tbuckley/cabot-search huggingface dataset:
Caveolin Plays a Central Role in Endothelial Progenitor Cell Mobilization and Homing in SDF-1–Driven Postischemic Vasculogenesis
Authors: Elhem Sbaa, Julie DeWever, Philippe Martinive, Caroline Bouzin, Françoise Frérart, Jean-Luc Balligand, Chantal Dessy, Olivier Feron
Journal: Circulation Research (2006)

When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav −/− ), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1 + Lin − progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav −/− mice, suggesting a defect in progenitor mobilization. The adhesion of Cav −/− EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 ( S tromal cell– D erived F actor- 1 ) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Symmetrically, the attachment of Cav −/− EPC to SDF-1–presenting endothelial cells was significantly increased. Finally, EPC transduction with caveolin small interfering RNA reproduced this advantage in vitro and, importantly, led to a more extensive rescue of the ischemic hindlimb after intravenous infusion (versus sham-transfected EPC). These results underline the critical role of caveolin in ensuring the caveolae-mediated endocytosis of CXCR4, regulating both the SDF-1–mediated mobilization and peripheral homing of progenitor cells in response to ischemia. In particular, a transient reduction in caveolin expression was shown to therapeutically increase the engraftment of progenitor cells.
Mannose Receptor 2 Attenuates Renal Fibrosis
Authors: Jesús M. López-Guisa, Xiaohe Cai, Sarah J. Collins, Ikuyo Yamaguchi, Daryl M. Okamura, Thomas H. Bugge, Clare M. Isacke, Claire L. Emson, Scott M. Turner, Stuart J. Shankland, Allison A. Eddy
Journal: Journal of the American Society of Nephrology (2011)

Mannose receptor 2 (Mrc2) expresses an extracellular fibronectin type II domain that binds to and internalizes collagen, suggesting that it may play a role in modulating renal fibrosis. Here, we found that Mrc2 levels were very low in normal kidneys but subsets of interstitial myofibroblasts and macrophages upregulated Mrc2 after unilateral ureteral obstruction (UUO). Renal fibrosis and renal parenchymal damage were significantly worse in Mrc2-deficient mice. Similarly, Mrc2-deficient Col4α3−/− mice with hereditary nephritis had significantly higher levels of total kidney collagen, serum BUN, and urinary protein than Mrc2-sufficient Col4α3−/− mice. The more severe phenotype seemed to be the result of reduced collagen turnover, because procollagen III (α1) mRNA levels and fractional collagen synthesis in the wild-type and Mrc2-deficient kidneys were similar after UUO. Although Mrc2 associates with the urokinase receptor, differences in renal urokinase activity did not account for the increased fibrosis in the Mrc2-deficient mice. Treating wild-type mice with a cathepsin inhibitor, which blocks proteases implicated in Mrc2-mediated collagen degradation, worsened UUO-induced renal fibrosis. Cathepsin mRNA profiles were similar in Mrc2-positive fibroblasts and macrophages, and Mrc2 genotype did not alter relative cathepsin mRNA levels. Taken together, these data establish an important fibrosis-attenuating role for Mrc2-expressing renal interstitial cells and suggest the involvement of a lysosomal collagen turnover pathway.
Ascorbate Prevents the Interaction of Superoxide and Nitric Oxide Only at Very High Physiological Concentrations
Authors: Terence S. Jackson, Aiming Xu, Joseph A. Vita, John F. Keaney
Journal: Circulation Research (1998)

