tbuckley/cabot-search huggingface dataset:
The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart
Authors: W HOOGAARS
Journal: Cardiovascular Research (2004)

The molecular mechanisms that regulate the formation of the conduction system are poorly understood. We studied the developmental expression pattern and functional aspects of the T-box transcription factor Tbx3, a novel marker for the murine central conduction system (CCS).The patterns of expression of Tbx3, and of Cx40, Cx43, and Nppa, which are markers for atrial and ventricular chamber-type myocardium in the developing heart, were analyzed in mice by in situ hybridization and three-dimensional reconstruction analysis. The function of Tbx3 in regulating Nppa and Cx40 promoter activity was studied in vitro.In the formed heart, Tbx3 is expressed in the sinoatrial node (SAN), atrioventricular node (AVN), bundle and proximal bundle branches (BBs), as well as the internodal regions and the atrioventricular region. Throughout cardiac development, Tbx3 is expressed in an uninterrupted myocardial domain that extends from the sinoatrial node to the atrioventricular region. This expression domain is present in the looping heart tube from E8.5 onwards. Expression of the chamber-type myocardial markers is specifically absent from the Tbx3 expression domain. Tbx3 is able to repress Nppa and Cx40 promoter activity and abolish the synergistic activation of the Nppa promoter by Tbx5 and Nkx2.5.We identified the T-box transcription factor Tbx3 as a novel and accurate marker for the central conduction system. Our analysis implicates a role for Tbx3 in repressing a chamber-specific program of gene expression in regions from which the components of the central conduction system are subsequently formed.
Loss of Reduced Folate Carrier Function and Folate Depletion Result in Enhanced Pemetrexed Inhibition of Purine Synthesis
Authors: Rongbao Zhao, Shubing Zhang, Marie Hanscom, Shrikanta Chattopadhyay, I. David Goldman
Journal: Clinical Cancer Research (2005)

Abstract Pemetrexed is a novel antifolate with polyglutamate derivatives that are potent inhibitors of thymidylate synthase (TS) and to a lesser extent glycinamide ribonucleotide formyltransferase (GARFT). Conditions that might modulate relative suppression of these sites were assessed by the pattern of hypoxanthine and thymidine protection. When grown with 25 nmol/L racemic 5-formyltetrahydrofolate, thymidine alone fully protected wild-type HeLa cells to at least 1 μmol/L pemetrexed, but protection of a reduced folate carrier (RFC)-null subline required both thymidine and hypoxanthine above a concentration of 30 nmol/L pemetrexed. As medium 5-formyltetrahydrofolate was decreased, protection by thymidine alone decreased, and was further diminished when HeLa cells were grown in dialyzed serum. There was little protection by thymidine of RFC-null HeLa cells under the latter conditions. Thymidine alone was not protective, and hypoxanthine alone produced only a small (2-fold) increase in IC50, in a HeLa-derived line 8-fold resistant to pemetrexed due to a modest increase in TS. Finally, in MCF-7 breast cancer cells there was greater protection with thymidine alone than in HeLa cells when cells were grown in medium containing a low concentration of 5-formyltetrahydrofolate. These observations indicate that as intracellular folates decrease in HeLa cells, due to decreased extracellular reduced folate, or loss of RFC function, pemetrexed inhibition of GARFT increases. These data support the concept that the contribution to pemetrexed activity by inhibition of GARFT, particularly at low folate levels, is a contributing factor to drug activity but relative inhibition of TS and GARFT may vary among human tumors and cell lines.
Comparison of the Short-Term Risk of Bleeding and Arterial Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Newly Treated With Dabigatran or Rivaroxaban Versus Vitamin K Antagonists
Authors: Géric Maura, Pierre-Olivier Blotière, Kim Bouillon, Cécile Billionnet, Philippe Ricordeau, François Alla, Mahmoud Zureik
Journal: Circulation (2015)

