tbuckley/cabot-search huggingface dataset:
Evaluation of the Insulin Resistance Syndrome in 5- to 10-Year-Old Overweight/Obese African-American Children
Authors: Deborah Young-Hyman, David G. Schlundt, Leanna Herman, Francesco De Luca, Debra Counts
Journal: Diabetes Care (2001)

OBJECTIVE—To characterize the insulin sensitivity of overweight and obese 5- to 10-year-old (Tanner stage 1–3) African-American children screened for participation in a diabetes prevention study and to identify the association of insulin sensitivity with obesity, hyperlipidemia, and hypertension. RESEARCH DESIGN AND METHODS—Measures of insulin resistance (homeostasis model assessment) and insulin sensitivity (Matsuda and DeFronzo’s whole-body insulin sensitivity) were calculated from a 2-h oral glucose tolerance test in 137 African-American children recruited into a diabetes prevention study. Measures of lipids (LDL, HDL, total cholesterol, and triglycerides), blood pressure, and body composition were obtained for a subset of the children. RESULTS—In response to a glucose challenge, girls and older and heavier children produced significantly more insulin. As BMI increased, there was a statistically significant decrease in insulin sensitivity, particularly in girls. Insulin sensitivity was inversely correlated with increases in blood pressure, triglycerides, subcutaneous fat, the percentage of total body fat, and Tanner stage, but it was not correlated with LDL and HDL. CONCLUSIONS—Reduced insulin sensitivity and the cluster of risk factors known as the insulin resistance syndrome (IRS) are already apparent in these overweight African-American children. Young African-American girls, in particular, already show evidence of hyperinsulinemia in response to a glucose load, suggesting that the early stages of metabolic decompensation that lead to type 2 diabetes are already occurring. Monitoring of those risk factors known to be part of IRS should become part of routine medical care for overweight or obese African-American children.
Pancreatitis associated protein as an early marker of acute pancreatitis.
Authors: E Kemppainen, J Sand, P Puolakkainen, S Laine, J Hedstrom, V Sainio, R Haapiainen, I Nordback
Journal: Gut (1996)

BACKGROUND: Measuring serum pancreatitis associated protein (PAP) in acute pancreatitis has proved valuable to monitoring the course of the disease and the recovery of the patient. AIMS: The aim was to analyze the utility of PAP on admission as a diagnostic and prognostic marker of acute pancreatitis. PATIENTS: Values of PAP were prospectively analyzed in 80 healthy volunteers, 164 patients with abdominal pain but without pancreatitis, 109 patients with mild acute pancreatitis, and 38 patients with severe acute pancreatitis. METHODS: The diagnosis of acute pancreatitis was verified with clinical, laboratory, radiological, and in some cases findings at operation or necropsy. RESULTS: Mean (95% confidence intervals) serum PAP values were 27 (24 to 29) micrograms/l in healthy volunteers, 78 (59 to 96) micrograms/l in patients with abdominal pain, 191 (134 to 247) micrograms/l, in patients with mild acute pancreatitis, and 599 (284 to 914) micrograms/l in patients with severe acute pancreatitis. Differences between the groups were significant (p = 0.04 - 0.01). Despite the differences in means, the ranges overlapped between the groups. The sensitivity of PAP on admission to detect acute pancreatitis was 38%-53% and the respective specificity 89%-77% depending on the cut off level. The sensitivity of PAP to detect severe acute pancreatitis was 45%-68% and the specificity 74%-59% depending on the cut off level. CONCLUSIONS: Admission PAP did not distinguish severe from mild acute pancreatitis better than C reactive protein. Measurement of PAP does not give appreciable diagnostic advantages in the early phase of acute pancreatitis.
Allogeneic Transplantation for Lymphoma
Authors: Ronjon Chakraverty, Stephen Mackinnon
Journal: Journal of Clinical Oncology (2011)

Historically, high levels of treatment-related mortality restricted the use of standard myeloablative allogeneic stem-cell transplantation to a minority of young and fit patients with lymphoma. Over the last decade, increasing numbers of patients with lymphoma have undergone allogeneic stem-cell transplantation using reduced-intensity protocols that are associated with lower toxicity and reduced transplantation-related mortality. Graft-versus-lymphoma effects contribute to the therapeutic effect in patients with indolent or Hodgkin's lymphoma. However, definitive evidence for efficacy of this strategy is lacking because most patients undergoing transplantation do so after failure of several lines of treatment, leaving no obvious comparator arm for randomized controlled studies. Nevertheless, encouraging results have been reported for selected patients for most lymphoma subtypes, with pretransplantation disease status emerging as the most important predictor of outcome. The major long-term toxicity is chronic graft-versus-host disease that contributes to ill health in a significant minority of survivors. In the future, risk-adapted trials that evaluate reduced-intensity allogeneic transplantation in patients with predicted poor outcomes with immunochemotherapy or autologous transplantation will be important in determining the role of this treatment.
Validating the Interval to Biochemical Failure for the Identification of Potentially Lethal Prostate Cancer
Authors: Mark K. Buyyounouski, Tom Pickles, Larry L. Kestin, Roger Allison, Scott G. Williams
Journal: Journal of Clinical Oncology (2012)

