tbuckley/cabot-search huggingface dataset:
Protease Nexin-1 Interacts With Thrombomodulin and Modulates Its Anticoagulant Effect
Authors: Marie-Christine Bouton, Laurence Venisse, Benjamin Richard, Cécile Pouzet, Véronique Arocas, Martine Jandrot-Perrus
Journal: Circulation Research (2007)

The endothelial cell membrane glycoprotein thrombomodulin (TM) plays a critical role in the regulation of coagulation. TM is an essential cofactor in protein C activation by thrombin, and a direct inhibitor of thrombin-induced platelet activation and fibrinogen clotting. Protease nexin-1 (PN-1) is a serpin synthesized and secreted by a variety of cells including endothelial cells. PN-1 bound to the cell surface through interactions with glycosaminoglycans, is an efficient inhibitor of thrombin and controls thrombin-induced cell responses. An investigation of the interaction of PN-1 with TM using purified proteins and cultured human aortic endothelial cells was performed. Purified PN-1 was observed to bind to purified TM in a concentration-dependent manner. Double immunofluorescence studies indicated that PN-1 and TM were colocalized at the endothelial cell surface from which they were coprecipitated. Pretreatment of the cells with chondroitinase ABC greatly decreased the amount of the PN-1 associated to TM at the cell surface demonstrating the involvement of the TM chondroitin-sulfate chain in the formation of complexes. The inhibitory activity of the PN-1/TM complexes on the catalytic activity of thrombin, and on thrombin-induced fibrinogen clotting, was markedly enhanced when compared with the inhibitory activity of each partner. PN-1-overexpressing human aortic endothelial cells and PN-1-underexpressing human aortic endothelial cells exhibited respectively a significantly reduced ability and enhanced capacity to activate protein C. Furthermore, PN-1 decreased the cofactor activity of TM on thrombin activable fibrinolysis inhibitor activation by thrombin. These data show for the first time that PN-1 forms complexes with TM and modulates its anticoagulant activity.
Pulmonary Gas Exchange in Nonnative Residents of High Altitude
Authors: F. C. Cerny, J. A. Dempsey, W. G. Reddan
Journal: Journal of Clinical Investigation (1973)

This study represented an initial attempt, by means of cross-sectional investigation, to determine the effects of chronic exposure to high altitude on pulmonary gas exchange. Single-breath D(Lco) and its components were determined at rest and during muscular work in two groups of healthy, non-smoking, sea level natives who had initiated 1-16 yr of residence at 3,100 m altitude either during physical maturation (at age 10+/-4 yr) or as adults (at age 26+/-4 yr). The relative degree of acclimatization achieved in these lowland residents was assessed through their comparison both with normal sea-level values and with two additional groups of short-term sojourners and natives to 3.100 m. D(Lco) at rest and work was significantly elevated above normal and above sojourner values in both groups of resident lowlanders at 3,100 m. The high D(Lco) in the native to 3,100 m was closely approximated in the younger resident lowlander at rest, but only during exercise in the adult resident lowlander. The high D(Lco) at rest and during exercise in the resident lowlanders was not attributable to differences in Hb concentration or in alveolar lung volume: and was accompanied primarily by an increased estimated Dm(co) and to a lesser extent by an expanded Vc. The interpretation and implications of these findings were limited by the low quantitative capability of Vc and Dm(co) estimates and by the cross-sectional nature of the study. Nevertheless, the higher than normal D(Lco) and Dm(co) in the non-native, long-term resident of 3,100 m was substantial, highly significant statistically, and consistent over a wide range of metabolic rates at rest and work. These data provide, then, a reasonable rationale upon which longitudinal experiments may be based to determine the true effects of chronic hypoxia on pulmonary gas exchange in man.
Cystic lung lesions as an immune reconstitution inflammatory syndrome (IRIS) in HIV-TB co-infection?
Authors: D Richardson
Journal: Thorax (2005)

A 33 year old man presented with a 3 week history of night sweats, fever, productive cough, and intermittent headaches. He was found to be HIV antibody positive and fully sensitive Mycobacterium tuberculosis was cultured from his cerebrospinal fluid, blood, and bronchoalveolar lavage fluid. He did not have Pneumocystis jiroveci . A thin section CT scan of his …
Postexercise Electrocardiogram in Patients With Abnormal Resting Electrocardiograms
Authors: PETER F. COHN, PANTEL S. VOKONAS, MICHAEL V. HERMAN, RICHARD GORLIN
Journal: Circulation (1971)

