tbuckley/cabot-search huggingface dataset:
Elevated Aortic Pulse Wave Velocity, a Marker of Arterial Stiffness, Predicts Cardiovascular Events in Well-Functioning Older Adults
Authors: Kim Sutton-Tyrrell, Samer S. Najjar, Robert M. Boudreau, Lakshmi Venkitachalam, Varant Kupelian, Eleanor M. Simonsick, Richard Havlik, Edward G. Lakatta, Harold Spurgeon, Stephen Kritchevsky, Marco Pahor, Douglas Bauer, Anne Newman
Journal: Circulation (2005)

Background— Aging results in vascular stiffening and an increase in the velocity of the pressure wave as it travels down the aorta. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. The objective of this investigation was to determine whether aPWV is associated with total and cardiovascular (CV) mortality and CV events in a community-dwelling sample of older adults. Methods and Results— aPWV was measured at baseline in 2488 participants from the Health, Aging and Body Composition (Health ABC) study. Vital status, cause of death and coronary heart disease (CHD), stroke, and congestive heart failure were determined from medical records. Over 4.6 years, 265 deaths occurred, 111 as a result of cardiovascular causes. There were 341 CHD events, 94 stroke events, and 181 cases of congestive heart failure. Results are presented by quartiles because of a threshold effect between the first and second aPWV quartiles. Higher aPWV was associated with both total mortality (relative risk, 1.5, 1.6, and 1.7 for aPWV quartiles 2, 3, and 4 versus 1; P =0.019) and cardiovascular mortality (relative risk, 2.1, 3.0, and 2.3 for quartiles 2, 3, and 4 versus 1; P =0.004). aPWV quartile was also significantly associated with CHD ( P =0.007) and stroke ( P =0.001). These associations remained after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events. Conclusions— Among generally healthy, community-dwelling older adults, aPWV, a marker of arterial stiffness, is associated with higher CV mortality, CHD, and stroke.
Structure, expression, and genomic mapping of the mouse natriuretic peptide type-B gene.
Authors: M E Steinhelper
Journal: Circulation Research (1993)

The structure of the mouse natriuretic peptide type-B (BNP) gene was determined by isolating and sequencing genomic clones. The mouse BNP gene was structurally similar to other natriuretic peptide genes and comprised three exons and two introns. Expression of the mouse BNP gene was found only in cardiac tissue as determined by ribonuclease protection analyses. Initiation of transcription was 31 bp downstream from a consensus TATA box as determined by primer extension analysis of cardiac RNA. Comparative DNA sequence analysis identified several DNA elements with potential transcriptional regulatory function. Comparative amino acid sequence analysis showed that the N-terminal portion of the mouse and rat BNP precursors was more conserved than the C-terminal 45-amino-acid sequence that constitute the bioactive BNP-45 peptide. The proteolytic processing site (RXXR-S) generating bioactive BNPs was highly conserved among all BNP precursors and was identical to the consensus site of furin, a calcium-dependent serine endoprotease. Finally, the BNP gene was mapped using recombinant inbred DNA and a polymerase chain reaction-based restriction fragment-length polymorphism assay to mouse chromosome 4 near the atrial natriuretic factor (Anf) locus. No recombination event between Bnp and Anf was evident in the 39 recombinant inbred and inbred strains examined. This physical linkage between the two natriuretic peptide genes expressed in cardiac tissue may be important for their transcriptional regulation.
VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth
Authors: Wen Hou, Dan Medynski, Shirley Wu, Xinli Lin, Lu-Yuan Li
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We determined the antiangiogenic and anticancer activity of VEGI-192, a new isoform of TNFSF15 (VEGI, TL1), with a Lewis lung cancer murine tumor model. Experimental Design: Recombinant human VEGI-192 was produced in Escherichia coli and purified to apparent homogeneity. The protein was given systemically via i.p., i.v., or s.c. injections to tumor-bearing C57BL/6 mice. Tumor growth rates, animal survival rates, and general toxicity were determined. Effect on endothelial cell/smooth muscle cell ratio of the tumor vasculature was analyzed. Results: Systemic administration of VEGI-192 gave rise to a marked inhibition of tumor growth. As much as 50% inhibition of the tumor growth rate was achieved with treatment initiated when the tumor volumes reached nearly 5% of the body weight. Inhibition of tumor formation was also observed when VEGI-192 was given at the time of tumor inoculation. Consistently, we observed an increased survival time of the treated animals. The VEGI-192-treated animals showed no liver or kidney toxicity. The treatment eliminated tumor endothelial cells but not vascular smooth muscle cells, which remained associated with a residual vascular structure consisting of the basement membrane. In addition, we carried out immunohistochemical analysis of rat kidneys and found that vascular endothelial cell growth inhibitor (VEGI) expression is largely limited to endothelial cells. Conclusions: Our findings indicate that VEGI is an endogenous inhibitor of angiogenesis, and that systemic administration of the VEGI-192 isoform resulted in inhibition of tumor angiogenesis and growth.
PI SZ phenotype in chronic obstructive pulmonary disease
Authors: L. Alvarez-Granda, M. J. Cabero-Perez, A. Bustamante-Ruiz, D. Gonzalez-Lamuno, M. Delgado-Rodriguez, M. Garcia-Fuentes
Journal: Thorax (1997)

