tbuckley/cabot-search huggingface dataset:
Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset
Authors: I Tillie-Leblond, M Wislez, D Valeyre, B Crestani, A Rabbat, D Israel-Biet, M Humbert, L J Couderc, B Wallaert, J Cadranel
Journal: Thorax (2007)

A multicentre retrospective study was undertaken to examine patients with interstitial lung disease (ILD) with the initial clinical manifestation of an anti-synthetase syndrome (anti-Jo-1 antibodies), and to analyse the characteristics and long-term outcome of these patients according to their clinical presentation (acute or gradual onset), treatment and adverse events related to treatment.32 patients, 15 (47%) presenting with acute onset and associated respiratory insufficiency (group A) and 17 (53%) with gradual onset (group G) were examined. Myositis was diagnosed at admission in only 31% of cases and was observed during follow-up in 56% of cases, but the prevalence did not differ between the two groups.Fever and radiological patterns including diffuse patchy ground-glass opacities, basal irregular lines and consolidation on high-resolution CT scan were more frequent in group A than in group G. More patients in group G had neutrophils in the bronchoalveolar lavage fluid and autoantibodies other than anti-Jo-1 (rheumatoid factor, anti SSa/SSb) than in group A. The percentage of patients in whom the ILD improved at 3 months was significantly higher in group A than in group G (13/15 vs 9/17; p = 0.006). In contrast, after 12 months, most patients with ILD progression were in group A and were treated with corticosteroids alone. A combination of corticosteroids and an immunosuppressive drug was required in most cases (84%) at the end of the follow-up period. Severe adverse effects of treatment were observed and varicella zoster virus infection was frequent.Early testing for anti-synthetase antibodies, particularly anti-Jo-1, and creatine kinase determination are useful procedures in patients presenting with ILD. Treatment with corticosteroids and immunosuppressive drugs is required in most patients. At the end of the study, around two-thirds of patients had stable ILD while the other third had disease progression with respiratory insufficiency.
Vitamin K2 therapy for myelodysplastic syndromes (MDS) and post-MDS acute myeloid leukemia: information through a questionnaire survey of multi-center pilot studies in Japan
Authors: K Miyazawa, J Nishimaki, K Ohyashiki, S Enomoto, S Kuriya, R Fukuda, T Hotta, M Teramura, H Mizoguchi, T Uchiyama, M Omine
Journal: Leukemia (2000)
HLA related genetic risk for coeliac disease
Authors: M. Bourgey, G. Calcagno, N. Tinto, D. Gennarelli, P. Margaritte-Jeannin, L. Greco, M. G. Limongelli, O. Esposito, C. Marano, R. Troncone, A. Spampanato, F. Clerget-Darpoux, L. Sacchetti
Journal: Gut (2007)

<b>Background:</b> Several studies have shown an elevated prevalence of coeliac disease (CD) in sibs of coeliac patients (risk 8–12%). <b>Aim and method:</b> We evaluated the risk that sibs of children with CD will also develop CD. This cohort of 188 Italian families was composed of probands with CD, at least one sib and both parents. CD status was determined and human leucocyte antigen (HLA)-DQ genotyping performed in all family members. The study also used a dataset of Italian triads (127 probands and both their parents) also genotyped for HLA-DQ. <b>Results:</b> The overall risk that a sib of a CD patient will develop the disease was estimated at 10% in this sample. The risk estimate ranged from 0.1% to 29% when HLA-DQ information of the proband, parents and sib was considered. We found a negligible risk (lower than 1%) for 40% of the sibs of probands, a risk greater than 1% but less than 10% for 30%, and finally a high or very high risk (above 25%) in one-third of families. <b>Conclusion:</b> These results make it possible to provide more accurate information to parents with a child with CD about the real risk for another child. An antenatal estimate of the order of risk of CD is now possible. Specific follow-up can thus be offered for babies at high risk.
Relation of measures of asthma severity and response to treatment to outcome in acute severe asthma.
Authors: C T Bolliger, P R Fourie, D Kotze, J R Joubert
Journal: Thorax (1992)