One hundred and ten patients with chest pain syndromes and resting electrocardiograms demonstrating ST-T abnormalities and/or prior transmural myocardial infarctions were studied by means of the Master's two-step exercise test and selective coronary cine arteriography. Criteria for negativity were modified so that subjects with postexercise heart rates less than 110 beats/min, who did not develop significant ST-segment changes, were excluded from evaluation. Eighty-six per cent of the coronary artery disease group and 27% of the normal coronary artery group had positive postexercise electrocardiograms. Conversely, of the patients with positive results, 88% had anatomic coronary artery disease. With this degree of stress, positive responses ≧2 mm were invariably associated with multi-vessel disease. The type of pre-existing ECG abnormality did not influence either the frequency or severity of positive responses. False-negative subjects had no distinctive features relating to type of abnormal electrocardiogram, or location of vessel involvement, although most of these patients had significant disease of only one major coronary artery.
Aortic Distensibility in Type 1 Diabetes
Authors: Evrim B. Turkbey, Alban Redheuil, Jye-Yu C. Backlund, Alexander C. Small, Patricia A. Cleary, John M. Lachin, Joao A.C. Lima, David A. Bluemke
Journal: Diabetes Care (2013)

To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes.Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models.The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (-26.3% per 10 years, -11.0% per 10 mmHg SBP, -1.8% per 10 mg/dL of LDL, and -9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (-3.4% per 0.1 g/mL; P < 0.0001).Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.
The Effect of Altitude on Dosing and Response to Erythropoietin in ESRD
Authors: M. Alan Brookhart, Sebastian Schneeweiss, Jerry Avorn, Brian D. Bradbury, Kenneth J. Rothman, Michael Fischer, Jyotsna Mehta, Wolfgang C. Winkelmayer
Journal: Journal of the American Society of Nephrology (2008)

For poorly understood reasons, patients with end-stage renal disease (ESRD) differ substantially in their response to treatment with recombinant erythropoietin (EPO). Because hypoxia influences many of the biologic pathways involved in erythropoiesis, the altitude at which a patient lives may affect the dose-response relationship of EPO. In this retrospective cohort study, clinical data from 341,737 incident hemodialysis patients registered in the U.S. Renal Data System were combined with elevation data from the U.S. Geological Survey to address this question. Higher altitude was associated with smaller EPO doses and higher hematocrit levels. For example, compared with patients at sea level, patients living above 6000 ft received 19% less EPO (12.9 versus 15.9 thousand units/wk) but had hematocrit levels 1.1 points higher (35.7% versus 34.6%). These associations were found within subgroups defined by sex, race, age, calendar time, cause of ESRD, and dialysis center profit status, and persisted after adjustment for various potential confounding factors. Furthermore, resistance to EPO decreased with elevation. Our results suggest that ESRD patients living at high altitude either increase endogenous EPO production or respond better to endogenous and exogenous EPO.
Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma
Authors: P G Gibson
Journal: Thorax (2003)

The relationship between the clinical pattern of asthma and airway inflammation in childhood asthma is poorly characterised, yet underpins the treatment recommendations in current asthma guidelines. A study was undertaken to examine the relationship between airway inflammation and clinical asthma in children.Children with asthma (n=146) and healthy controls (C, n=37) were recruited from primary and specialist clinics. Sputum induction and hypertonic saline challenge were performed.As the frequency of asthma episodes in the past 12 months increased, there were significant increases in sputum eosinophils (median; infrequent episodic (IE) 1.5%, frequent episodic (FE) 2.3%, persistent (P) 3.8%, control (C) 1.0%; p=0.002), sputum eosinophil cationic protein (ECP) (IE 113 ng/ml, FE 220, P 375, C 139; p=0.003), and desquamated bronchial epithelial cells (IE 2.0%, FE 6.0%, P 5.0%, C 2.5%; p=0.04). Treatment intensity was also associated with increased sputum eosinophils (p=0.005). The relationships between other severity markers (current symptoms, lung function) were less strong.Children with more frequent episodes of clinical asthma exhibit increasing airway inflammation that is characterised by sputum eosinophilia and bronchial epithelial desquamation. The results support clinical assessment by frequency of wheezing episodes over the past 12 months when determining anti-inflammatory treatment requirements, and indicate that current symptoms are determined by mechanisms in addition to sputum eosinophilia.
Notched T Waves on Holter Recordings Enhance Detection of Patients With LQT2 ( <i>HERG</i> ) Mutations
Authors: J. M. Lupoglazoff, I. Denjoy, M. Berthet, N. Neyroud, L. Demay, P. Richard, B. Hainque, G. Vaksmann, D. Klug, A. Leenhardt, G. Maillard, P. Coumel, P. Guicheney
Journal: Circulation (2001)