To validate the interval to biochemical failure (IBF) as a prognostic factor at the time of biochemical failure for prostate cancer mortality (PCM) following radiotherapy (RT).From a collaborative data set of men with clinically localized prostate cancer treated with RT from four institutions in three countries, we identified 1,722 men with biochemical failure (BF; prostate-specific antigen nadir + 2 ng/mL). The IBF was defined as the time interval from completion of treatment to the date of BF. The primary outcome measure was discriminatory power in the form of the concordance index (c-index).Seventeen percent of men had an IBF ≤ 18 months. Median potential follow-up beyond the time of BF was 67 months. There were 290 deaths from prostate cancer. The IBF was the most discriminating individual prognostic factor overall, with a sensitivity of IBF ≤ 18 months to predict PCM within 10 years of 48.4% (95% CI, 43.3% to 54.1%); the specificity was 86.1% (95% CI, 84.5% to 87.7%), equating to a c-index of 0.611 (95% CI, 0.578 to 0.647). The 5-year cumulative incidence of PCM for IBF more than 18 months versus IBF ≤ 18 months was 9.4% (95% CI, 7.7% to 11.5%) versus 26.3% (95% CI, 21.2% to 31.8%); corresponding 10-year estimates were 26.2% (95% CI, 21.5% to 30.8%) versus 55.9% (95% CI, 48.9% to 63.0%), respectively (P < .001 for both). IBF exhibited minimal change in performance across various follow-up durations.IBF is the single most robust prognostic factor for PCM following RT without androgen deprivation therapy. This external validation demonstrates that patients and clinicians can use this information to make decisions about subsequent treatments.
The AGE-RAGE System and Diabetic Nephropathy
Authors: Shigeru Sakurai, Hideto Yonekura, Yasuhiko Yamamoto, Takuo Watanabe, Nobushige Tanaka, Hui Li, A.K.M. Azadur Rahman, Khin-Mar Myint, Chul-Hee Kim, Hiroshi Yamamoto
Journal: Journal of the American Society of Nephrology (2003)

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease.
C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation
Authors: Agustín Tortajada, Hugo Yébenes, Cynthia Abarrategui-Garrido, Jaouad Anter, Jesús M. García-Fernández, Rubén Martínez-Barricarte, María Alba-Domínguez, Talat H. Malik, Rafael Bedoya, Rocío Cabrera Pérez, Margarita López Trascasa, Matthew C. Pickering, Claire L. Harris, Pilar Sánchez-Corral, Oscar Llorca, Santiago Rodríguez de Córdoba
Journal: Journal of Clinical Investigation (2013)

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H–related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.
New classification for probe-based confocal laser endomicroscopy in the colon
Authors: T. Kuiper, F. van den Broek, S. van Eeden, M. Wallace, A. Buchner, A. Meining, K. van Hee, P. Fockens, E. Dekker
Journal: Endoscopy (2011)