Background— The safety and effectiveness of non–vitamin K antagonist (VKA) oral anticoagulants, dabigatran or rivaroxaban, were compared with VKA in anticoagulant-naive patients with nonvalvular atrial fibrillation during the early phase of anticoagulant therapy. Methods and Results— With the use of the French medico-administrative databases (SNIIRAM and PMSI), this nationwide cohort study included patients with nonvalvular atrial fibrillation who initiated dabigatran or rivaroxaban between July and November 2012 or VKA between July and November 2011. Patients presenting a contraindication to oral anticoagulants were excluded. Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, or December 31 of the inclusion year. Hazard ratios of hospitalizations for bleeding and arterial thromboembolic events were estimated in an intent-to-treat analysis using Cox regression models. The population was composed of 19 713 VKA, 8443 dabigatran, and 4651 rivaroxaban new users. All dabigatran- and rivaroxaban-treated patients were matched to 16 014 and 9301 VKA-treated patients, respectively. Among dabigatran-, rivaroxaban-, and their VKA-matched–treated patients, 55 and 122 and 31 and 68 bleeding events and 33 and 58 and 12 and 28 arterial thromboembolic events were observed during follow-up, respectively. After matching, no statistically significant difference in bleeding (hazard ratio, 0.88; 95% confidence interval, 0.64–1.21) or thromboembolic (hazard ratio, 1.10; 95% confidence interval, 0.72–1.69) risk was observed between dabigatran and VKA new users. Bleeding (hazard ratio, 0.98; 95% confidence interval, 0.64–1.51) and ischemic (hazard ratio, 0.93; 95% confidence interval, 0.47–1.85) risks were comparable between rivaroxaban and VKA new users. Conclusions— In this propensity-matched cohort study, our findings suggest that physicians should exercise caution when initiating either non-VKA oral anticoagulants or VKA in patients with nonvalvular atrial fibrillation.
The PRaCTICaL study of nurse led, intensive care follow-up programmes for improving long term outcomes from critical illness: a pragmatic randomised controlled trial
Authors: B H Cuthbertson, J Rattray, M K Campbell, M Gager, S Roughton, A Smith, A Hull, S Breeman, J Norrie, D Jenkinson, R Hernandez, M Johnston, E Wilson, C Waldmann
Journal: BMJ (2009)

<b>Objectives</b> To test the hypothesis that nurse led follow-up programmes are effective and cost effective in improving quality of life after discharge from intensive care. <b>Design</b> A pragmatic, non-blinded, multicentre, randomised controlled trial. <b>Setting</b> Three UK hospitals (two teaching hospitals and one district general hospital). <b>Participants</b> 286 patients aged ≥18 years were recruited after discharge from intensive care between September 2006 and October 2007. <b>Intervention</b> Nurse led intensive care follow-up programmes versus standard care. <b>Main outcome measure(s)</b> Health related quality of life (measured with the SF-36 questionnaire) at 12 months after randomisation. A cost effectiveness analysis was also performed. <b>Results</b> 286 patients were recruited and 192 completed one year follow-up. At 12 months, there was no evidence of a difference in the SF-36 physical component score (mean 42.0 (SD 10.6) <i>v</i> 40.8 (SD 11.9), effect size 1.1 (95% CI −1.9 to 4.2), P=0.46) or the SF-36 mental component score (effect size 0.4 (−3.0 to 3.7), P=0.83). There were no statistically significant differences in secondary outcomes or subgroup analyses. Follow-up programmes were significantly more costly than standard care and are unlikely to be considered cost effective. <b>Conclusions</b> A nurse led intensive care follow-up programme showed no evidence of being effective or cost effective in improving patients’ quality of life in the year after discharge from intensive care. Further work should focus on the roles of early physical rehabilitation, delirium, cognitive dysfunction, and relatives in recovery from critical illness. Intensive care units should review their follow-up programmes in light of these results. <b>Trial registration</b> ISRCTN 24294750
Femoral head alive 16 years after a non-consolidated intracapsular fracture of the femoral neck. An anatomical and radiological study.
Authors: R Lagier, J Forestier
Journal: Annals of the Rheumatic Diseases (1973)

Before the era of modern therapy, intracapsular fractures of the femoral neck were notorious for their frequent lack of union.The head frequently developed aseptic necrosis, but occasionally it retained its vitality.It is now difficult to observe such 'pure' cases, un- modified by surgery.A femoral head which retained its vitality under such circumstances has been studied both radiologically and anatomically.This is now described, not because of its rarity, but because it permits certain observations on an interesting point of articular pathology-the natural history of a femoral head which is placed in an abnormal mechanical and nutritional situation for purely local and accidental reasons.
Report shows strong sex differences in teenage health behaviour
Authors: Bryan Christie
Journal: BMJ (2004)

Strong sex differences have been found in the health behaviours of school age children across Europe and North America in one of the largest surveys ever carried out into young people's health.