Abstract —The bioactivity of nitric oxide ( • NO) depends, in part, on its interaction with superoxide. Usually, superoxide dismutase (SOD) preserves • NO bioactivity by limiting the availability of superoxide. Ascorbic acid also effectively scavenges superoxide, but the extent to which this interaction is necessary for intact • NO bioactivity is not known. Therefore, the present study examined the effect of ascorbic acid on • NO bioactivity with isolated rabbit arterial segments. A steady flux of superoxide (1.15 to 2.3 μmol · L −1 · min −1 ) produced either by pyrogallol autoxidation or a hypoxanthine/xanthine oxidase system inhibited endothelium-derived • NO-mediated arterial relaxation elicited by acetylcholine. This effect of superoxide was completely blocked by SOD (300 IU/mL) and the manganese SOD mimic EUK-8 (300 μmol/L) and partially inhibited by ascorbic acid (10 mmol/L). Lower concentrations of ascorbic acid were ineffective despite scavenging &gt;90% of superoxide. We increased the endogenous flux of superoxide (3.2±0.3-fold) by inhibiting vascular copper-zinc SOD with diethyldithiocarbamate. This increased endogenous flux of superoxide produced an impairment of • NO-mediated arterial relaxation that was reversed by EUK-8 (300 μmol/L) but not ascorbic acid (10 mmol/L) despite equivalent scavenging of the endogenous superoxide flux. We used 3-nitrotyrosine formation (from peroxynitrite) as an indicator of • NO interaction with superoxide and found that SOD and EUK-8 compete more effectively with • NO for superoxide than does ascorbic acid. These data indicate that preservation of • NO bioactivity by superoxide scavengers depends not only on superoxide scavenging activity, but also on the rate of superoxide scavenging. Normal extracellular concentrations of ascorbic acid (30 to 150 μmol/L) are not likely to prevent the interaction of • NO with superoxide under physiological conditions.
Extracellular Matrix Metalloproteinase Inducer (CD147) Is a Novel Receptor on Platelets, Activates Platelets, and Augments Nuclear Factor κB–Dependent Inflammation in Monocytes
Authors: Roland Schmidt, Andreas Bültmann, Sina Fischel, Angelika Gillitzer, Paul Cullen, Axel Walch, Philipp Jost, Martin Ungerer, Neal D. Tolley, Stephan Lindemann, Meinrad Gawaz, Albert Schömig, Andreas E. May
Journal: Circulation Research (2007)

In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation and enhanced recruitment of leukocytes into the vascular wall. The invasion of monocytes is accompanied by overexpression of matrix metalloproteinases (MMPs), which are thought to promote atherosclerosis and trigger plaque rupture. Following interaction with itself, the extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed upregulation of EMMPRIN on monocytes during acute myocardial infarction. EMMPRIN also stimulates secretion of MMP-9 by monocytes and of MMP-2 by smooth muscle cells, indicating that it may be an important regulator of MMP activity. Expression of EMMPRIN on platelets has not been described until now. Here, we demonstrate that resting platelets show low surface expression of EMMPRIN, which is upregulated by various platelet stimulators (flow cytometry). EMMPRIN is located in the open canalicular system and in α granules of platelets (according to electron microscopy and sucrose gradient ultracentrifugation). Platelet stimulation with recombinant EMMPRIN-Fc induced surface expression of CD40L and P-selectin (according to flow cytometry), suggesting that EMMPRIN-EMMPRIN interaction activates platelets. Coincubation of platelets with monocytes induced EMMPRIN-mediated nuclear factor κB activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor-α secretion (according to ELISA) by monocytes. In conclusion, EMMPRIN displays a new platelet receptor that is upregulated on activated platelets. Binding of EMMPRIN to platelets fosters platelet degranulation. Platelet–monocyte interactions via EMMPRIN stimulate nuclear factor κB–driven inflammatory pathways in monocytes, such as MMP and cytokine induction. Thus, EMMPRIN may represent a novel target to diminish the burden of protease activity and inflammation in atherosclerosis.
The effect of faecal diversion on human ileum
Authors: L. Williams, M. Armstrong, P. Finan, P. Sagar, D. Burke
Journal: Gut (2007)

