tbuckley/cabot-search huggingface dataset:
Individualized Anemia Management Reduces Hemoglobin Variability in Hemodialysis Patients
Authors: Adam E. Gaweda, George R. Aronoff, Alfred A. Jacobs, Shesh N. Rai, Michael E. Brier
Journal: Journal of the American Society of Nephrology (2013)

One-size-fits-all protocol-based approaches to anemia management with erythropoiesis-stimulating agents (ESAs) may result in undesired patterns of hemoglobin variability. In this single-center, double-blind, randomized controlled trial, we tested the hypothesis that individualized dosing of ESA improves hemoglobin variability over a standard population-based approach. We enrolled 62 hemodialysis patients and followed them over a 12-month period. Patients were randomly assigned to receive ESA doses guided by the Smart Anemia Manager algorithm (treatment) or by a standard protocol (control). Dose recommendations, performed on a monthly basis, were validated by an expert physician anemia manager. The primary outcome was the percentage of hemoglobin concentrations between 10 and 12 g/dl over the follow-up period. A total of 258 of 356 (72.5%) hemoglobin concentrations were between 10 and 12 g/dl in the treatment group, compared with 208 of 336 (61.9%) in the control group; 42 (11.8%) hemoglobin concentrations were <10 g/dl in the treatment group compared with 88 (24.7%) in the control group; and 56 (15.7%) hemoglobin concentrations were >12 g/dl in the treatment group compared with 46 (13.4%) in the control group. The median ESA dosage per patient was 2000 IU/wk in both groups. Five participants received 6 transfusions (21 U) in the treatment group, compared with 8 participants and 13 transfusions (31 U) in the control group. These results suggest that individualized ESA dosing decreases total hemoglobin variability compared with a population protocol-based approach. As hemoglobin levels are declining in hemodialysis patients, decreasing hemoglobin variability may help reduce the risk of transfusions in this population.
Inactivation of the Carney Complex Gene 1 (<i>Protein Kinase A Regulatory Subunit 1A</i>) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells
Authors: Bruno Ragazzon, Laure Cazabat, Marthe Rizk-Rabin, Guillaume Assie, Lionel Groussin, Hélène Fierrard, Karine Perlemoine, Antoine Martinez, Jérôme Bertherat
Journal: Cancer Research (2009)

The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I alpha regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor beta (TGFbeta) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFbeta pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFbeta. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFbeta stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFbeta-induced apoptosis. This cross-talk between the PKA and the TGFbeta signaling pathways reveals a new mechanism of endocrine tumorigenesis.
Urinary metabolic signatures of human adiposity
Authors: Paul Elliott, Joram M. Posma, Queenie Chan, Isabel Garcia-Perez, Anisha Wijeyesekera, Magda Bictash, Timothy M. D. Ebbels, Hirotsugu Ueshima, Liancheng Zhao, Linda van Horn, Martha Daviglus, Jeremiah Stamler, Elaine Holmes, Jeremy K. Nicholson
Journal: Science Translational Medicine (2015)

In a large-scale population-based metabolic phenotyping study, diverse sets of urinary metabolites, including gut microbial co-metabolites, were reproducibly associated with human adiposity.
Users' Guides to the Medical Literature
Authors: Thomas G. McGinn, Gordon H. Guyatt, Peter C. Wyer, C. David Naylor, Ian G. Stiell, W. Scott Richardson, None for the Evidence-Based Medicine Working Group
Journal: JAMA (2000)

