tbuckley/cabot-search huggingface dataset:
Poor Prognosis of Young Adults With Type 1 Diabetes
Authors: Kathryn S. Bryden, David B. Dunger, Richard A. Mayou, Robert C. Peveler, H. Andrew W. Neil
Journal: Diabetes Care (2003)

OBJECTIVE—To determine the role of early behavioral and psychological factors on later outcomes in young adults with childhood- or adolescent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS—We conducted a longitudinal cohort study of patients recruited from the register of the young adult outpatient diabetes clinic, Oxford, U.K. A total of 113 individuals (51 male subjects) aged 17–25 years completed assessments, and 87 (77%) were reinterviewed as older adults (aged 28–37 years). Longitudinal assessments were made of glycemic control (HbA1c) and complications. Psychological state at baseline was assessed using the Present State Examination and self-report Symptom Checklist, with corresponding interview schedules administered at follow-up. RESULTS—There was no significant improvement between baseline and follow-up in mean HbA1c levels (8.5 vs. 8.6% in men, 9.3 vs. 8.7% in women). The proportion of individuals with serious complications (preproliferative or laser-treated retinopathy, proteinuria or more severe renal disease, peripheral neuropathy, and autonomic neuropathy) increased from 3–37% during the 11-year period. Women were more likely than men to have multiple complications (23 vs. 6%, difference 17%, 95% CI 4–29%, P = 0.02). Psychiatric disorders increased from 16 to 28% (20% in men, 36% in women at follow-up, difference NS), and 8% had psychiatric disorders at both assessments. Baseline psychiatric symptom scores predicted follow-up scores (β = 0.32, SE [β] 0.12, P = 0.008, 95% CI 0.09–0.56) and recurrent admissions with diabetic ketoacidosis (odds ratio 9.1, 95% CI 2.9–28.6, P &amp;lt; 0.0001). CONCLUSIONS—The clinical and psychiatric outcome in this cohort was poor. Psychiatric symptoms in later adolescence and young adulthood appeared to predict later psychiatric problems.
Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis
Authors: Maurits C F J de Rotte, Ethan den Boer, Pascal H P de Jong, Saskia M F Pluijm, Maja Bulatović Ćalasan, Angelique E Weel, A Margriet Huisman, Andreas H Gerards, Barbara van Schaeybroeck, Nico M Wulffraat, Jan Lindemans, Johanna M W Hazes, Robert de Jonge
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events. <h3>Methods</h3> We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1–5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication. <h3>Results</h3> In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=−0.005), MTX-PG2 (ß=−0.022), MTX-PG3 (β=−0.007) and total MTX-PG (ß=−0.004) were associated (p&lt;0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=−0.015), MTX-PG3 (ß=−0.010), MTX-PG4 (ß=−0.008) and total MTX-PG (ß=−0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events. <h3>Conclusions</h3> In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA.
A major histocompatibility complex class I–dependent subset of memory phenotype CD8+ cells
Authors: Onur Boyman, Jae-Ho Cho, Joyce T. Tan, Charles D. Surh, Jonathan Sprent
Journal: The Journal of Experimental Medicine (2006)

Most memory phenotype (MP) CD44(hi) CD8(+) cells are resting interleukin (IL)-15-dependent cells characterized by high expression of the IL-2/IL-15 receptor beta (CD122). However, some MP CD8(+) cells have a CD122(lo) phenotype and are IL-15 independent. Here, evidence is presented that the CD122(lo) subset of MP CD8(+) cells is controlled largely by major histocompatibility complex (MHC) class I molecules. Many of these cells display surface markers typical of recently activated T cells (CD62L(lo), CD69(hi), CD43(hi), and CD127(lo)) and show a high rate of background proliferation. Cells with this phenotype are highly enriched in common gamma chain-deficient mice and absent from MHC-I(-/-) mice. Unlike CD122(hi) CD8(+) cells, CD122(lo) MP CD8(+) cells survive poorly after transfer to MHC-I(-/-) hosts and cease to proliferate. Although distinctly different from typical antigen-specific memory cells, CD122(lo) MP CD8(+) cells closely resemble the antigen-dependent memory CD8(+) cells found in chronic viral infections.
Postmenopausal Hormone Replacement Therapy and the Primary Prevention of Cardiovascular Disease
Authors: Linda L. Humphrey, Benjamin K.S. Chan, Harold C. Sox
Journal: Annals of Internal Medicine (2002)