Background —The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. Methods and Results —The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P &lt;0.001). G1 notches were relatively more frequent in LQT2 (18% versus 8% [LQT1] and 4% [control], P &lt;0.01), and G2 notches were seen exclusively in LQT2 (63%). Predictors for G2 were young age, missense mutations, and core domain mutations in HERG . Conclusions —This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.
Variability, reproducibility, and applications of precordial ST-segment mapping following acute myocardial infarction.
Authors: T Hardarson, H Henning, R A O'Rourke, J S Karliner, W Ryan, J Ross
Journal: Circulation (1978)

In 58 patients with uncomplicated acute anterior myocardial infarction, a mean decline in the sum of ST segments (sigmaST) of 34% was observed when comparing sigmaST values recorded at 3-6 hours with those recorded at 6-9 hours after the onset of symptoms (P less than 0.05). The mean absolute difference between 19 paired readings 1-2 hours apart was 2.9 +/- 3.0 mm and between 29 readings 2-4 hours apart 3.0 +/- 3.0 mm. However, the mean absolute difference between 38 paired readings 4-8 hours apart was 12.2 +/- 11.8 mm with a wide range of differences. Left ventricular failure and pericarditis were also associated with significantly higher sigmaST values. We conclude that there is a complex relationship between ST-segment elevation and a number of clinical factors during the first 48 hours after infarction. Nevertheless, precordial mapping remains a useful method for the evaluation of short-term (less than 4 hours) therapeutic interventions, if other relevant variables are unaltered and if carefully matched control groups are employed.
Long-Term Safety and Efficacy of Empagliflozin, Sitagliptin, and Metformin
Authors: Ele Ferrannini, Andreas Berk, Stefan Hantel, Sabine Pinnetti, Thomas Hach, Hans J. Woerle, Uli C. Broedl
Journal: Diabetes Care (2013)

To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.Changes from baseline in HbA1c at week 90 were -0.34 to -0.63% (-3.7 to -6.9 mmol/mol) with empagliflozin, -0.56% (-6.1 mmol/mol) with metformin, and -0.40% (-4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were -2.2 to -4.0 kg with empagliflozin, -1.3 kg with metformin, and -0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2-74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0-5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8-12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.
A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity
Authors: Senthil K. Radhakrishnan, Andrei L. Gartel
Journal: Cancer Research (2006)

Abstract Using a high-throughput cell-based assay, we identified a nucleoside analogue 4-amino-6-hydrazino-7-β-d-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide (ARC), which has the properties of a general transcriptional inhibitor. Specifically, ARC inhibits the phosphorylation of RNA polymerase II by positive transcription elongation factor-b, leading to a block in transcriptional elongation. ARC was able to potently repress p53 targets p21 and hdm2 (human homologue of mdm2) protein levels, but dramatically increased p53 levels similar to other transcriptional inhibitors, including flavopiridol. This increase in p53 corresponded to the down-regulation of short-lived protein hdm2, which is a well-established negative regulator of p53. Remarkably, ARC induced potent apoptosis in human tumor and transformed, but not in normal cells, and possessed strong antiangiogenic activity in vitro. Although ARC promoted the accumulation of p53, ARC-induced apoptosis in tumor cells was p53-independent, suggesting that it may be useful for the treatment of tumors with functionally inactive p53. Furthermore, cell death induced by ARC had a strong correlation with down-regulation of the antiapoptotic gene survivin, which is often overexpressed in human tumors. Taken together, our data suggests that ARC may be an attractive candidate for anticancer drug development. (Cancer Res 2006; 66(6): 3264-70)
Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed of healthy volunteers
Authors: J. Baan, P. C. Chang, P. Vermeij, M. Pfaffendorf, P. A. van Zwieten
Journal: Cardiovascular Research (1996)