It would be helpful if patients with asthma who require admission to hospital for an acute attack could be identified.The relation between the severity of an attack of asthma as determined by admission assessment and the eventual outcome was studied in 52 asthmatic patients aged 14 to 44 years and admitted to an asthma emergency room. The patient's history, including medication and previous admissions to hospital, was recorded and a clinical assessment, including a full inspiratory and expiratory flow-volume loop, was performed on four occasions: on admission, at two hours and at 12-18 hours after the start of a standardised treatment, and two weeks later on an outpatient basis. Patients who were discharged and who had an uneventful follow up at the two week assessment were defined as good responders. Patients who had to be admitted to hospital after 12 to 18 hours or were readmitted during the two weeks, or both, were defined as poor responders.Thirty eight patients were good responders and 14 were poor responders (seven admitted at 12 to 18 hours, seven returned to hospital). All four patients with a raised arterial carbon dioxide tension (PaCO2) (> or = 6 kPa) and the three with cyanosis were in the poor responder group, and this group had lower peak expiratory flow (PEF) values (21% v 30% predicted) on admission. There was, however, considerable overlap in PEF between the two groups and no clinical measure was able to distinguish between the good and the poor responders reliably. Poor responders had a history of more chronic systemic steroid administration, regular use of inhaled beta agonists, and asthma related hospital admissions. Nearly all the subjects showing a good response to standardised treatment had a PEF > 75% predicted and an FEV1 > 65% predicted 12 to 18 hours after the start of treatment.Prediction of outcome at admission was not possible in individual patients. A history of poor long term control of asthma, a PEF < 30% of predicted, a PaCO2 > or = 6 kPa, the presence of cyanosis, and lack of early response to treatment indicated a group of asthmatic patients who are less likely to respond to conventional emergency treatment over a short period.
Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy
Authors: Hiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino
Journal: Journal of the American Society of Nephrology (2012)

Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.
Partial, but not Complete, Tumor-Debulking Surgery Promotes Protective Antitumor Memory when Combined with Chemotherapy and Adjuvant Immunotherapy
Authors: Steve Broomfield, Andrew Currie, Robbert G. van der Most, Matthew Brown, Ivonne van Bruggen, Bruce W.S. Robinson, Richard A. Lake
Journal: Cancer Research (2005)

Resection alone is rarely curative for advanced tumors, but the outcome generally improves with adjuvant therapy. We have previously shown that a combination of traditional chemotherapy (gemcitabine) and immunotherapy (anti-CD40/FGK-45) without surgery is synergistic and can lead to long-term cure when applied to small tumors. Such cured animals have immunologic memory and are protected from rechallenge. Here we investigate the effectiveness of combination chemotherapy and immunotherapy after partial or complete surgical debulking of large tumors. We found that complete resection followed by combination chemotherapy/immunotherapy led to a high rate of cure (>80%) but failed to induce a long-term, tumor-specific memory. Partial debulking followed by combination therapy elicited the same proportion of cured animals but in contrast to complete resection, a memory response was invoked. We postulate that chemotherapy induced apoptosis of the residual tumor cells following incomplete resection is absolutely required for the induction of long-term immunologic memory.
Regulatory T cells control the transition from acute into chronic inflammation in glucose-6-phosphate isomerase-induced arthritis
Authors: O. Frey, A. Reichel, K. Bonhagen, L. Morawietz, U. Rauchhaus, T. Kamradt
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> Glucose-6-phosphate isomerase (G6PI)-induced arthritis is a spontaneously remitting experimental arthritis model. It was hypothesised that regulatory T cells (Tregs) are involved in remission and their role in G6PI-induced arthritis was investigated. <h3>Methods</h3> Tregs were depleted by injection of anti-CD25 before immunisation of DBA/1 mice with G6PI. The severity of arthritis was assessed clinically and histologically and the number and function of G6PI-specific T helper (Th) cells were determined by flow cytometry. Th cells and monocytes/macrophages were depleted using anti-CD4 or clodronate-containing liposomes. <h3>Results</h3> Injection of anti-CD25 depleted Tregs transiently. Normal numbers of Tregs were restored 5 weeks after G6PI immunisation. Whereas arthritis started to resolve in control mice 3 weeks after immunisation with G6PI, severe arthritis was still present in the anti-CD25-treated mice 12 weeks after immunisation. The most striking ex vivo correlate of non-remitting arthritis was a strong increase in G6PI-specific Th cells 3 days after G6PI immunisation. This difference between treated and control mice declined at later time points. Depletion of CD4 cells ameliorated arthritis in controls but not in anti-CD25-treated mice. In contrast, clodronate-containing liposomes were an effective treatment in both groups. <h3>Conclusions</h3> Tregs control the transition from acute self-limiting to non-remitting destructive G6PI-induced arthritis already in the preclinical disease stage. Once established, non-remitting destructive arthritis is not controlled by restoration of normal Treg numbers. These findings question the rationale of therapeutic approaches augmenting Treg number or function in established arthritis.
Early head injury and attention deficit hyperactivity disorder: retrospective cohort study
Authors: H. T Keenan, G. C Hall, S. W Marshall
Journal: BMJ (2008)