<b>Background:</b> The use of a loop ileostomy is an effective method in protecting pelvic anastomoses. Its use has increased recently, although there is some debate as to the routine use of a stoma. Reversal of the ileostomy is associated with a significant morbidity, which may be related to impaired function of the bypassed distal limb of the ileum. <b>Aim:</b> To investigate the changes that might occur in the distal limb after an interval of faecal diversion. <b>Methods:</b> Full-thickness intestinal circular muscle (CM) strips were prepared from excised loop ileostomies taken at the time of closure. The study sample was from the distal limb and the control from the proximal limb. Contractile activity was measured using an organ bath set up to record isometric contraction after stimulation by acetylcholine (ACh). Histological sections were assessed for an index of villous atrophy, smooth muscle area, and nerve and vessel density. Analysis was with the Wilcoxon signed ranks test for paired data and the Mann–Whitney U test for unpaired data. <b>Results:</b> Samples were acquired prospectively from 35 consecutive patients. The median time between formation and closure of ileostomy was 34 weeks. Significant reduction was observed in the strength of CM contraction, smooth muscle area and median villous index of the distal limb compared with the proximal limb. <b>Conclusion:</b> Impaired intestinal function has been proposed as a contributory factor in the morbidity that may follow closure of loop ileostomy. Significant loss of contractility and smooth muscle strength and villous atrophy occur in the distal ileal limb after faecal diversion. Methods of preventing these changes should be considered.
<i>miR-146a</i> controls the resolution of T cell responses in mice
Authors: Lili Yang, Mark P. Boldin, Yang Yu, Claret Siyuan Liu, Chee-Kwee Ea, Parameswaran Ramakrishnan, Konstantin D. Taganov, Jimmy L. Zhao, David Baltimore
Journal: The Journal of Experimental Medicine (2012)

T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell–mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.
Psychiatrists' attitudes to abortion.
Authors: J C Little
Journal: BMJ (1972)

SIR,-In your leading article on "Clofibrate in Ischaemic Heart Disease" (25 December, p. 765) mention is made of the numbers and percentages of patients in the clofibrate and placebo groups who "died suddenly from myocardial infarction."This statement embraces both sudden deaths and fatal myocardial infarction.In the analysis of the results we deliberately distinguished sudden deaths from fatal myocardial infarcts and believe that this distinction may be important in such clinical trials.-Weare, etc.,
Effects of<i>In Utero</i>and Environmental Tobacco Smoke Exposure on Lung Function in Boys and Girls with and without Asthma
Authors: YU-FEN LI, FRANK D. GILLILAND, KIROS BERHANE, ROB McCONNELL, W. JAMES GAUDERMAN, EDWARD B. RAPPAPORT, JOHN M. PETERS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

To investigate whether the effects of in utero exposure to maternal smoking and environmental tobacco smoke (ETS) exposure on lung function vary by sex or asthma status, we examined medical history and tobacco smoke exposure data for 5,263 participants in the Children's Health Study. At study enrollment, parents or guardians of each subject completed a questionnaire, and lung function was measured spirometrically with maximum forced expiratory flow-volume maneuvers. To assess the in utero effects of maternal smoking and ETS exposure on lung function, we used regression splines that accounted for the nonlinear relationship between pulmonary function, height, and age. In utero exposure to maternal smoking was independently associated with deficits in lung function that were larger for children with asthma. Boys and girls with a history of in utero exposure to maternal smoking showed deficits in maximum midexpiratory flow (MMEF) and a decrease in the FEV(1)/FVC ratio. As compared with children without asthma, boys with asthma had significantly larger deficits from in utero exposure in FVC, MMEF, and FEV(1)/FVC, and girls with asthma had larger decreases in FEV(1)/FVC. The effect of ETS exposure varied by children's gender and asthma status. Deficits in flows associated with current ETS exposure were present in children with and without asthma but were significant only among children without asthma. Past ETS exposure was associated with reduced FEV(1), MMEF, and FEV(1)/FVC among boys with asthma. In contrast, past ETS exposure was associated with decreased flow rates in girls without asthma. In summary, both in utero exposure to maternal smoking and ETS exposure were associated with persistent deficits in lung function. The effects of in utero exposure were greatest among children with asthma.
Postmastectomy Radiation Therapy and Breast Reconstruction—Marching Forward Together or Apart?
Authors: Abram Recht
Journal: JAMA Oncology (2015)