Purpose: To evaluate the value of hormone replacement therapy (HRT) in the primary prevention of cardiovascular disease (CVD) and coronary artery disease (CAD). Data Sources: MEDLINE and Cochrane databases were searched for all primary prevention studies reporting CVD or CAD incidence, mortality, or both in association with HRT; reference lists, letters, editorials, and reviews were also reviewed. Data Extraction: All studies were reviewed, abstracted, and rated for quality. Study Selection: Only studies of good or fair quality, according to U.S. Preventive Services Task Force (USPSTF) criteria, were included in the detailed review and meta-analysis. Data Synthesis: The summary relative risk with any HRT use was 0.75 (95% credible interval [CrI], 0.42 to 1.23) for CVD mortality and 0.74 (CrI, 0.36 to 1.45) for CAD mortality. The summary relative risk with any use was 1.28 (CrI, 0.86 to 2.00) for CVD incidence and 0.87 (CrI, 0.62 to 1.21) for CAD incidence. Further analysis of studies adjusting for socioeconomic status, as well as other major CAD risk factors, showed a summary relative risk of 1.07 (CrI, 0.79 to 1.48) for CAD incidence associated with any HRT use. Similar results were found when the analysis was stratified by studies adjusting for alcohol consumption, exercise, or both, in addition to other major risk factors, suggesting confounding by these factors. Conclusions: This meta-analysis differs from previous meta-analyses by evaluating potential explanatory variables of the relationship between HRT, CVD, and CAD. The adjusted meta-analysis is consistent with recent randomized trials that have shown no benefit in the secondary or primary prevention of CVD events. A valid answer to the role of HRT in the primary prevention of CVD will best come from randomized, controlled trials.
Gonococcal pilus subunit size heterogeneity correlates with transitions in colony piliation phenotype, not with changes in colony opacity.
Authors: J Swanson, O Barrera
Journal: The Journal of Experimental Medicine (1983)

The apparent subunit sizes for pili of gonococci (Gc) have been visualized by using either Iodogen 125I-labeled whole Gc or immunoblotting with antipilus antiserum. These methods permitted definition of pilus subunit sizes for Gc of a given strain that had undergone changes either in piliation phenotype or in colonial opacity/protein II phenotype. The results indicate that pilus subunit size does not change coincident with changes in colony opacity/protein II phenotypes; but change in pilus subunit size is seen after a change in piliation phenotype (P+ leads to P++, and vice versa). Marked diversity in pilus subunit sizes is found for Gc of individual strains when P+ derivatives of P- colonies are compared. This diversity extends to pilus subunits of Gc found in single colonies; two distinct pilus forms were demonstrated for Gc residing in several single colonies. These findings show that Gc of a given strain are able to express any of a number of different pilus subunit size forms.
Aggravating cough in a patient with suspected sarcoidosis
Authors: Jonas Yserbyt, Vincent Ninane
Journal: Thorax (2012)

A middle-aged patient with a recent history of a complete surgical resection of a nodular melanoma of the lower back, was referred to the clinic because of increasing exertional dyspnoea. A chest CT showed multiple enlarged mediastinal adenopathies with a micronodular interstitial pattern (figure 1). Transbronchial biopsies revealed non caseating granulomas. Moreover, because ofatrioventricular junctional arrhythmia, an MRI scan of the heart was performed, which showed myocardial granulomas. Sarcoidosis was diagnosed and treated with steroids.



Figure 1 
Chest CT scan showing an enlargement of multiple mediastinal adenopathies, with a multinodular interstitial pattern of perilymphatic distribution on top, predominantly on the right side.



Because of the aggravating cough, a second flexible bronchoscopy was performed four months later this and showed a dark …
Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease
Authors: Cynthia A. Moylan, Herbert Pang, Andrew Dellinger, Ayako Suzuki, Melanie E. Garrett, Cynthia D. Guy, Susan K. Murphy, Allison E. Ashley-Koch, Steve S. Choi, Gregory A. Michelotti, Daniel D. Hampton, Yuping Chen, Hans L. Tillmann, Michael A. Hauser, Manal F. Abdelmalek, Anna Mae Diehl
Journal: Hepatology (2013)

Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, “mild” NAFLD patients (fibrosis stage 0–1; n = 40) and high-risk, “severe” NAFLD patients (fibrosis stage 3–4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. Conclusion : By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality. (Hepatology 2014;59:471–482)
Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma
Authors: Michelle L. Gumz, Hongzhi Zou, Pamela A. Kreinest, April C. Childs, Leandra S. Belmonte, Shauna N. LeGrand, Kevin J. Wu, Bruce A. Luxon, Mala Sinha, Alexander S. Parker, L-Z. Sun, David A. Ahlquist, Christopher G. Wood, John A. Copland
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling. Experimental Design: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1 loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized. Results: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1 occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1 in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice. Conclusions: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1 as a tumor suppressor in cRCC and that perhaps loss of sFRP1 is an early, aberrant molecular event in renal cell carcinogenesis.
An investigation of the support required for development of high performance swimmers
Authors: L A Algar, A MacNamara
Journal: British Journal of Sports Medicine (2011)

It is important that the support structures offered to young athletes provide the skills, structures and environmental factors that act as key determinants and mechanisms of development. Baker and Horton (2004) suggest that there are both primary (ie, genetics, training, and psychological factors) and secondary (ie, socio-cultural factors and contextual factors) influences on talent development. Reflecting the latter, this study examined the effect of social, physical and life-skill factors within a high performance (HP) environment. Semi-structured, qualitative interviews were held with a group of swimmers (n = 7), purposefully sampled on the basis of their established potential for elite performance. To triangulate the data, and guard against bias, a sample of coaches (n=7) and support staff (n = 2) were also recruited. An inductive content analysis was conducted following the recommendations of Coté et al (1993). Results suggest that a range of factors (eg, parental support, medical services, and time-management skills) impact on an athlete's ability to progress through a development programme and succeed as an elite athlete. Coach communication and the development of performance coaches were both identified as areas of weakness in the current support system. The coaches felt inadequately equipped with the skills and knowledge to develop HP athletes, and recommended a more ‘open door' policy between clubs and in turn between club and the HP Centre. This policy could rectify another key deficient issue identified by coaches and athletes by ‘bridging the gap' from club to HP Centre where talented athletes are not equipped, either physically or mentally, to deal with the increased demand and change in environment. Further research is currently taking place to track the needs analysis of HP athletes over the course of a year in the lead up to World Championship qualification.
Involvement of p59fynT in interleukin-5 receptor signaling.
Authors: M W Appleby, J D Kerner, S Chien, C R Maliszewski, S Bondada, R M Perlmutter, S ] Bondadaa S [corrected to Bondada
Journal: The Journal of Experimental Medicine (1995)

Previous studies implicate the nonreceptor protein tyrosine kinase (PTK) p59fyn in the propagation of signals from the B cell antigen receptor. To elucidate the functions of this kinase, we examined B cell responsiveness in mice engineered to lack the hematopoietic isoform of p59fyn. Remarkably, antigen receptor signaling was only modestly defective in fynTnull B cells. In contrast, signaling from the interleukin (IL)-5 receptor which ordinarily provides a comitogenic stimulus with antiimmunoglobulin, was completely blocked. Our results document the importance of p59fynT in IL-5 responses in B cells, and they support a general model for cytokine receptor signal transduction involving the simultaneous recruitment of at least three families of PTK.
MicroRNAs in lung diseases: Figure 1
Authors: Tom Pagdin, Paul Lavender
Journal: Thorax (2011)

The advent of RNA sequencing technology has stimulated rapid advances in our understanding of the transcriptome, including discovery of the vast RNA complement generated by transcript splice variation and the expansion of our knowledge of non-coding RNAs. One non-coding RNA subtype, microRNAs (miRNAs), are particularly well studied, primarily because of their important roles as post-transcriptional gene regulators. The first miRNA was identified in the early 1990s and there are now thought to be around 1000 distinct miRNAs in man, with each cell type expressing a distinct repertoire. Increasing evidence has implicated miRNAs as having causative roles in a variety of lung diseases and has driven investigations into their potential as therapeutic targets.
Reality check: the cost–effectiveness of removing body checking from youth ice hockey
Authors: Sarah Lacny, Deborah A Marshall, Gillian Currie, Nathalie A Kulin, Willem H Meeuwisse, Jian Kang, Carolyn A Emery
Journal: British Journal of Sports Medicine (2014)

