced less IL-6 but more IL-5. Protection in IFN-α1<sup>+</sup> mice was associated with decreased polarisation to Th17 and increased polarisation to Th1/Th2 lymphocytes and IFN-γ-positive NK cells. Osteoclast differentiation/activity were decreased in IFN-α1<sup>+</sup> mice. Particularly, CIA protection in IFN-α1-overexpressing mice was associated with an <i>in vivo</i> expansion of Treg with a higher ectonucleotidase CD39 expression, higher ATPase activity and a higher capacity to inhibit Teff. Most importantly, adoptive transfer of those highly suppressive Treg purified from CIA IFN-α1<sup>+</sup> mice impaired CIA development in IFN-α1<sup>-</sup> recipients in comparison to adoptive transfer of Treg purified from CIA IFN-α1<sup>-</sup> mice. <h3>Conclusions</h3> This is the first study evidencing a potent therapeutic window in which IFN-α1 protects against CIA. Protection is associated with an expansion of more suppressive Treg able to confer protection upon adoptive transfer.
Abstract 1267: Genetic Variant rs1051730 C>T in the Nicotinic Acetylcholine Receptor Gene Cluster on Chromosome 15q24 Significantly Predicts Smoking Severity in Coronary Artery Disease Patients
Authors: Christoph H Saely, Axel Mundlein, Alexander Vonbank, Philipp Rein, Stefan Beer, Johannes Breuss, Heinz Drexel
Journal: Circulation (2009)

Background:  Smoking is a major cause of preventable premature death, mainly due to its strong and dose-dependent impact on coronary artery disease (CAD). Recently, genetic determinants of nicotine dependence (which correlates with the amount of smoked cigarettes rather than with the smoker status per se) have been suggested. No data are available for patients already affected by CAD.   Methods:  We genotyped variant rs1051730 C>T in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 in a large cohort of 1303 consecutive Caucasian patients with angiographically proven CAD.   Results:  From our patients, 62.1% had a history of smoking (n=809; 226 current and 581 past smokers). Genotype distributions of variant rs1051730 were not significantly different between patients with a history of smoking and those who had never smoked (p trend  across genotypes=0.471). However, the variant among smokers proved strongly predictive for the average amount of cigarettes smoked per day (24/d, 23/d, and 30/d for subjects with the AA, the AT, and the TT genotypes; p    Conclusions:  Genetic variant rs1051730 C>T in the nicotinic acetylcholine receptor gene cluster significantly predicts smoking severity in patients with angiographically proven CAD.
04.02 Influence of adipokines on differentiation of osteoarthritis and osteoporosis spongiosa-derived mesenchymal stromal cells
Authors: Lali Tsiklauri, Janina Werner, Klaus W Frommer, Rosel Engel, Stefan Rehat, Sabine Wenisch, Ulf Müller-Ladner, Elena Neumann
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The role of fat–bone interactions in the pathogenesis of osteoporosis is poorly understood. An inverse relationship between bone marrow adipose tissue and bone mineral density during ageing and in osteoporosis is well documented. Adipokines (eg, visfatin, resistin and leptin) are adipocyte-derived factors with immunomodulatory properties and they might influence the differentiation of bone marrow-derived mesenchymal stem cells (MSC) into osteoblasts and adipocytes. The aim was to analyse the presence of adipokines in the bone marrow cavity and their effects on MSC differentiation. <h3>Methods</h3> Spongiosa from femoral heads containing bone marrow were collected (hip replacement of osteoarthritis patients or after osteoporotic femoral neck fracture). MSC were cultured in adipogenic and osteogenic media with/without adipokines. For the transfer and differentiation of MSC on cancellous bone, bone fragments were purified and sterilised. mRNA expression of adipokines, bone marker genes, TIMPs and MMPs of stimulated MSC and of bone samples were evaluated by real time PCR. Matrix mineralization was investigated using Alizarin red S staining. Proinflammatory factors were measured by ELISA. <h3>Results</h3> Visfatin and leptin level were increased in osteoporotic bone vs. non-osteoporotic bone (n=14). Visfatin induced the secretion of proinflammatory factors (IL-6, IL-8, MCP-1) during both, osteogenic and adipogenic differentiation but not leptin or resistin. Visfatin markedly increased mineralization during osteogenic differentiation, whereas the Coll.1-expression was significantly downregulated (eg, d21: −4.6-fold). In contrast to resistin and leptin visfatin also reduced the expression of MMP2, MMP13, RunX2, TIMP1 and TIMP2 (eg, d21: −2.4-fold/−3.18 fold/−5.85 fold/−3.2 fold/−4.3 fold respectively) in osteogenic differentiated cells. In contrast to osteogenesis, visfatin significantly increased MMP13 expression (eg, d21: 104-fold) during adipogenic differentiation under standard cell culture conditions, however visfatin induced MMP13-Expression was markedly reduced during differentiation on purified autologous cancellous bone. <h3>Conclusion</h3> Visfatin and leptin were elevated in osteoporotic bone tissue. Visfatin-mediated increase of matrix mineralization and reduction of Coll.1 expression could enhance bone fragility and contribute to the pathogenesis of osteoporosis. Visfatin might impair bone remodelling at the adipose tissue/bone interface through enhancing secretion of proinflammatory factors and dysregulated MMP- and TIMP-expression during MSC-differentiation.
リンパ節におけるシグナル伝達脂質S1Pの勾配が,ナチュラルキラー細胞を配置し,それらのインターフェロンγ応答を調節する
Authors: Fang Victoria, Chaluvadi V Sai, Ramos‐Perez Willy D, Mendoza Alejandra, Baeyens Audrey, Rivera Richard, Chun Jerold, Cammer Michael, Schwab Susan R
Journal: Nature Immunology (2017)
More on idiopathic pulmonary arterial hypertension with a low diffusing capacity
Authors: Karen M. Olsson, Jan Fuge, Katrin Meyer, Tobias Welte, Marius M. Hoeper
Journal: European Respiratory Journal (2017)

Pulmonary arterial hypertension (PAH) is defined by the presence of pre-capillary pulmonary hypertension (PH) in the absence of underlying causes such as lung diseases, chronic thromboembolic pulmonary hypertension (CTEPH) or other rare conditions [1, 2]. While the idiopathic form of PAH (IPAH) was originally described as a disease affecting primarily younger women [3, 4], it is now increasingly being diagnosed in elderly patients, many of whom present with cardiopulmonary comorbidities, which can make the exact diagnostic classification of such patients difficult [5–8]. Elderly patients with IPAH, a smoking history and a low D LCO may suffer from a distinct pulmonary vasculopathy <http://ow.ly/sdGh30dxd0G>