A study was undertaken to clarify whether the PI SZ phenotype of the protease inhibitor system predisposes to chronic obstructive pulmonary disease (COPD).The prevalence of PI Z and PI SZ deficient phenotypes was investigated in a population of 702 patients with COPD followed up at the Chest Unit of a tertiary hospital and in 15400 newborn infants from the same geographical area. Individuals with deficiency were detected by screening of dried blood spots on filter paper using a comparative electro-immunodiffusion technique for alpha 1-antitrypsin and transferrin. The serum phenotype was confirmed by means of isoelectrofocusing on polyacrylamide gel.Of the 702 blood samples from patients with COPD, six PI Z subjects (0.85%) and one PI SZ (0.14%) were detected. Of the 15400 samples from neonates, the number of PI Z subjects was eight (0.052%) and that of PI SZ was 24 (0.156%). The difference between the two groups was significant for PI Z but not for PI SZ.The data do not indicate an increased risk for development of COPD associated with the PI SZ phenotype but confirm the predisposition of PI Z individuals for the development of COPD.
Attenuation of Nitrate Tolerance and Oxidative Stress by an Angiotensin II Receptor Blocker in Patients With Coronary Spastic Angina
Authors: Nobutaka Hirai, Hiroaki Kawano, Hirofumi Yasue, Hideki Shimomura, Shinzo Miyamoto, Hirofumi Soejima, Ichiro Kajiwara, Tomohiro Sakamoto, Michihiro Yoshimura, Hajime Nakamura, Junji Yodoi, Hisao Ogawa
Journal: Circulation (2003)

Background— Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by the rapid development of tolerance. Recently, the renin-angiotensin system has been suggested to play an important role in the development of nitrate tolerance. Methods and Results— Sixty-four patients with coronary spastic angina were investigated to clarify the effect of angiotensin II type 1 receptor blocker (ARB) therapy on nitrate tolerance. Transdermal nitroglycerin (10 mg/d) and an ARB (candesartan, 8 mg/d) were administered to 21 patients (GTN+ARB group) for 3 days, whereas transdermal nitroglycerin and placebo were administered to 19 patients (GTN group). Another 18 patients were treated with placebo skin patches and placebo tablets for 3 days (control group). The brachial artery response to incremental doses of intravenous nitroglycerin (0.01, 0.1, and 1.0 μg/kg) was measured by ultrasound before and after transdermal nitroglycerin therapy. Before treatment, the arterial diameter was increased by nitroglycerin injection in each group. After treatment, the increase of arterial diameter was significantly suppressed in the GTN group but not in the control or GTN+ARB groups. The plasma level of thioredoxin (a marker of oxidative stress) was increased in the GTN group after treatment ( P &lt;0.01) but not in the control or GTN+ARB groups. Conclusions— An ARB suppressed the development of nitrate tolerance during transdermal nitroglycerin therapy. These results suggest that increased oxidative stress induced by activation of angiotensin II may play an important role in the development of nitrate tolerance.
Lorazepam vs Diazepam for Pediatric Status Epilepticus
Authors: James M. Chamberlain, Pamela Okada, Maija Holsti, Prashant Mahajan, Kathleen M. Brown, Cheryl Vance, Victor Gonzalez, Richard Lichenstein, Rachel Stanley, David C. Brousseau, Joseph Grubenhoff, Roger Zemek, David W. Johnson, Traci E. Clemons, Jill Baren
Journal: JAMA (2014)

