tbuckley/cabot-search huggingface dataset:
A Quantitative Trait Locus Analysis of Social Responsiveness in Multiplex Autism Families
Authors: Jacqueline A. Duvall, Ake Lu, Rita M. Cantor, Richard D. Todd, John N. Constantino, Daniel H. Geschwind
Journal: American Journal of Psychiatry (2007)

Autism is a complex genetic disorder with a highly heterogeneous phenotype defined by repetitive behaviors, language deficits, and problems with reciprocal social interactions. The authors present the first genome-wide scan for a social endophenotype in autism using the Social Responsiveness Scale, which provides a quantitative measure of autistic-like behavior, primarily focused on social relatedness.A nonparametric quantitative genome scan was performed using the Social Responsiveness Scale in a cohort of about 100 families with two or more autistic probands from the Autism Genetic Resource Exchange to identify autism loci. To determine which additional loci were detected, linkage analysis with the same autism cohort using the qualitative diagnosis of autism was performed. To assess whether there were likely to be sex-specific genetic risk factors, the cohort was stratified by the sex of affected individuals.The quantitative Social Responsiveness Scale genome scan identified two loci on chromosomes 11 and 17, with the highest score on chromosome 11 (z=3.22). In contrast, no linkage signals reached significance in the Autism Diagnostic Interview-Revised qualitative scan. The Social Responsiveness Scale scan with only male affected identified the same signals on chromosomes 11 and 17, as well as three other regions on chromosomes 4, 8, and 10.This study demonstrates the utility of the Social Responsiveness Scale quantitative endophenotype to detect autism-related genetic loci using quantitative behavioral information that may more closely relate to underlying genetic factors.
Telaprevir‐based treatment effects on hepatitis C virus in liver and blood
Authors: Andrew H. Talal, Rositsa B. Dimova, Eileen Z. Zhang, Min Jiang, Marina S. Penney, James C. Sullivan, Martyn C. Botfield, Ananthsrinivas Chakilam, Rishikesh Sawant, Christine M. Cervini, Marija Zeremski, Ira M. Jacobson, Ann D. Kwong
Journal: Hepatology (2014)

Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments.These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.
Cardiovascular comorbidities antedating the diagnosis of rheumatoid arthritis
Authors: Anne M Kerola, Tuomas Kerola, Markku J Kauppi, Hannu Kautiainen, Lauri J Virta, Kari Puolakka, Tuomo V M Nieminen
Journal: Annals of the Rheumatic Diseases (2012)

To assess the prevalence of coronary heart disease (CHD) and chronic hypertension among patients with rheumatoid arthritis (RA) at the time of diagnosis, in comparison with age-specific and sex-specific non-RA subjects. Furthermore, the impacts of age at the onset of RA, as well as gender and the presence of rheumatoid factor (RF) on the risk of these comorbidities, were evaluated.A cohort of 7209 RA patients diagnosed between January 2004 and December 2007 was identified, based on a Finnish nationwide register on special reimbursements for medication costs. The presence of CHD and chronic hypertension antedating the diagnosis of RA was identified from the same register. The prevalence of the cardiovascular comorbidities was compared with the general Finnish population, and a standardised rate ratio (SRR) for both these cardiovascular diseases was calculated.The risk of having CHD at RA diagnosis was slightly elevated, the SRR being 1.10 (95% CI 1.01 to 1.20). Younger age at the onset of RA seemed to be related with higher SRR for CHD. In a subset analysis, an increased prevalence of hypertension (SRR 1.19, 95% CI 1.10 to 1.30) and CHD (SRR 1.15, 95% CI 1.00 to 1.32) was apparent only among the RF negative RA cases.The SRR for CHD is augmented in RA patients already at disease onset, and more pronouncedly in early onset RA. The findings highlight the importance of early prevention of atherosclerosis, regardless of RF status.
S1 TOMADO: A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea
Authors: TG Quinnell, MA Pittman, M Bennett, J Jordan, AL Clutterbuck-James, CL East, MG Davies, N Oscroft, M Cameron, R Chadwick, IE Smith, M Morrell, M Glover, JA Fox-Rushby, LD Sharples
Journal: Thorax (2013)