Probe-based confocal laser endomicroscopy (pCLE; Cellvizio, Mauna Kea Technologies, Paris, France) enables in vivo histology during colonoscopy and may allow endoscopists to make real-time diagnoses. A collaboration of five experts proposed a new pCLE classification for colonic use. The aim of this study was to assess interobserver agreement and accuracy of the new pCLE classification in the colon.Eligible patients were prospectively investigated by pCLE. A subset of 13 pCLE video sequences was reviewed post hoc for the establishment of a new classification, which comprised three vessel categories and seven crypt categories. All five blinded observers then scored another set of 102 video sequences, using the new classification. Histopathology was used as a reference standard.The interobserver agreements on vessel and crypt architecture were 'fair' with kappa values of 0.29 and 0.27, respectively. When the classification was reduced to neoplasia vs. non-neoplasia (i.e. vessel or crypt type 3), overall agreement became 'moderate' (κ = 0.56). Overall sensitivity and specificity for predicting neoplasia was 66 % and 83 %, respectively. When all observers agreed (69 % of videos), the corresponding figures became 80 % and 95 %.A new classification for pCLE in the colon had a 'moderate' interobserver agreement for differentiating neoplasia from non-neoplastic tissue in the colon. The overall accuracy (81 %) for predicting neoplasia was acceptable and became excellent (94 %) when all five observers agreed. Future research should focus on refinement and validation of the classification.
The Farnesyltransferase Inhibitor R115777 Up-regulates the Expression of Death Receptor 5 and Enhances TRAIL-Induced Apoptosis in Human Lung Cancer Cells
Authors: Yuanzheng Qiu, Xiangguo Liu, Wei Zou, Ping Yue, Sagar Lonial, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2007)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in transformed or malignant cells, thus exhibiting potential as a tumor-selective apoptosis-inducing cytokine for cancer treatment. Many studies have shown that the apoptosis-inducing activity of TRAIL can be enhanced by various cancer therapeutic agents. R115777 (tipifarnib) is the first farnesyltransferase inhibitor (FTI) that showed clinical activity in myeloid malignancies. In general, R115777, like other FTIs, exerts relatively weak effects on the induction of apoptosis in cancer cells with undefined mechanism(s). In the current study, we studied its effects on the growth of human lung cancer cells, including induction of apoptosis, and examined potential underlying mechanisms for these effects. We showed that R115777 induced apoptosis in human lung cancer cells, in addition to inducing G(1) or G(2)-M arrest. Moreover, we found that R115777 up-regulated the expression of death receptor 5 (DR5), an important death receptor for TRAIL, and exhibited an augmented effect on the induction of apoptosis when combined with recombinant TRAIL. Blockage of DR5 induction by small interfering RNA (siRNA) abrogated the ability of R115777 to enhance TRAIL-induced apoptosis, indicating that R115777 augments TRAIL-induced apoptosis through up-regulation of DR5 expression. Thus, our findings show the efficacy of R115777 in human lung cancer cells and suggest that R115777 may be used clinically in combination with TRAIL for treatment of human lung cancer.
Are smokers with acute cough in primary care prescribed antibiotics more often, and to what benefit? An observational study in 13 European countries
Authors: N. Stanton, K. Hood, M. J. Kelly, J. Nuttall, D. Gillespie, T. Verheij, P. Little, M. Godycki-Cwirko, H. Goossens, C. C. Butler
Journal: European Respiratory Journal (2009)

Little is known about actual clinical practice regarding management of smokers compared with ex-smokers and nonsmokers presenting with acute cough in primary care, and whether a lower threshold for prescribing antibiotics benefits smokers. This was a multicentre 13-country European prospective observational study of primary care clinician management of acute cough in consecutive immunocompetent adults presenting with an acute cough of ≤28 days duration. There was complete smoking status data for 2,549 out of 3,402 participants. 28% were smokers, 24% ex-smokers and 48% nonsmokers. Smokers and ex-smokers had more chronic respiratory conditions (18.5% and 20.5% <i>versus</i> 12.5%). Median symptom severity scores were similar. Smokers were prescribed antibiotics more frequently (60%) than ex-smokers (51%) and nonsmokers (53%). After adjusting for clinical presentation and patient characteristics, the odds ratio of being prescribed antibiotics for smokers compared with nonsmokers was 1.44 (95% CI 1.12–1.86; p = 0.005). Patient recovery was not significantly different for smokers and nonsmokers, after adjusting for clinical presentation and patient characteristics. Smoking status was used as an independent factor to determine whether or not to prescribe an antibiotic. Being prescribed an antibiotic was not associated with recovery in smokers.
The British Pharmacop ia, with Reference to Weights and Measures
Authors: W. P. Stiff
Journal: BMJ (1862)

inclination of the reflectors R' it' suffices (on the principle of Wheatstone's reflecting stereoscope) to effect the coalescence of the double images without any additional prisms.*This form of instrument admits of adjustment of the eye-mirrors (II'u') to suit both the different separ- ation of the eyes met with in different individuals, as also aDy deviations of acconmmodation.
Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy
Authors: Phuong K. Morrow, Gerburg M. Wulf, Joe Ensor, Daniel J. Booser, Julia A. Moore, Peter R. Flores, Yan Xiong, Siyuan Zhang, Ian E. Krop, Eric P. Winer, David W. Kindelberger, Jeanna Coviello, Aysegul A. Sahin, Rodolfo Nuñez, Gabriel N. Hortobagyi, Dihua Yu, Francisco J. Esteva
Journal: Journal of Clinical Oncology (2011)