The study, funded by the World Health Organization, is based on interviews with 162 000 young people, aged 11, 13, and 15 in 35 countries. It found that girls are more concerned about their body size, yet boys are more likely to be overweight.

Girls in all countries reported a poorer health …
Beneficial Effects of Inhibition of Angiotensin-Converting Enzyme on Ischemic Myocardium During Coronary Hypoperfusion in Dogs
Authors: Masafumi Kitakaze, Tetsuo Minamino, Koichi Node, Kazuo Komamura, Yoshiro Shinozaki, Hidezo Mori, Hiroaki Kosaka, Michitoshi Inoue, Masatsugu Hori, Takenobu Kamada
Journal: Circulation (1995)

Background Angiotensin-converting enzyme (ACE) produces angiotensin II, causing vasoconstriction of coronary arteries and reduction of coronary blood flow. The present study was undertaken to test the hypothesis that an ACE inhibitor increases coronary blood flow and improves myocardial metabolic and contractile functions of ischemic myocardium. Methods and Results In 65 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When cilazaprilat (3 μg/kg per minute) was infused into the bypass tube for 10 minutes after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 30±1 to 43±2 mL/100 g per minute despite there being no changes in coronary perfusion pressure (43±1 mm Hg). The ratio of myocardial endocardial flow to epicardial flow increased during an infusion of cilazaprilat. Both fractional shortening and lactate extraction ratio of the perfused area were increased (fractional shortening: 4.1±0.6% to 8.9±0.6%, P &lt;.001; lactate extraction ratio: −55.7±3.3% to −36.7±3.9%, P &lt;.001). During an infusion of cilazaprilat, the bradykinin concentration of coronary venous blood was markedly increased. The increased coronary blood flow due to cilazaprilat was attenuated by HOE-140 (an inhibitor of bradykinin receptors; coronary blood flow: 35±2 mL/100 g per minute), and by N ω -nitro- l -arginine methyl ester (an inhibitor of nitric oxide synthase; coronary blood flow: 34±2 mL/100 g per minute). Intracoronary administration of bradykinin mimicked the beneficial effects of cilazaprilat. Cyclic GMP content of the coronary artery was increased by cilazaprilat compared with the untreated condition in the ischemic myocardium. In the denervated hearts, the increased coronary blood flow due to cilazaprilat was not attenuated. On the other hand, CV11974, an inhibitor of angiotensin II receptors, slightly increased coronary blood flow to 34±2 from 30±1 mL/100 g per minute. Conclusions We conclude that an inhibitor of ACE can increase coronary blood flow and ameliorate myocardial ischemia, primarily due to accumulation of bradykinin and production of nitric oxide from the ischemic myocardium. Inhibition of angiotensin II production due to inhibition of ACE partially contributes to coronary vasodilation in the ischemic myocardium.
Cisplatin nephrotoxicity aggravated by cardiovascular disease and diabetes in lung cancer patients
Authors: C. Máthé, A. Bohács, L. Duffek, J. Lukácsovits, Z.I. Komlosi, K. Szondy, I. Horváth, V. Müller, G. Losonczy
Journal: European Respiratory Journal (2010)