<b>Objective</b> To explore the hypothesis that medically attended head injury in young children may be causal in the later development of attention deficit hyperactivity disorder. <b>Design</b> Retrospective cohort study. <b>Setting</b> Health improvement network database (1988-2003), a longitudinal UK general practice dataset. <b>Participants</b> All children registered in the database from birth until their 10th birthday. <b>Main outcome measures</b> Risk of a child with a head injury before age 2 developing attention deficit hyperactivity disorder before age 10 compared with children with a burn injury before age 2 and children with neither a burn nor a head injury. <b>Results</b> Of the 62 088 children who comprised the cohort, 2782 (4.5%) had a head injury and 1116 (1.8%) had a burn injury. The risk of diagnosis of attention deficit hyperactivity disorder before 10 years of age after adjustment for sex, prematurity, socioeconomic status, and practice identification number was similar in the head injury (relative risk 1.9, 95% confidence interval 1.5 to 2.5) and burn injury groups (1.7, 1.2 to 2.5) compared with all other children. <b>Discussion</b> Medically attended head injury before 2 years of age does not seem to be causal in the development of attention deficit hyperactivity disorder. Medically attended injury before 2 years of age may be a marker for subsequent diagnosis of attention deficit hyperactivity disorder.
Implementation of Timeline Reforms Speeds Initiation of National Cancer Institute-Sponsored Trials
Authors: J. S. Abrams, M. M. Mooney, J. A. Zwiebel, E. L. Korn, S. H. Friedman, S. R. Finnigan, P. R. Schettino, A. M. Denicoff, M. G. Kruhm, M. Montello, R. R. Misra, S. S. Ansher, K. J. DiPiazza, E. M. Souhan, D. L. Wickerham, B. J. Giantonio, R. T. O'Donnell, D. M. Sullivan, N. I. Soto, G. F. Fleming, S. A. Prindiville, R. A. Petryshyn, J. A. Hautala, O. Grad, B. L. Zuckerman, R. M. Meyer, J. C. Yao, L. A. Baker, J. C. Buckner, G. N. Hortobagyi, J. H. Doroshow
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundThe National Cancer Institute (NCI) organized the Operational Efficiency Working Group in 2008 to develop recommendations for improving the speed with which NCI-sponsored clinical trials move from the idea stage to a protocol open to patient enrollment.
The translation of cancer genomics: time for a revolution in clinical cancer care
Authors: Elaine R Mardis
Journal: Genome Medicine (2014)

The introduction of next-generation sequencing technologies has dramatically impacted the life sciences, perhaps most profoundly in the area of cancer genomics. Clinical applications of next-generation sequencing and associated methods are emerging from ongoing large-scale discovery projects that have catalogued hundreds of genes as having a role in cancer susceptibility, onset and progression. For example, discovery cancer genomics has confirmed that many of the same genes are altered by mutation, copy number gain or loss, or structural variation across multiple tumor types, resulting in a gain or loss of function that likely contributes to cancer development in these tissues. Beyond these frequently mutated genes, we now know there is a 'long tail' of less frequently mutated, but probably important, genes that play roles in cancer onset or progression. Here, I discuss some of the remaining barriers to clinical translation, and look forward to new applications of these technologies in cancer care.
Development of a New Method for Endovascular Aortic Repair
Authors: Masaki Kajimoto, Takatsugu Shimono, Koji Hirano, Yoichiro Miyake, Yasuhiro Sawada, Noriyuki Kato, Hitoshi Hirata, Kyoko Imanaka-Yoshida, Masakatsu Nishikawa, Toshimichi Yoshida, Hideto Shimpo, Takashi Horiuchi, Keiichi Miyamoto
Journal: Circulation (2006)