Clinical experience provides clinicians with an intuitive sense of which findings on history, physical examination, and investigation are critical in making an accurate diagnosis, or an accurate assessment of a patient's fate. A clinical decision rule (CDR) is a clinical tool that quantifies the individual contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis, prognosis, or likely response to treatment in a patient. Clinical decision rules attempt to formally test, simplify, and increase the accuracy of clinicians' diagnostic and prognostic assessments. Existing CDRs guide clinicians, establish pretest probability, provide screening tests for common problems, and estimate risk. Three steps are involved in the development and testing of a CDR: creation of the rule, testing or validating the rule, and assessing the impact of the rule on clinical behavior. Clinicians evaluating CDRs for possible clinical use should assess the following components: the method of derivation; the validation of the CDR to ensure that its repeated use leads to the same results; and its predictive power. We consider CDRs that have been validated in a new clinical setting to be level 1 CDRs and most appropriate for implementation. Level 1 CDRs have the potential to inform clinical judgment, to change clinical behavior, and to reduce unnecessary costs, while maintaining quality of care and patient satisfaction.
Does breastfeeding influence development of atopy? A cohort study
Authors: Cristian MIhai Dogaru, Anina Pescatore, Ben Spycher, Caroline Beardsmore, Michael Silverman, Claudia Kuehni
Journal: European Respiratory Journal (2012)

Aim   It has been postulated that breastfeeding (BF) reduces the risk of allergy in children. However, recent studies failed to show a protective effect or suggested an increased risk of atopy with BF. We examined the association between BF and atopy, measured by skin prick test (SPT), in a large population-based cohort, stratifying by maternal hayfever.   Method   We assessed BF in the first years of life in children from Leicestershire, UK. At school age (9-14 years), we performed SPT for 4 allergens (cat, dog, dust, grass) in 1515 children. A child was defined as atopic if any wheal size was >3mm. We used logistic regression, adjusting for age, sex, ethnicity, birth season, family history of atopy and socio-economic status. We stratified by maternal hayfever and investigated potential reverse causation in analysis that excluded children with eczema or wheeze in infancy.   Results   465 (31%) children were not breastfed, 435 (29%) had BF  6 mo. 437 mothers (29%) had hayfever. We found no evidence for differences in risk of atopy by BF; the odds-ratios (95% confidence intervals) for BF 6 mo were 0.97 (0.69,1.37), 1.07 (0.72,1.59) and 1.19 (0.83,1.71), respectively, compared with no BF (p-trend=0.297). We did not find differential association by maternal hayfever (p-interaction=0.489) nor evidence for reverse causation.   Conclusion   Using objective measures and controlling for reverse causation, our study did not find evidence for an effect of breastfeeding on atopy in children of mothers either with or without hayfever. We can continue recommending breastfeeding for atopic and non-atopic mothers.   Funding   Asthma UK 07/048; SNF 3200B0-122341; SNF PDFMP3-123162.
Intrasubject variability of pulmonary function testing in healthy children.
Authors: A A Hutchison, A Erben, L A McLennan, L I Landau, P D Phelan
Journal: Thorax (1981)

The intrasubject variability of repeat pulmonary function testing was examined in 20 healthy children aged 10 to 16 years. The children were tested a maximum of 11 times over a period of two months. The tests examined were spirometry, maximum expiratory flow-volume curves, body plethysmograph determination of lung volumes, and single breath nitrogen washout. The time of day or the length of the re-test interval, up to a period of two months, did not significantly affect the variability. Standard deviation was used when comparing the variability of measurements with the same units and coefficient of variation was used when comparing measurements of different units. The vital capacity measured by spirometry was the least variable measurement. Functional residual capacity, residual volume and total lung capacity were equally reproducible but as a group were more variable than vital capacity. There was no significant difference between the variability of the following measurements: forced expired flow from 25 to 75% of the vital capacity, flows at 70%, 50% and 40% total lung capacity, and flows at 50% vital capacity. Flows at 25% vital capacity were significantly less variable than other measurements of flow. The variability of forced expired volume in one second was examined and the use of this measurement in determining significant bronchial hyper-reactivity was assessed.
Arterial hypoxaemia in cirrhosis: fact or fiction?
Authors: S Møller, J Hillingsø, E Christensen, J H Henriksen
Journal: Gut (1998)