<h3>Introduction</h3> Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness (EDS), impairs quality of life (Qol), and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure therapy is effective but undermined by intolerance and cost effectiveness is borderline in milder cases. Mandibular Advancement Devices (MADs) are another treatment option but evidence is lacking regarding their effectiveness compared to no treatment in milder disease. This study compared clinical and cost effectiveness of a range of MADs and no treatment in these patients. <h3>Methods</h3> This 4-period, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with mild to moderate OSAH and EDS (Apnoea-Hypopnoea Index (AHI) 5-&lt;30/hour; Epworth Sleepiness Scale score (ESS) &gt; = 9) underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SP1); semi-bespoke (SP2); fully-bespoke (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment and analysed by intention to treat. Secondary outcomes included ESS and QoL. Cost effectiveness was evaluated using validated tools, treatment costs and healthcare usage. <h3>Results</h3> Ninety patients were recruited. Sixteen withdrew before trial end. Seven did not complete any treatment and were excluded from analyses. All devices reduced AHI against no treatment, by 26% (95%CI 11%, 38%, p = 0.001) for SP1 to 36% (95%CI 24%, 45%, p &lt; 0.001) for bMAD. ESS was 1.51 (SP1) to 2.37 (bMAD) lower versus no treatment (p &lt; 0.001 for all). Compliance was lower for SP1 which was unpopular at trial exit. All devices were cost-effective compared with no treatment at a willingness to pay (WTP) of £20,000/quality-adjusted life year (QALY), based on mean costs and QALYs. SP2 was most cost-effective up to a WTP of £39,800/QALY after which, bMAD superseded it. Serious adverse events occurred in four patients (4%). <h3>Conclusions</h3> Mandibular Advancement Devices achieve clinically important improvements in mild to moderate OSAH syndrome and are cost effective. A semi-bespoke non-adjustable MAD would appear to be the appropriate first choice in most patients. Future work should explore whether adjustable MADs give additional clinical and cost benefits in this patient group. <h3>Funding</h3> NIHR Health Technology Assessment Programme, UK.
Marathon Rat
Authors: Paul G.A. Volders
Journal: Circulation (2010)

adaptation to intensive exercise has long intrigued cardiologists and physiologists, particularly in relation to the notion that different types of exercise drive divergent remodeling.On the basis of a meta-analysis of 59 echocardiographic studies (including 1451 male athletes 18 to 40 years of age), Pluim et al 1 concluded that endurance-trained runners, who are known to develop eccentric cardiac hypertrophy, demonstrated a more pronounced left ventricular (LV) wall thickening than expected.Strength-trained sportsmen showed an unanticipated increase in LV internal diameter besides concentric cardiac hypertrophy.These adaptations accounted for a higher LV mass, whereas no differences were found between athletes and nonathletes regarding LV ejection fraction, fractional shortening, and early and late ventricular filling velocity ratio.Recently, Pelliccia and colleagues 2 reported on a longitudinal assessment in young Olympic athletes engaged in rowing, canoeing, cycling, middle-and long-distance running, cross-country skiing, swimming, or participating in triathlons.The investigators concluded that extreme endurance training over long stretches of time (4 to 17 years) was not associated with significant changes in LV shape and function or the occurrence of cardiovascular symptoms and events.However, this unique study has been criticized for including only athletes who had undergone mandatory cardiovascular screening before enrollment, so those already having exercise-induced cardiac abnormalities would have been excluded. 3A second criticism was that no analysis of the right ventricle (RV) was performed, although extreme exercise can cause RV dysfunction and arrhythmias. 3Generally, the risk of primary cardiac arrest is increased among men with infrequent vigorous exercise, whereas, for those exercising habitually, the overall risk is decreased.There is a striking male predominance of sudden death among athletes.
Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma.
Authors: H Hisamatsu, N Shimbara, Y Saito, P Kristensen, K B Hendil, T Fujiwara, E Takahashi, N Tanahashi, T Tamura, A Ichihara, K Tanaka
Journal: The Journal of Experimental Medicine (1996)