<h3>Importance</h3> Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication. <h3>Objective</h3> To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus. <h3>Design, Setting, and Participants</h3> This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam. <h3>Interventions</h3> Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered. <h3>Main Outcomes and Measures</h3> The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration. <h3>Results</h3> Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, −11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, −9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%). <h3>Conclusions and Relevance</h3> Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00621478
Day and night pain measurement in rheumatoid arthritis
Authors: B Rojkovich, T Gibson
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> An attempt was made to see if rheumatoid arthritis (RA) patients can use visual analogue scales (VAS) to distinguish and grade the severity of pain at night, during rest, and on joint movement and to determine if discriminate measurement of these three pain components enhances the value of VAS estimation. <h3>METHODS</h3> Two hundred and fifty two consecutive RA patients were evaluated by a single observer using 10 cm VAS for pain at night, at rest during the day, and on movement. Values were correlated against age, disease duration, joint tenderness, swollen joint count, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Larsen<i>x</i> ray scores. <h3>RESULTS</h3> Night pain was recorded by 71 (28%) and this component of pain was lower than VAS scores for daytime rest and movement. However, those with nocturnal pain had significantly more joint tenderness (p&lt;0.0001), swollen joints (p&lt;0.0001), and higher ESR and CRP. Age, disease duration, and radiographic scores were similar in those with and without night pain. Correlations of joint tenderness were apparent for all three pain scores but only nocturnal pain correlated with swollen joints (p&lt;0.001) and CRP (p&lt;0.005). Age, disease duration, and radiographic severity correlated with daytime rest or movement scores but not nocturnal pain. <h3>CONCLUSION</h3> Patients were able to distinguish and estimate the severity of pain at rest, on movement, and at night. The occurrence of night pain characterised those with more active disease and night pain VAS measurement correlated best with measures of joint inflammation whereas daytime pain scores, both at rest and on movement, seemed influenced by the degree of permanent joint damage. Thus, discrete measurement of rest, movement, and nocturnal pain may provide useful information about RA disease status.
Evaluation of Statistical Designs in Phase I Expansion Cohorts: The Dana-Farber/Harvard Cancer Center Experience
Authors: Suzanne E. Dahlberg, Geoffrey I. Shapiro, Jeffrey W. Clark, Bruce E. Johnson
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundPhase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess endpoints in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined.
NOD2 and pouch complications in UC patients: old-world clinical dogmas give way to biological definitions
Authors: Iris Dotan, Scott Eric Plevy
Journal: Gut (2013)

The paper by Tyler et al 1 describing genetic associations in patients with ulcerative colitis (UC) preoperatively who then develop chronic pouchitis (CP) and a Crohn's disease (CD) like phenotype postoperatively further extend our clinical definitions of CD and UC based on an evolving knowledge of inflammatory bowel disease (IBD) genetics. Many described human IBD susceptibility genes are shared between UC and CD, highlighting overlapping clinical and pathophysiological features. However, single nucleotide polymorphisms (SNPs) in NOD2 (nucleotide-binding oligomerisation domain 2) are the most important genetic risk factors for the occurrence of CD. In individuals of European ancestry, heterozygous carriage of one of the three major risk alleles confers a 2.4-fold increase in risk for CD; homozygous or compound heterozygous carriage confers a 17.1-fold increase in risk for CD.2 ,3 Clinically, NOD2 mutations have been consistently associated with ileal location and stricturing disease.3 ,4 Of the major risk alleles, the insertion mutation NOD2insC which codes for a truncated protein, confers the greatest risk for CD.2

NOD2 is a member of the NOD-Like Receptor (NLR) (NOD, leucine-rich repeat-containing protein) family of intracellular sensors of microbes and microbial products.5 Progress has been made in understanding NOD2 function in relation to CD pathogenesis. NOD2 has been implicated in the expression of antimicrobial peptides which consequently shape the composition of the enteric microbiota.6 Macrophage and dendritic cell NOD2 regulates the expression of proinflammatory and anti-inflammatory cytokines central to IBD pathogenesis.7 Emerging evidence in mice and humans suggests that NOD2 represents a global regulatory pathway for small bowel inflammation. In mice, loss of Nod2 function alone does not cause intestinal inflammation. However, Nod2 -deficient mice express low levels of antimicrobial peptides and reduced capacity to clear enteric microbes.8 Moreover, Nod2 -deficient mice in which granulocyte macrophage colony …
Relationship between serum glucose and mortality post pneumonia
Authors: D Komrower
Journal: Thorax (2012)