Ageing lung cancer patients may be at increased risk of Cisplatin (Cp) nephrotoxicity, because of comorbidities leading to accelerated ageing of the kidneys. Therefore, the Cp-induced impairement of renal function was compared between no comorbidity (NC) and hypertension plus ischaemic heart disease (CD) patients or others having diabetes mellitus plus ischaemic heart disease (DMIH). In a preliminary study, glomerular filtration rate (GFR) was measured by clearance of technetium 99m-labelled diethylene-thiamine penta-acetate in 38 lung cancer patients with normal serum creatinine concentration ([creat]). Then, the incidence of nephrotoxicity was analysed retrospectively over 1st–4th cycles of Cp treatment among 242 lung cancer patients with initially normal [creat]. GFR was repeatedly estimated using calculated creatinine clearance. Pre-treatment GFR was 57±3 mL·min −1 ·m −2 in those with normal (n = 15) and 42±2 mL·min −1 ·m −2 in those with pathologically increased (n = 23) [creat] any time following their 2nd–4th Cp cycle (p&lt;0.05). The retrospective analysis revealed that Cp-induced nephrotoxicity developed in 7.5% of the NC (n = 80), in 20.9% of the CD (n = 110) and in 30.8% of the DMIH (n = 52) subgroups. Within the overall dropout rate from further Cp chemotherapy, nephrotoxicity was responsible in 14% of NC, 38% in CD and 75% in DMIH patients. A major portion of our ageing lung cancer patients suffered from comorbidities leading to reduced renal resistance to Cp nephrotoxicity.
Citalopram is safe
Authors: A S Hale
Journal: BMJ (1998)

EDITOR Power comments on my assertion that all selective serotonin reuptake inhibitors seem safe in overdose,1 citing six published cases of suicide in which citalopram was strongly suggested to have caused death. Although no drug is absolutely safe in overdose, the relative safety of the selective serotonin reuptake inhibitors compared with tricyclic antidepressants in this regard has been shown …
Imatinib inhibits bone marrow-derived c-kit+ cell mobilisation in hypoxic pulmonary hypertension
Authors: N. Gambaryan, F. Perros, D. Montani, S. Cohen-Kaminsky, G.M. Mazmanian, M. Humbert
Journal: European Respiratory Journal (2010)

Sarcoidosis and lymphoma, mainly NHL, may occur together, with sarcoidosis usually preceding lymphoma.Because many features of sarcoidosis and lymphoma are similar, histological confirmation of malignancy is necessary, especially if new nodal disease and splenomegaly are present.Sarcoidosis, although rare, may complicate the course of lymphoma.Prominent features of sarcoidosis were respiratory symptoms, high ACE levels, BHL in asymptomatic subjects and lung disease.Despite the limitations of this study, the above described features should alert clinicians to pursue a second diagnosis, in order either to properly diagnose malignancy in the sarcoidosis setting or to save cancer patient from a potentially toxic treatment escalation due to a presumed lymphoma recurrence.
Drug for Esophagitis and GERD
Authors: Bernard A. Schwetz
Journal: JAMA (2001)

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SURFACE TENSION OF SERUM
Authors: P. Lecomte du Noüy
Journal: The Journal of Experimental Medicine (1922)

1. The equilibrium of the serum corresponding to its normal minimal surface tension is as stable and difficult to break, under ordinary conditions, as the osmotic tension equilibrium. The addition of a strong surface-active substance (sodium oleate, glycocholate, or taurocholate), will not lower it definitely, unless the substance is present in large amounts and in solution. After the first rapid drop has occurred, a process of recovery takes place, which brings back the normal surface tension in a short time (from 2 to 6 minutes in the case of pure serum). As a drop in the surface tension of the serum of animals may be very injurious to the red cells, this process of recovery is a normal one of defense in all cases in which surface-active substances (bile) are set free in the blood. 2. When diluted, the serum shows the same phenomenon to a smaller extent; the time of recovery is very much longer and the final surface tension is always lower than the original value. At a dilution of 1/10,000, no recovery takes place, the dilution being too high to overcome the lowering action of 1/10,000 of sodium oleate. 3. The recovery is stronger when the surface-active substance is added powdered or in a highly concentrated solution, and not stirred. 4. The recovery does not seem to be inversely proportional to the concentration of sodium oleate, when added superficially. Doubling the concentration at 1/2,000, for example, gives the same curve of recovery. This happens under certain conditions; namely, when the liquid is not stirred after the addition of sodium oleate. 5. This recovery is due to a purely physical phenomenon, namely adsorption, and is not specific for the serum. Other colloidal solutions, such as gum arabic, egg albumin, gelatin, and silver and gold sols, show it, only to a smaller degree. The process of recovery follows a logarithmic law in all cases, expressed by an equation of the form See PDF for Equation 6. Temperature affects this phenomenon. At first it enhances it, but finally decreases it. This would seem to connect the loss of the property of the serum known as complement in a serum with a modification of the physical properties of this serum. This phenomenon is being investigated further.
Antitumor Effect of SN-38–Releasing Polymeric Micelles, NK012, on Spontaneous Peritoneal Metastases from Orthotopic Gastric Cancer in Mice Compared with Irinotecan
Authors: Takako Eguchi Nakajima, Kazuyoshi Yanagihara, Misato Takigahira, Masahiro Yasunaga, Ken Kato, Tetsuya Hamaguchi, Yasuhide Yamada, Yasuhiro Shimada, Keichiro Mihara, Takahiro Ochiya, Yasuhiro Matsumura
Journal: Cancer Research (2008)