Interferon (IFN) gamma induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity. We found a third pair of proteasome subunits expressed reciprocally in response to IFN-gamma. Molecular cloning of a cDNA encoding one subunit designated as Z, downregulated by IFN-gamma, showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by IFN-gamma. Thus, IFN-gamma induces subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for immunological processing of endogenous antigens. When processed from their precursors, three pairs of the 10 homologous, but distinct, beta-type subunits of eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2-terminal threonine residue, assumed to be part of a catalytic center. These findings suggest that the altered molecular organization of the proteasome induced by IFN-gamma may be responsible for acquisition of its functional change.
Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy
Authors: J. Grisar, D. Aletaha, C. W Steiner, T. Kapral, S. Steiner, M. Saemann, I. Schwarzinger, B. Buranyi, G. Steiner, J. S Smolen
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> To study the effects of short-term intermediate dose glucocorticoid (GC) therapy in patients with active rheumatoid arthritis (RA) on circulating endothelial progenitor cells (EPC), which are known to influence cardiovascular risk, and to elucidate mechanisms potentially responsible for the reduction of EPCs in patients with active RA. <h3>Methods:</h3> EPCs were quantified in 29 patients with active RA by flow cytometry, colony forming unit (CFU) and circulating angiogenic cell (CAC) assays before and after 7 days of intermediate dose GC therapy. CFU from patients with RA and from healthy referents (HR) were cultured in vitro in the absence or presence of dexamethasone (Dex) and/or TNF. <h3>Results:</h3> After 1 week of GC therapy, EPC increased from 0.026 (SD 0.003)% to 0.053 (SD 0.010)% (p&lt;0.01), and from 12 (SD 4) to 27 (SD 7) CFU/well (p&lt;0.02); CAC also increased from 7 (SD 2) to 29 (SD 8) cells/high power field (p&lt;0.05). In parallel, disease activity decreased significantly after GC treatment. TNF serum levels also decreased from 36 (SD 10) to 14 (SD 6) pg/ml (p&lt;0.0001). Addition of Dex to the RA CFU led to a significant increase of mean CFU counts, whereas addition of TNF induced a decrease of CFU. <h3>Conclusions:</h3> Our data indicate that TNF may be at least partly responsible for the reduction of EPC seen in patients with RA. Intermediate doses of GCs for a short period of time, apart from reducing disease activity, significantly increase circulating EPC.
Urinary Angiotensinogen Level Predicts AKI in Acute Decompensated Heart Failure
Authors: Xiaobing Yang, Chunbo Chen, Jianwei Tian, Yan Zha, Yuqin Xiong, Zhaolin Sun, Pingyan Chen, Jun Li, Tiecheng Yang, Changsheng Ma, Huafeng Liu, Xiaobin Wang, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2015)

A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of high-performance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiver-operating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase-associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF.
Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice.
Authors: N S Yee, I Paek, P Besmer
Journal: The Journal of Experimental Medicine (1994)