The angiotensin type 1 (AT1) receptor antagonist, losartan (orally administered), decreases vasoconstrictor effects of angiotensin II (Ang II). Oral losartan is converted into the active metabolite, Exp3174, which causes most of the antagonistic effects. Effects of losartan as such have not been studied after its intra-arterial administration in humans. Therefore, we investigated the effects of both intra-arterially and orally administered losartan on AT1-receptor-mediated vasoconstriction.Forearm vascular resistance (FVR) was determined by venous occlusion plethysmography in 24 healthy subjects. Ang II (0.01, 0.1, 1.0, and 10.0 ng/kg/min) was infused into the brachial artery, before and after losartan, administered intra-arterially (dose range 100-3000 ng/kg/min) or orally (50 mg once daily for 5 days).Ang II concentration-dependently increased FVR (P < 0.05); tachyphylaxis did not occur. Losartan alone did not change FVR. Intra-arterially infused losartan dose-dependently inhibited Ang-II-induced vasoconstriction. At a concentration of 10(-8) M Ang II, losartan reduced FVR, as a percentage of baseline values, from 287 +/- 30 to 33 +/- 8% (mean +/- s.e.m.; P < 0.05). Orally given losartan reduced FVR from 297 +/- 40 to 73 +/- 19% (P < 0.05).Losartan, intra-arterially administered, causes no effect on baseline vascular resistance, but markedly inhibits Ang-II-induced vasoconstriction in the human forearm vascular bed. Relatively high doses of intra-arterial losartan were required when compared to the antagonism by the orally administered drug. These data indicate that Ang-II-induced vasoconstriction is mediated by AT1-receptors, which are blocked by losartan. The more effective antagonism exerted by oral losartan is presumably explained by the formation of Exp3174. Endogenous Ang II does not contribute to baseline vascular tone in healthy, sodium-replete, subjects.
Involvement of vascular peroxidase 1 in angiotensin II-induced vascular smooth muscle cell proliferation
Authors: Ruizheng Shi, Changping Hu, Qiong Yuan, Tianlun Yang, Jun Peng, Yuanjian Li, Yongping Bai, Zehong Cao, Guangjie Cheng, Guogang Zhang
Journal: Cardiovascular Research (2011)

Vascular peroxidase 1 (VPO1) is a newly identified haem-containing peroxidase that catalyses the oxidation of a variety of substrates by hydrogen peroxide (H(2)O(2)). Considering the well-defined effects of H(2)O(2) on the vascular remodelling during hypertension, and that VPO1 can utilize H(2)O(2) generated from co-expressed NADPH oxidases to catalyse peroxidative reactions, the aims of this study were to determine the potential role of VPO1 in vascular remodelling during hypertension.The vascular morphology and the expression of VPO1 in arterial tissues of spontaneously hypertensive rats and Wistar-Kyoto rats were assessed. The VPO1 expression was significantly increased concomitantly with definite vascular remodelling assessed by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats. In addition, in cultured rat aortic smooth muscle cells we found that the angiotensin II-mediated cell proliferation was inhibited by knockdown of VPO1 using small hairpin RNA. Moreover, the NADPH oxidase inhibitor, apocynin, and the hydrogen peroxide scavenger, catalase, but not the ERK1/2 inhibitor, PD98059, attenuated angiotensin II-mediated up-regulation of VPO1 and generation of hypochlorous acid.VPO1 is a novel regulator of vascular smooth muscle cell proliferation via NADPH oxidase-H(2)O(2)-VPO1-hypochlorous acid-ERK1/2 pathways, which may contribute to vascular remodelling in hypertension.
Recurrence of Pressure Ulcers
Authors: J. Elizabeth Morgan
Journal: JAMA (1976)

THE RECURRENT pressure ulcer is a surgical failure in which not all contributing factors may be recognized. Even major rehabilitation centers struggle with a certain number of recurrences.<sup>1-3</sup>In 1964, Dansereau and Conway<sup>3</sup>reported the surgical treatment of 2,000 pressure ulcers. Recurrences developed in 5% of ischial ulcers, 14% of trochanteric ulcers, and 15% of sacral ulcers. We have cared for five paraplegic patients, all of whom had prolonged hospital courses because of recurrent pressure ulcers. In each of our five patients, their own carelessness contributed to recurrence. <h3>Report of Cases</h3> Five paraplegic patients were treated consecutively for recurrent pressure ulcers at the New England Medical Center Hospitals from September 1973 to October 1974. Each patient was paraplegic as a result of trauma and had undergone full rehabilitation in one or more institutions. Four of the five patients were under 30 years of age. Three were living at