Background/aim The risk of injury among Pee Wee (ages 11–12 years) ice hockey players in leagues that allow body checking is threefold greater than in leagues that do not allow body checking. We estimated the cost–effectiveness of a no body checking policy versus a policy that allows body checking in Pee Wee ice hockey. Methods Cost–effectiveness analysis alongside a prospective cohort study during the 2007–2008 season, including players in Quebec (n=1046), where policy did not allow body checking, and in Alberta (n=1108), where body checking was allowed. Injury incidence rates (injuries/1000 player-hours) and incidence proportions (injuries/100 players), adjusted for cluster using Poisson regression, allowed for standardised comparisons and meaningful translation to community stakeholders. Based on Alberta fee schedules, direct healthcare costs (physician visits, imaging, procedures) were adjusted for cluster using bootstrapping. We examined uncertainty in our estimates using cost–effectiveness planes. Results Associated with significantly higher injury rates, healthcare costs where policy allowed body checking were over 2.5 times higher than where policy disallowed body checking ($C473/1000 player-hours (95% CI $C358 to $C603) vs $C184/1000 player-hours (95% CI $C120 to $C257)). The difference in costs between provinces was $C289/1000 player-hours (95% CI $C153 to $C432). Projecting results onto Alberta Pee Wee players registered in the 2011–2012 season, an estimated 1273 injuries and $C213 280 in healthcare costs would be avoided during just one season with the policy change. Conclusion Our study suggests that a policy disallowing body checking in Pee Wee ice hockey is cost-saving (associated with fewer injuries and lower costs) compared to a policy allowing body checking. As we did not account for long-term outcomes, our results underestimate the economic impact of these injuries.
Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome
Authors: M Rook
Journal: Cardiovascular Research (1999)

Primary dysrhythmias other than those associated with the long QT syndrome, are increasingly recognized. One of these are represented by patients with a history of resuscitation from cardiac arrest but without any structural heart disease. These patients exhibit a distinct electrocardiographic (ECG) pattern consisting of a persistent ST-segment elevation in the right precordial leads often but not always accompanied by a right bundle branch block (Brugada syndrome). This syndrome is associated with a high mortality rate and has been shown to display familial occurrence.Pharmacological sodium channel blockade elicits or worsens the electrocardiographic features associated with this syndrome. Hence, a candidate gene approach directed towards SCN5A, the gene encoding the alpha-subunit of the cardiac sodium channel, was followed in six affected individuals. In two patients missense mutations were identified in the coding region of the gene: R1512W in the DIII-DIV cytoplasmic linker and A1924T in the C-terminal cytoplasmic domain. In two other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wild-type and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function, most notably a 4-5 mV negative voltage shift of the steady-state activation and inactivation curves in R1512W and a 9 mV negative voltage shift of the steady-state activation curve in A1924T, measured at 22 degrees C. Recovery from inactivation was slightly prolonged for R1512W channels. The time dependent kinetics of activation and inactivation at -20 mV were not significantly affected by either mutation.Two SCN5A mutations associated with the Brugada syndrome, significantly affect cardiac sodium channel characteristics. The alterations seem to be associated with an increase in inward sodium current during the action potential upstroke.
Crohn's disease of the distal ileum.
Authors: C S Higgens, R N Allan
Journal: Gut (1980)

A clinical and statistical analysis has been undertaken in a consecutive series of 227 patients with Crohn9s disease involving the distal ileum under long-term review between 1944 and 1978. We have determined the long-term prognosis, cumulative reoperation rates after each resection, mortality rates, and their causes. Actuarial analysis has shown that the reoperation rates are similar after first, second, and third resections. There was no evidence that additional operations increase the risk of yet more resections. Reoperation rates were very little influenced by the age at diagnosis of the underlying Crohn9s disease. A short interval from diagnosis of Crohn9s disease to the first resection tended to increase the reoperation rate in the short term but there was no overall long-term effect. There was a two-fold increase in mortality risk when compared with the general population. Half the deaths were unrelated to the underlying Crohn9s disease and, in this group, the incidence and causes were similar to those expected in the general population matched for age, sex, and years at risk. Of the disease related deaths many occurred in the early years of experience. Only four patients in the series have died of Crohn9s disease in the last 10 years. One hundred and ninety-three patients are still alive after a mean interval of 16.1 years from the diagnosis of Crohn9s disease. Full information is available on 185, of whom 161 are well and symptom free. Seven have minor problems, while 17 are unwell (nine with radiological evidence of recurrent disease).