Background— Endovascular aortic repair by stent grafts (S/Gs) has been developed as a less invasive treatment for aortic aneurysms. However, some aneurysmal cavities can remain without organization, causing re-expansion. We demonstrated previously that transplantation of a cell combination (myoblasts and fibroblasts) promoted thrombus organization in a rat model. We also developed basic fibroblast growth factor (bFGF) slow-delivery S/Gs coated with elastin and impregnated with bFGF. Here, we evaluated the effects of cell transplantation combined with bFGF slow release on canine thoracic aortic aneurysmal sacs after S/Gs repair. Methods and Results— Thoracic aortic aneurysms were surgically created with jugular vein patches in 15 beagles. Myoblasts and fibroblasts of autologous skeletal muscle were isolated and cultured for cell transplantation. The S/Gs had 6 holes and produced endoleaks in the excluded cavities. Collagen gel (gel group, n=5) or a mixture of skeletal myoblasts and fibroblasts with collagen gel (cell group, n=5) were injected into the aneurysmal sacs excluded by the S/Gs. We also studied the effects of combined therapy of bFGF slow-release S/Gs and cell transplantation (hybrid group, n=5). After 14 days, histological analyses revealed that the excluded aneurysmal cavities of the gel group were filled with fresh thrombus, whereas the excluded cavities in the cell-transplanted groups were occupied by organized tissue. The percentages of the organized areas relative to the excluded cavities, evaluated by Masson’s trichrome staining, were 18.1±4.0%, 52.6±4.0%, and 77.1±6.9% in the gel, cell, and hybrid groups, respectively. Collagen fibers had already appeared, and increased numbers of α-smooth muscle actin-positive cells were observed in the hybrid group. Conclusions— Cell transplantation accelerated thrombus organization. Moreover, slow release of bFGF enhanced the effects of cell transplantation. Cell transplantation into unorganized spaces may improve the outcomes of endovascular treatments of aortic aneurysms.
Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD
Authors: Simon Thom
Journal: JAMA (2013)

Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment.To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C).The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012.Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002).Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline.At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups.Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C.clinicaltrials.gov Identifier: NCT01057537.
A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics
Authors: W Groenewegen
Journal: Cardiovascular Research (2003)

The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A. Objective: The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome. Methods: The human cardiac sodium channel gene SCN5A was screened for mutations by single-stranded conformation polymorphism. The functional consequences of mutant sodium channels were characterized after expressing mutant and wild-type cRNAs in Xenopus oocytes by two-electrode voltage clamp measurements. Results: SCN5A screening revealed an A→G substitution at codon 1768, close to the C-terminal end of domain IVS6, which changes an isoleucine to a valine. Functional expression of mutant I1768V-channels in Xenopus oocytes showed that the voltage-dependence and slope factors of activation and inactivation were unchanged compared to wild-type channels. No difference in persistent TTX-sensitive current could be detected between wild-type and I1768V channels, a channel feature often increased in LQT3 mutants. However, I1768V mutant channels recovered faster from inactivation (2.4 times) than wild-type channels and displayed less slow inactivation. Conclusions: We postulate that severe destabilization of the inactivated state leads to increased arrhythmogenesis and QT prolongation in I1768V mutation carriers in the absence of a persistent inward sodium current.
Intraoperative qRT-PCR for Detection of Lymph Node Metastasis in Head and Neck Cancer
Authors: Robert L. Ferris, Liqiang Xi, Raja R. Seethala, Jon Chan, Shaun Desai, Benjamin Hoch, William Gooding, Tony E. Godfrey
Journal: Clinical Cancer Research (2011)

Sentinel node biopsy (SNB) has been shown to accurately stage the regional lymphatics in oral carcinoma. However, intraoperative pathology is only moderately sensitive and final pathology takes several days to complete. The purpose of this study was to develop a rapid, automated, and quantitative real-time PCR (qRT-PCR) assay that can match final pathology in an intraoperative time frame.Four hundred forty-eight grossly tumor-negative lymph nodes were evaluated for expression of 3 markers [PVA (pemphigus vulgaris antigen), PTHrP (parathyroid hormone-related protein), and TACSTD1 (tumor-associated calcium signal transducer 1)]. Conformity of metastasis detection by qRT-PCR was determined using hematoxylin and eosin and immunohistochemistry staining as the gold standard. PVA and TACSTD1 were then multiplexed with β-glucuronidase to develop a rapid, automated single-tube qRT-PCR assay using the Cepheid GeneXpert system. This assay was used to analyze 103 lymph nodes in an intraoperative time frame.Four hundred forty-two nodes produced an informative result for both qRT-PCR and pathologic examination. Concordance of qRT-PCR for individual markers with final pathology ranged from 93% to 98%. The best marker combination was TACSTD1 and PVA. A rapid, multiplex assay for TACSTD1 and PVA was developed on the Cepheid GeneXpert and demonstrated an excellent reproducibility and linearity. Analysis of 103 lymph nodes demonstrated 94.2% accuracy of this assay for identifying positive and negative nodes. The average time for each assay to yield results was 35 minutes.A rapid, automated qRT-PCR assay can detect lymph node metastasis in head and neck cancer with high accuracy compared to pathologic analysis and may be more accurate than intraoperative pathology. Combined, SNB and rapid qRT-PCR could more appropriately guide surgical treatment of patients with head and neck cancer.