The receptor tyrosine kinase Kit and its cognate ligand KL/steel factor are encoded at the white spotting (W) and Steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl loci affect hematopoiesis including the stem cell hierarchy, erythropoiesis, and mast cells, as well as gametogenesis and melanogenesis. In addition, mutant mice display an increased sensitivity to lethal doses of irradiation. The role of KL/c-kit in cell proliferation and survival under conditions of growth factor-deprivation and gamma-irradiation was studied by using bone marrow-derived mast cells (BMMC) as a model. Whereas apoptosis induced by growth factor deprivation in BMMC is a stochastic process and follows zero order kinetics, gamma-irradiation-induced apoptosis is an inductive process and follows higher order kinetics. In agreement with these results, gamma-irradiation-induced apoptosis in BMMC was shown to be dependent on p53 whereas apoptosis induced by deprivation is partly dependent on p53, implying that there are other mechanisms mediating apoptosis in KL-deprived BMMC. In the presence and in the absence of serum, KL stimulated proliferation by promoting cell cycle progression. The presence of KL was required only during the early part of the G1 phase for entry into the S phase. At concentrations lower than those required for proliferation, KL suppressed apoptosis induced by both growth factor-deprivation and gamma-irradiation, and internucleosomal DNA fragmentation characteristic of apoptosis. The ability of KL to suppress apoptosis was independent of the phase of the cell cycle in which the cells were irradiated and suppression of apoptosis was a prerequisite for subsequent cell cycle progression. Moreover, addition of KL to gamma-irradiated and growth factor-deprived cells could be delayed for up to 1 h after irradiation or removal of growth factors when cells became irreversibly committed to apoptosis. KL and IL-3 induce suppression of apoptosis in mast cells by different mechanisms based on the observations of induction of bcl-2 gene expression by IL-3 but not by KL. It is proposed that the increased sensitivity of W and Sl mutant mice to lethal irradiation results from paucity of the apoptosis suppressing and proliferative effects of KL.
Management of the Child with a Serious Infection or Severe Malnutrition. Guidelines for Care at the First-Referral Level in Developing Countries
Authors: C DOHERTY
Journal: Gut (2001)

<h3>Objective.</h3> Youth with systemic lupus erythematosus (SLE) transferring from pediatric to adult care are at risk for poor outcomes. We describe patterns of rheumatology/nephrology care and changes in healthcare use and medication adherence during transfer. <h3>Methods.</h3> We identified youth ages 15–25 with SLE using US private insurance claims from Optum’s deidentified Clinformatics Data Mart. Rheumatology/nephrology visit patterns were categorized as (1) unilateral transfers to adult care within 12 months, (2) overlapping pediatric and adult visits, (3) lost to followup, or (4) continuing pediatric care. We used negative binomial regression and paired t tests to estimate changes in healthcare use and medication possession ratios (MPR) after the last pediatric (index) visit. We compared MPR between youth who transferred and age-matched peers continuing pediatric care. <h3>Results.</h3> Of the 184 youth transferred out of pediatric care, 41.8% transferred unilaterally, 31.5% had overlapping visits over a median of 12 months before final transfer, and 26.6% were lost to followup. We matched 107 youth continuing pediatric care. Overall, ambulatory care use decreased among those lost to followup. Acute care use decreased across all groups. MPR after the index date were lower in youth lost to followup (mean 0.24) compared to peers in pediatric care (mean 0.57, p &lt; 0.001). <h3>Conclusion.</h3> Youth with SLE with continuous private insurance coverage do not use more acute care after transfer to adult care. However, a substantial proportion fail to see adult subspecialists within 12 months and have worse medication adherence, placing them at higher risk for adverse outcomes.
Is gastric cancer preventable?
Authors: P Correa
Journal: Gut (2004)

Gastric cancer is a major health burden worldwide and prevention is the most promising strategy to control the disease. The available scientific evidence indicates that curing <i>Helicobacter pylori</i> infection results in a modest retardation of the precancerous process but does not prevent all cancers. Individuals at the highest risk should be cured of their infection and monitored endoscopically to detect dysplasia and "early" cancer, amenable to successful treatment.
Tumor Growth Rate Is an Early Indicator of Antitumor Drug Activity in Phase I Clinical Trials
Authors: Charles Ferté, Marianna Fernandez, Antoine Hollebecque, Serge Koscielny, Antonin Levy, Christophe Massard, Rastislav Balheda, Brian Bot, Carlos Gomez-Roca, Clarisse Dromain, Samy Ammari, Jean-Charles Soria
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Experimental Design: Medical records from all patients (N = 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores [Royal Marsden Hospital (RMH) score], and outcome [progression-free survival (PFS) and overall survival (OS)] were computed (multivariate analysis). Results: We observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P &amp;lt; 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P = 0.004), whereas the RMH score was the only variable associated with OS (P = 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P &amp;lt; 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity. Conclusions: Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs. Clin Cancer Res; 20(1); 246–52. ©2013 AACR.