Background —Although low arterial oxygen tension (P o 2 ) has been claimed to occur in one to two thirds of patients with cirrhosis, hypoxaemia appears to be rare in clinical practice. Aims —To assess the frequency of arterial hypoxaemia in cirrhosis in relation to clinical and haemodynamic characteristics. Patients —One hundred and forty two patients with cirrhosis without significant hepatic encephalopathy (grades 0–I) (41 patients in Child class A, 57 in class B, and 44 in class C) and 21 patients with hepatic encephalopathy. Results —Mean P o 2 in kPa was 11.3 in Child class A, 10.8 in class B, 10.6 in class C, and 10.6 in patients with encephalopathy (p&lt;0.05). The fraction of patients with P o 2 below the lower normal limit of 9.6 kPa was 10%, 28%, 25%, and 43%, respectively in class A, B, C, and in patients with encephalopathy (p&lt;0.05). Oxygen saturation (S o 2 ) in these groups was respectively: 96%, 96%, 96%, and 93% (NS). S o 2 was below the lower limit of 92% in 0%, 9%, 7%, and 24% (p&lt;0.05). In patients without hepatic encephalopathy, a multivariate regression analysis revealed that independent determinants of a low P o 2 were a high arterial carbon dioxide tension, a low systemic vascular resistance, and a low indocyanine green clearance (p&lt;0.0001). Conclusion —The prevalence of arterial hypoxaemia in cirrhosis is about 22% in patients without encephalopathy, but it varies from 10–40% depending on the degree of hepatic dysfunction. Arterial hypoxaemia in patients with cirrhosis of differing severity seems lower than previously reported, and patients with severe arterial hypoxaemia are rare.
Monitoring the athlete training response: subjective self-reported measures trump commonly used objective measures: a systematic review
Authors: Anna E Saw, Luana C Main, Paul B Gastin
Journal: British Journal of Sports Medicine (2015)

Background Monitoring athlete well-being is essential to guide training and to detect any progression towards negative health outcomes and associated poor performance. Objective (performance, physiological, biochemical) and subjective measures are all options for athlete monitoring. Objective We systematically reviewed objective and subjective measures of athlete well-being. Objective measures, including those taken at rest (eg, blood markers, heart rate) and during exercise (eg, oxygen consumption, heart rate response), were compared against subjective measures (eg, mood, perceived stress). All measures were also evaluated for their response to acute and chronic training load. Methods The databases Academic search complete, MEDLINE, PsycINFO, SPORTDiscus and PubMed were searched in May 2014. Fifty-six original studies reported concurrent subjective and objective measures of athlete well-being. The quality and strength of findings of each study were evaluated to determine overall levels of evidence. Results Subjective and objective measures of athlete well-being generally did not correlate. Subjective measures reflected acute and chronic training loads with superior sensitivity and consistency than objective measures. Subjective well-being was typically impaired with an acute increase in training load, and also with chronic training, while an acute decrease in training load improved subjective well-being. Summary This review provides further support for practitioners to use subjective measures to monitor changes in athlete well-being in response to training. Subjective measures may stand alone, or be incorporated into a mixed methods approach to athlete monitoring, as is current practice in many sport settings.
Fructose and Vitamin C Intake Do Not Influence Risk for Developing Hypertension
Authors: John P. Forman, Hyon Choi, Gary C. Curhan
Journal: Journal of the American Society of Nephrology (2009)