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Effects of Cardiovascular Disease Risk Communication for Patients With Type 2 Diabetes on Risk Perception in a Randomized Controlled Trial
Authors: Laura M.C. Welschen, Sandra D.M. Bot, Piet J. Kostense, Jacqueline M. Dekker, Daniëlle R.M. Timmermans, Trudy van der Weijden, Giel Nijpels
Journal: Diabetes Care (2012)

OBJECTIVE Patients with type 2 diabetes mellitus (T2DM) underestimate their risk of developing severe complications, and they do not always understand the risk communication by their caregivers. The aim of this study was to investigate the effects of an intervention focused on the communication of the absolute 10-year risk of developing cardiovascular disease (CVD) in patients with T2DM. RESEARCH DESIGN AND METHODS A randomized controlled trial was performed in T2DM patients newly referred to the Diabetes Care System (DCS) West-Friesland, a managed-care system in the Netherlands. The intervention group (n = 131) received a six-step CVD risk communication. Control subjects (n = 130) received standard managed care. The primary outcome measure was appropriateness of risk perception (difference between actual CVD risk calculated by the UK Prospective Diabetes Study risk engine and risk perception). Secondary outcome measures were illness perceptions, attitude and intention to change behavior, satisfaction with the communication, and anxiety and worry about CVD risk. Patients completed questionnaires at baseline, at 2 weeks (immediately after the intervention), and at 12 weeks. RESULTS Appropriateness of risk perception improved between the intervention and control groups at 2 weeks. This effect disappeared at 12 weeks. No effects were found on illness perceptions, attitude and intention to change behavior, or anxiety and worry about CVD risk. Patients in the intervention group were significantly more satisfied with the communication. CONCLUSIONS This risk communication method improved patients’ risk perception at 2 weeks but not at 12 weeks. Negative effects were not found, as patients did not become anxious or worried after the CVD risk communication.
Ckap2 Regulates Aneuploidy, Cell Cycling, and Cell Death in a p53-Dependent Manner
Authors: Katsuya Tsuchihara, Valentina Lapin, Christopher Bakal, Hitoshi Okada, Lauren Brown, Masami Hirota-Tsuchihara, Kathrin Zaugg, Alexandra Ho, Annick Itie-YouTen, Marees Harris-Brandts, Robert Rottapel, Christopher D. Richardson, Samuel Benchimol, Tak Wah Mak
Journal: Cancer Research (2005)