Abstract 7-Ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity. Moreover, we have reported the strong antitumor activity of NK012 (i.e., SN-38–releasing polymeric micelles) against human cancer xenografts compared with CPT-11. Here, we investigated the advantages of NK012 over CPT-11 treatment in mouse models of gastric cancer with peritoneal dissemination. NK012 or CPT-11 was i.v. administered thrice every 4 days at their respective maximum tolerable doses (NK012, 30 mg/kg/day; CPT-11, 67 mg/kg/day) to mice receiving orthotopic transplants of gastric cancer cell lines (44As3Luc and 58As1mLuc) transfected with the luciferase gene (n = 5). Antitumor effect was evaluated using the photon counting technique. SN-38 concentration in gastric tumors and peritoneal nodules was examined by high-performance liquid chromatography (HPLC) 1, 24, and 72 hours after each drug injection. NK012 or CPT-11 distribution in these tumors was evaluated using a fluorescence microscope on the same schedule. In both models, the antitumor activity of NK012 was superior to that of CPT-11. High concentrations of SN-38 released from NK012 were detected in gastric tumors and peritoneal nodules up to 72 hours by HPLC. Only a slight conversion from CPT-11 to SN-38 was observed from 1 to 24 hours. Fluorescence originating from NK012 was detected up to 72 hours, whereas that from CPT-11 disappeared until 24 hours. NK012 also showed antitumor activity against peritoneal nodules. Thus, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. [Cancer Res 2008;68(22):9318–22]
Cellular Regulation by Hydrogen Peroxide
Authors: Sue Goo Rhee, Tong-Shin Chang, Yun Soo Bae, Seung-Rock Lee, Sang Won Kang
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Substantial evidence suggests that the transient production of H<sub>2</sub>O<sub>2</sub> is an important signaling event triggered by the activation of various cell surface receptors. Understanding the intracellular messenger function of H<sub>2</sub>O<sub>2</sub> calls for studies of how receptor occupation elicits the production of H<sub>2</sub>O<sub>2</sub>, what kinds of molecules are targeted by the produced H<sub>2</sub>O<sub>2</sub>, and how H<sub>2</sub>O<sub>2</sub> is eliminated after the completion of its mission. Recent studies suggest that growth factor–induced H<sub>2</sub>O<sub>2</sub> production requires the activation of PtdIns 3-kinase. The essential role of PtdIns 3-kinase is likely to provide PI(3,4,5)P<sub>3</sub> that recruits and activates a guanine nucleotide exchange factor of Rac, which is required for the activation of NADPH oxidase. The targets of H<sub>2</sub>O<sub>2</sub> action include proteins that contain a reactive Cys residue. Thus, H<sub>2</sub>O<sub>2</sub> produced in response to growth factor causes inactivation of protein tyrosine phosphatases in various cells by oxidizing specifically the catalytic Cys. These results, together with other observations, indicate that the activation of a receptor tyrosine kinase <i>per se</i> by binding of the corresponding growth factor might not be sufficient to increase the steady-state level of protein tyrosine phosphorylation in cells. Rather, the concurrent inhibition of protein tyrosine phosphatases by H<sub>2</sub>O<sub>2</sub> might also be required. Peroxiredoxins, members of a newly discovered family of peroxidases, efficiently reduced the intracellular level of H<sub>2</sub>O<sub>2</sub> produced in the cells stimulated with various cell surface ligands. Furthermore, the activity of peroxiredoxin enzymes seems to be regulated via protein phosphorylation as in the case of many other intracellular messenger metabolizing enzymes. E-mail: sgrhee@nih.gov