Higher uric acid levels are associated with an increased risk for developing hypertension. Higher intake of fructose increases plasma uric acid levels and higher intake of vitamin C reduces uric acid levels, but whether these nutrients are independently associated with the risk for developing hypertension is unknown. We studied this question by analyzing data from participants of three large and independent prospective cohorts: Nurses’ Health Study 1 (n = 88,540), Nurses’ Health Study 2 (n = 97,315), and the Health Professionals Follow-up Study (n = 37,375). Relative risks and 95% confidence intervals for incident hypertension were computed according to quintiles of fructose intake and categories of vitamin C intake using multivariable Cox proportional hazards regression. Fructose intake was not associated with the risk for developing hypertension; the multivariable relative risks (95% confidence intervals) for the highest compared with the lowest quintile of fructose intake were 1.02 (0.99 to 1.06) in Nurses’ Health Study 1, 1.03 (0.98 to 1.08) in Nurses’ Health Study 2, and 0.99 (0.93 to 1.05) in Heath Professionals Follow-up Study. Regarding vitamin C, the relative risks for individuals who consumed ≥1500 mg/d compared with those who consumed <250 mg/d were 0.89 (0.83 to 0.96) in Nurses’ Health Study 1, 1.02 (0.91 to 1.14) in Nurses’ Health Study 2, and 1.06 (0.97 to 1.15) in Health Professionals Follow-up Study. In conclusion, fructose and vitamin C intake do not substantially influence the risk for developing hypertension.
Unique Recombinant Human Ribonuclease and Inhibition of Kaposi's Sarcoma Cell Growth
Authors: D. L. Newton, S. M. Rybak
Journal: JNCI Journal of the National Cancer Institute (1998)

Preparations of human chorionic gonadotropin (hCG) have been shown to exhibit anti-Kaposi's sarcoma (KS) activity, but the identity of the responsible agent(s) remains controversial. One candidate agent is an eosinophil-derived neurotoxin (EDN)-like polypeptide that contaminates preparations of hCG. We have genetically engineered a unique form of hEDN, which is a ribonuclease, and have evaluated the cytotoxic effects of the recombinant protein on KS Y-1 cells and on cells of other cancer types.The amino-terminus of hEDN was extended by four amino acid residues, corresponding to the proximal part of the hEDN signal peptide (serine, leucine, histidine, and valine; positions -4 to -1, respectively), by use of the polymerase chain reaction and an hEDN complementary DNA. The recombinant protein was isolated from bacterial inclusion bodies. The cytotoxic activity of this hEDN variant, (-4)rhEDN, was tested on KS Y-1 cells and human glioma, melanoma, breast carcinoma, and renal carcinoma cells.Approximately half of the anti-KS activity in a crude commercial preparation of hCG was associated with a polypeptide that reacted with anti-recombinant-hEDN (rhEDN) polyclonal antibodies. Although rhEDN protein displayed little cytotoxicity against KS Y-1 cells (IC50 [50% inhibition concentration] = >100 microg/mL), (-4)rhEDN markedly inhibited cell viability (IC50 = 6 microg/mL). Neither version of rhEDN inhibited the viability of other tested human cancer cell types.A four amino acid extension of the amino-terminus of rhEDN confers cytotoxicity against KS Y-1 cells in vitro. Design of the (-4)rhEDN variant was based on the sequence of a natural human protein associated with hCG. Our results suggest that (-4)rhEDN is one of the agents in hCG responsible for anti-KS activity. A purified molecule is thus available for in vitro and in vivo mechanistic and, possibly, future clinical studies.
NF1 Inactivation Revs Up Ras in Adult Acute Myelogenous Leukemia
Authors: Ann Mullally, Benjamin L. Ebert
Journal: Clinical Cancer Research (2010)

Abstract Mutations in the Ras pathway are common in myeloid malignancies. NF1, a tumor suppressor and negative regulator of Ras, is inactivated in a subset of adult acute myelogenous leukemia (AML) cases. Loss of NF1 function sensitizes cells to inhibition of mammalian target of rapamycin (mTOR), a downstream effector of Ras activation, highlighting a potential therapeutic opportunity for some AML patients. Clin Cancer Res; 16(16); 4074–6. ©2010 AACR.
Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress.
Authors: C K Zarins, D P Giddens, B K Bharadvaj, V S Sottiurai, R F Mabon, S Glagov
Journal: Circulation Research (1983)