Purpose Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. Patients and Methods This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. Results Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. Conclusion Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
Phospholipase A2 and signal transduction.
Authors: J V Bonventre
Journal: Journal of the American Society of Nephrology (1992)

Phospholipases A2 (PLA2) comprise a family of enzymes that hydrolyze the acyl bond at the sn-2 position of phospholipids to generate free fatty acids and lysophospholipids. Different forms of PLA2 are involved in digestion, inflammation, and intercellular and intracellular signal transduction. The sn-2 position of phospholipids in mammalian cells is enriched in arachidonic acid, the precursor of eicosanoids, which have diverse physiologic and pathophysiologic effects on the kidney and other organs. Thus, the regulation of PLA2 activity has important implications for kidney function. PLA2 regulation involves: calcium, pH, protein kinases, GTP-binding proteins, inhibitory and activating proteins, metabolic product inhibition, and transcriptional control. The various roles of arachidonic acid and cyclooxygenase, lipoxygenase, and cytochrome P450 mono-oxygenase products of arachidonic acid metabolism, as intracellular messengers, in the regulation of membrane channel activities, intracellular enzyme activities, cellular calcium homeostasis, mitogenesis, differentiation, cytokine and early response gene expression are discussed.
Influence of Ejection Fraction on Cardiovascular Outcomes in a Broad Spectrum of Heart Failure Patients
Authors: Scott D. Solomon, Nagesh Anavekar, Hicham Skali, John J.V. McMurray, Karl Swedberg, Salim Yusuf, Christopher B. Granger, Eric L. Michelson, Duolao Wang, Stuart Pocock, Marc A. Pfeffer
Journal: Circulation (2005)

Left ventricular function is a principal determinant of cardiovascular risk in patients with heart failure. The growing number of patients with preserved systolic function heart failure underscores the importance of understanding the relationship between ejection fraction and risk.We studied 7599 patients with a broad spectrum of symptomatic heart failure enrolled in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Program. All patients were randomized to candesartan at a target dose of 32 mg once daily or matching placebo and followed up for a median of 38 months. We related left ventricular ejection fraction (LVEF), measured before randomization at the sites, to cardiovascular outcomes and causes of death. Mean LVEF in patients enrolled in CHARM was 38.8+/-14.9% (median LVEF 36%). Patients with lower LVEF tended to have higher baseline New York Heart Association class. The hazard ratio for all-cause mortality increased by 39% for every 10% reduction in ejection fraction below 45% (hazard ratio 1.39, 95% CI 1.32 to 1.46), with adjustment for baseline covariates. All-cause mortality, cardiovascular death, and all components of cardiovascular death declined with increasing ejection fraction until an ejection fraction of 45%, after which the risk of these outcomes remained relatively stable with increasing LVEF. The absolute change in rate per 100 patient-years for each 10% reduction in LVEF was greatest for sudden death and heart failure-related death. The effect of candesartan in reducing cardiovascular outcomes was consistent across LVEF categories.LVEF is a powerful predictor of cardiovascular outcome in heart failure patients across a broad spectrum of ventricular function. Nevertheless, once elevated to a range above 45%, ejection fraction does not further contribute to assessment of cardiovascular risk in heart failure patients.
Comparison of nebulized glycopyrrolate and metaproterenol in chronic obstructive pulmonary disease
Authors: G Tzelepis, S Komanapolli, D Tyler, D Vega, A Fulambarker
Journal: European Respiratory Journal (1996)

We assessed the bronchodilating effect of glycopyrrolate (GP) and compared it with that of metaproterenol (MP), alone and in combination (GP+MP), in patients with chronic obstructive pulmonary disease (COPD). In a double-blind study, 11 patients (aged (mean +/- SD) 69 +/- 6 yrs; forced expiratory volume in one second (FEV1) 1.2 +/- 0.4 L) with stable COPD inhaled nebulized GP 1.0 mg, MP 15 mg, or GP 1.0 mg+MP 15 mg. Spirometry was performed before inhalation and at hourly intervals for 8 h after inhalation. It was found that GP produced a bronchodilating effect that was about equal to that of MP but lasted longer (8 vs 5 h). The combination of GP and MP produced a bronchodilating effect that was greater than that of either drug alone and was evident mostly during the effect of MP. The mean peak percentage improvement in FEV1 over baseline was 35% for GP+MP and 25% for either drug alone. These data suggest that nebulized glycopyrrolate is an effective bronchodilator in some patients with chronic obstructive pulmonary disease. Concurrent administration of glycopyrrolate and metaproterenol produces additional bronchodilation that is primarily apparent during the bronchodilator effect of metaproterenol.