Relationship between serum glucose and mortality post pneumoniaThis multicentre prospective cohort study used data from the German collaborative network on community acquired pneumonia.It tested the hypothesis that admission serum glucose levels and pre-existing diabetes are associated with mortality in patients admitted to hospital with community acquired pneumonia.Seven thousand four hundred patients were included in the registry.6.8% were excluded due to vital data being missing.A further 12.6% had missing serum glucose levels which were accounted for by using multiple imputations.The primary endpoint was death at 90 days but death at 28 days and 180 days was also analysed.Hazard models were adjusted for gender, CURB-65 score, comorbidities, smoking and infectious agent.Overall mortality was higher in patients with diabetes than without.Patients without preexisting diabetes but with high serum glucose levels on admission had a higher 90 days mortality.Ninety days mortality increased in a stepwise manner as glucose concentration increased in patients without diabetes.This association of glucose level and mortality was not evident in patients with pre-existing diabetes.Low serum glucose levels (<4 mmol/l) were not associated with increased mortality.This study did not establish a causal relationship between serum glucose levels on admission and mortality.Also, it was not designed to look at treatment of hyperglycaemia as there was no structured treatment protocol and therefore further studies are needed to determine if treating hyperglycaemia reduces mortality.
The Evolution of Airway Function in Early Childhood Following Clinical Diagnosis of Cystic Fibrosis
Authors: Sarath C. Ranganathan, Janet Stocks, Carol Dezateux, Andrew Bush, Angie Wade, Siobhán Carr, Rosemary Castle, Robert Dinwiddie, Ah-Fong Hoo, Sooky Lum, John Price, John Stroobant, Colin Wallis
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

This study aimed to investigate the evolution of airway function in infants newly diagnosed with cystic fibrosis (CF). FEV(0.5) was measured soon after diagnosis (median age of 28 weeks) and 6 months later in subjects with CF and on two occasions 6 months apart (median ages of 7.4 and 33.7 weeks) in healthy infants, using the raised-volume technique. Repeated measurements were successful in 34 CF and 32 healthy subjects. After adjustment for age, length, sex, and exposure to maternal smoking, mean FEV(0.5) was significantly lower in infants with CF both shortly after diagnosis and at the second test, with no significant difference in rate of increase in FEV(0.5) with growth between the two groups. When compared with published reference data, FEV(0.5) was reduced by an average of two z scores on both test occasions in those with CF, with 72% of individuals having an FEV(0.5) of less than 1.64 z-scores (i.e., less than the fifth percentile) on one or both test occasions. On longitudinal analysis, subjects with CF experienced a mean (95% confidence interval) reduction in FEV(0.5) of 20% (11, 28). Airway function is diminished soon after diagnosis in infants with CF and does not catch up during infancy and early childhood. These findings have important implications for early interventions in CF.
Role of the Multiple T Cell Receptor (TCR)-ζ Chain Signaling Motifs in Selection of the T Cell Repertoire
Authors: Elizabeth W. Shores, Tom Tran, Alexander Grinberg, Connie L. Sommers, Howard Shen, Paul E. Love
Journal: The Journal of Experimental Medicine (1997)

Immature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC–restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR–ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-γ, -δ, -ε, and ζ) that contain either one (CD3-γ, -δ, -ε) or three (-ζ) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-ζ chain ITAMs in thymocyte selection, transgenes encoding α/βTCRs with known specificity were bred into mice in which ζ chains lacking one or more ITAMs had been genetically substituted for endogenous ζ. A direct relationship was observed between the number of ζ chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.
Association Among SF36 Quality of Life Measures and Nutrition, Hospitalization, and Mortality in Hemodialysis
Authors: Kamyar Kalantar-Zadeh, Joel D. Kopple, Gladys Block, Michael H. Humphreys
Journal: Journal of the American Society of Nephrology (2001)

Patients on maintenance hemodialysis (MHD) often show substantial reductions in quality of life (QoL). The SF36 (Short Form with 36 questions), a well-documented, self-administered QoL scoring system that includes eight independent scales and two main dimensions, has been widely used and validated. In 65 adult outpatients on MHD, the SF36 and its scales and dimensions, scored as a number between 0 and 100, and the nutritional and inflammatory state measured by subjective global assessment, near-infrared (NIR) body fat, body mass index (BMI), and pertinent laboratory values, including hemoglobin, albumin, and C-reactive protein were assessed. Twelve-month prospective hospitalization rates and mortality were used as the clinical outcomes. Multivariate (case-mix) adjusted correlation coefficients were statistically significant between SF36 scores and serum albumin and hemoglobin concentrations. There were significant inverse correlations between SF36 scores and the BMI and NIR body fat percentage. Hypoalbuminemic, anemic, and obese patients on MHD had a worse QoL. Prospective hospitalizations correlated significantly with the SF36 total score and its two main dimensions (r between -0.28 and -0.40). The Cox proportional regression relative risk of death for each 10 unit decrease in SF36 was 2.07 (95% CI, 1.08 to 3.98; P = 0.02). Of the eight components and two dimensions of the SF36, the Mental Health dimension and the SF36 total score had the strongest predictive value for mortality. Thus, in patients on MHD the SF36 appears to have significant associations with measures of nutritional status, anemia, and clinical outcomes, including prospective hospitalization and mortality. Even though obesity, unlike undernutrition, is not generally an indicator of poor outcome in MHD, the SF36 may detect obese patients on MHD at higher risk for morbidity and mortality.