The distribution of nonstenosing, asymptomatic intimal plaques in 12 adult human carotid bifurcations obtained at autopsy was compared with the distribution of flow streamline patterns, flow velocity profiles, and shear stresses in corresponding scale models. The postmortem specimens were fixed while distended to restore normal in vivo length, diameter, and configuration. Angiograms were used to measure branch angles and diameters, and transverse histological sections were studied at five standard sampling levels. Intimal thickness was determined at 15 degrees intervals around the circumference of the vessel sections from contour tracings of images projected onto a digitizing plate. In the models, laser-Doppler anemometry was used to determine flow velocity profiles and shear stresses at levels corresponding to the standard specimen sampling sites under conditions of steady flow at Reynolds numbers of 400, 800, and 1200, and flow patterns were visualized by hydrogen bubble and dye-washout techniques. Intimal thickening was greatest and consistently eccentric in the carotid sinus. With the center of the flow divider as the 0 degree index point, mid-sinus sections showed minimum intimal thickness (0.05 +/- 0.02 mm) within 15 degrees of the index point, while maximum thickness (0.9 +/- 0.1 mm) occurred at 161 +/- 16 degrees, i.e., on the outer wall opposite the flow divider. Where the intima was thinnest, along the inner wall, flow streamlines in the model remain axially aligned and unidirectional, with velocity maxima shifted toward the flow divider apex. Wall shear stress along the inner wall ranged from 31 to 600 dynes/cm2 depending on the Reynolds number. Where the intima was thickest, along the outer wall opposite the flow divider apex, the pattern of flow was complex and included a region of separation and reversal of axial flow as well as the development of counter-rotating helical trajectories. Wall shear stress along the outer wall ranged from 0 to -6 dynes/cm2. Intimal thickening at the common carotid and distal internal carotid levels of section was minimal and was distributed uniformly about the circumference. We conclude that in the human carotid bifurcation, regions of moderate to high shear stress, where flow remains unidirectional and axially aligned, are relatively spared of intimal thickening. Intimal thickening and atherosclerosis develop largely in regions of relatively low wall shear stress, flow separation, and departure from axially aligned, unidirectional flow. Similar quantitative evaluations of other atherosclerosis-prone locations and corresponding flow profile studies in geometrically accurate models may reveal which of these hemodynamic conditions are most consistently associated with the development of intimal disease.
Role of Hyperglycemia in Nitrotyrosine Postprandial Generation
Authors: Antonio Ceriello, Lisa Quagliaro, Barbara Catone, Roberta Pascon, Marta Piazzola, Bruno Bais, Giampiero Marra, Laura Tonutti, Claudio Taboga, Enrico Motz
Journal: Diabetes Care (2002)

Recently, much attention has been paid to the possibility that postprandial hyperglycemia may be a cardiovascular risk factor in diabetes. Oxidative stress has been involved in the pathogenesis of diabetic complications, and increased plasma levels of nitrotyrosine, a product of peroxynitrite action, have been found in the plasma of diabetic subjects. The aim of the present study was to evaluate whether postprandial hyperglycemia is accompanied by nitrotyrosine generation and, if so, to explore a possible direct role of hyperglycemia in such a phenomenon.A total of 23 type 2 diabetic patients and 15 matched normal healthy subjects were recruited for this study. Two different tests were performed in diabetic patients: a standard meal preceded by regular insulin (0.15 units/kg body wt) or insulin aspart (0.15 units/kg body wt) to achieve different levels of postprandial hyperglycemia. The meal test was also performed in healthy control subjects. At 0 min and 1, 2, 4, and 6 h after each meal, blood glucose, triglyceride, and nitrotyrosine levels were measured.Fasting nitrotyrosine was significantly increased in diabetic patients and was further increased during both meal tests in diabetic subjects but not normal subjects. As compared with regular insulin, aspart administration significantly reduced the area under the curve of both glycemia (P < 0.04) and nitrotyrosine (P < 0.03), whereas that of triglycerides was not significantly affected by the treatment.This study shows a direct correlation between postprandial hyperglycemia and the production of nitrotyrosine, a marker of oxidative stress, in patients with type 2 diabetes.