Abstract We used DNA microarray screening to identify Ckap2 (cytoskeleton associated protein 2) as a novel p53 target gene in a mouse erythroleukemia cell line. DNA damage induces human and mouse CKAP2 expression in a p53-dependent manner and p53 activates the Ckap2 promoter. Overexpressed Ckap2 colocalizes with and stabilizes microtubules. In p53-null cells, overexpression of Ckap2 induces tetraploidy with aberrant centrosome numbers, suggesting disturbed mitosis and cytokinesis. In p53-competent cells, Ckap2 does not induce tetraploidy but activates p53-mediated cell cycle arrest and apoptosis. Our data suggest the existence of a functional positive feedback loop in which Ckap2 activates the G1 tetraploidy checkpoint and prevents aneuploidy.
Effective Treatment of Pancreatic Cancer Xenografts with a Conditionally Replicating Virus Derived from Type 2 Herpes Simplex Virus
Authors: Xinping Fu, Lihua Tao, Min Li, William E. Fisher, Xiaoliu Zhang
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Pancreatic cancer is a devastating disease that is almost universally fatal because of the lack of effective treatments. We recently constructed a novel oncolytic virus (FusOn-H2) from the type 2 herpes simplex virus. Because the replication potential of FusOn-H2 depends on the activation of the Ras signaling pathway, we evaluated its antitumor effect against pancreatic cancer, which often harbors K-ras gene mutations. Experimental Design: Human pancreatic cancer xenografts were established in nude mice either s.c. or orthotopically (n = 8/group). FusOn-H2 was injected either directly (s.c. tumors) or by the i.v. or i.p. route (orthotopic tumors). Tumor volume, weight, and survival time were recorded for each animal. Statistical analyses were done by Student's t test. Results: A single intratumor injection of FusOn-H2 completely eradicated s.c. pancreatic cancers in all animals. Systemic injection of the oncolytic virus produced clear antitumor effects but did not abolish tumors in any animal. The most striking antitumor effect was seen when the virus was given i.p. Delivery of FusOn-H2 by this route completely eradicated established orthotopic tumors in 75% of the animals and completely prevented local metastases. Conclusions: FusOn-H2 has potent activity against human pancreatic cancer xenografts and may be a promising candidate for investigative virotherapy of this malignancy.
Intensification of Insulin Therapy for Type 2 Diabetic Patients in Primary Care: Basal-Bolus Regimen Versus Premix Insulin Analogs
Authors: Ofri Mosenzon, Itamar Raz
Journal: Diabetes Care (2013)

In April 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint position statement regarding treatment of hyperglycemia in type 2 diabetes, “Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach” (1). As most diabetic patients (>366 million worldwide) (2) are treated by their primary family physician and not by an endocrinologist or diabetologist, the guidelines were intended to help physicians choose the best treatment for their patients. Some of the advantages of this position statement, over previous guidelines (3–8), are as follows: emphasizing the importance of individualization of treatment, widening treatment options, and stating the pros and cons of the different treatment option. However, as the statement was written by a group of world-known diabetologists, without the input of nurses, dietitians, family physicians, or the patients themselves, questions have been raised as to how “patient-centered” it actually is and how useful and relevant it is to the primary care setting. Choosing the best insulin regimen for initiation and intensification of insulin therapy in type 2 diabetic patients is still debatable both in the specialist clinic and in the primary care setting. The intention of this article is to review the data available and offer reasonable guidance regarding the selection of the preferred insulin regimen for initiation and intensification of insulin treatment, especially in a primary care setting.

The ADA/EASD statement includes recommendations for the initiation and titration of insulin therapy (1). The recommendations point out three important aspects that need to be addressed when choosing or adjusting insulin regimens: the number of injections needed and the complexity and the flexibility of the regimens. The insulin regimens under consideration include basal insulin, premixed, basal insulin with one premeal short-acting insulin injection (referred to as basal plus regimen), and …
PEDIATRIC OBESITY AND INSULIN RESISTANCE: Chronic Disease Risk and Implications for Treatment and Prevention Beyond Body Weight Modification
Authors: M.L. Cruz, G.Q. Shaibi, M.J. Weigensberg, D. Spruijt-Metz, G.D.C. Ball, M.I. Goran
Journal: Annual Review of Nutrition (2005)

The study of childhood obesity has continued to grow exponentially in the past decade. This has been driven in part by the increasing prevalence of this problem and the widespread potential effects of increased obesity in childhood on lifelong chronic disease risk. The focus of this review is on recent findings regarding the link between obesity and disease risk during childhood and adolescence. We describe recent reports relating to type 2 diabetes in youth (2), prediabetes (69, 166), metabolic syndrome (33, 35), polycystic ovarian syndrome (77), and nonalcoholic fatty liver disease (58, 146), and the mediating role of insulin resistance in these conditions. In addition, we review the implications of this research for the design of more effective treatment and prevention strategies that focus more on the improvement of obesity-related metabolic abnormalities and chronic disease risk reduction than on the conventional energy balance approach that focuses on weight management.