tbuckley/cabot-search huggingface dataset:
Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis
Authors: C Albrecht, D K Meijer, C Lebbe, H Sagesser, B N Melgert, K Poelstra, J Reichen
Journal: Hepatology (1997)

Endotoxin is thought to play a major role in cirrhotic liver disease. Cyclo-oxygenase inhibitors were shown to be partially protective against endotoxin but cannot be used in cirrhotic patients because of renal side-effects. We argued that administration of naproxen (NAP) linked to human serum albumin (HSA), which results in specific delivery of NAP to endothelial cells (EC) and Kupffer cells (KC) and exhibited hepatoprotective effects against lipopolysaccharide (LPS) in vitro, could protect cirrhotic rats from LPS toxicity while preserving renal function. The studies were performed in rats rendered cirrhotic by bile duct ligation (BDL); animals received LPS ( Escherichia coli , 800 μg/kg) intravenously. Five groups were studied: LPS alone, rats pretreated with a conventional dose of NAP (50 mg/kg), NAP-HSA (22 mg/kg), NAP equimolar to NAP-HSA (1.5 mg/kg), or the HSA carrier. LPS induced significant mortality (55%); this was not affected by equimolar NAP (57%) but accentuated by conventional NAP (88%). In contrast, NAP-HSA provided significant protection (9%; P &lt; .05). After conventional NAP treatment, significant renal toxicity was observed as evidenced by a marked reduction in sodium excretion (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 33 ± 22 vs. 50 ± 39 vs. 4 ± 3 μmol/h; P &lt; .05). Renal prostaglandin E2 (PGE2) excretion was reduced by NAP in all groups, but most markedly at the conventional dosage (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 132 ± 115 vs. 39 ± 19 vs. 9 ± 8 ng/mL; P &lt; .05). Successful targeting was evidenced by a significant hepatic enrichment of NAP in the NAP-HSA group compared with the equimolar untargeted group (30.16 ± 9.33 vs. 1.13 ± 1.95 nmol/g liver). Thus, targeting NAP to EC/KC results in improved survival, higher efficacy, and sparing of renal function in cirrhotic rats.
c-Kit Expression in Patients with Uterine Leiomyosarcomas
Authors: Maria Rosaria Raspollini, Gianni Amunni, Alessandro Villanucci, Pamela Pinzani, Lisa Simi, Milena Paglierani, Gian Luigi Taddei
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Uterine leiomyosarcomas are rare tumors characterized by their resistance to chemotherapy and radiation treatment. Surgery is the primary method of treatment, but for patients with unresectable disease, alternate therapeutic options are clearly warranted. According to initial observations of c-KIT expression, correlation with a bad prognosis, and the successful therapeutic possibility of STI571 in gastrointestinal stromal tumors, the data have encouraged us to study c-KIT expression in these tumors. Experimental Design: We analyzed the expression of c-KIT and genetic assessment of exon 11 of c-kit gene in 32 uterine leiomyosarcomas. Results: In 17 cases (53.1%), we observed a c-KIT expression in tumor cells. Of the 17 patients with distinct c-KIT-positive immunoreactivity, eight had I or II stage disease and nine had III or IV stage disease. Molecular genetic analysis of exon 11, analyzed by direct DNA sequencing, was performed for all of the c-KIT-positive uterine leiomyosarcomas. No mutations were found. Conclusion: The conventional chemotherapy in leiomyosarcomas appears to be ineffective for patients with metastatic or unresectable disease, and the management of these patients poses a special problem. In these women, new therapeutic strategies are warranted. The treatment with STI571 in leiomyosarcoma patients might be hypothesized, because uterine leiomyosarcomas also express c-KIT.
Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man
Authors: Maren Luchtefeld, Heribert Schunkert, Monika Stoll, Tina Selle, Rachel Lorier, Karsten Grote, Christian Sagebiel, Kumaravelu Jagavelu, Uwe J.F. Tietge, Ulrike Assmus, Konrad Streetz, Christian Hengstenberg, Marcus Fischer, Björn Mayer, Karen Maresso, Nour Eddine El Mokhtari, Stefan Schreiber, Werner Müller, Udo Bavendiek, Christina Grothusen, Helmut Drexler, Christian Trautwein, Ulrich Broeckel, Bernhard Schieffer
Journal: The Journal of Experimental Medicine (2007)

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P &amp;lt; 0.05) with decreased plaque macrophages (P &amp;lt; 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P &amp;lt; 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P &amp;lt; 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population–based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.
Restoration of Electrical Activity of Guinea Pig Atria during Hypothermia: EFFECTS OF NOREPINEPHRINE AND ELECTRICAL STIMULATION ON MEMBRANE POTENTIALS
Authors: Robert Carpentier, Mario Vassalle
Journal: Circulation Research (1972)

Guinea pig right atria were perfused in vitro at 30°C. When the temperature was lowered to about 20°C, atrial activity ceased and the resting potential of atrial fibers decreased significantly. When activity was restored during hypothermia by electrical stimulation, both the resting and the action potentials were similar to those recorded at 30°C. Blockade of receptors by atropine or propranolol reduced the effects of electrical stimulation on the membrane potentials, and the reduction was greatest when both drugs were present. In particular, propranolol reduced the amplitude of the action potential. Strophanthidin also reduced the increment in resting potential induced by electrical stimulation at low temperature. Norepinephrine restored atrial activity, but the action potential and its rate of rise were small and the resting potential remained low. We concluded that (1) electrical stimulation restored atrial activity by simultaneously depolarizing the membrane to threshold, liberating autonomic mediators, and stimulating the sodium-potassium pump and (2) norepinephrine removed the sinoatrial block induced by low temperature by increasing the slow calcium and sodium currents.
Factor Associated With Neutral Sphingomyelinase Activation and Its Role in Cardiac Cell Death
Authors: Nicole W. O’Brien, Nicole M. Gellings, Mei Guo, Steven B. Barlow, Christopher C. Glembotski, Roger A. Sabbadini
Journal: Circulation Research (2003)

Generation of proapoptotic sphingolipids by neutral sphingomyelinase activation is an early response to hypoxia/reoxygenation (HR) in cardiomyocytes. Factor associated with neutral sphingomyelinase activation (FAN) mediates activation of sphingomyelinase and subsequent apoptosis. However, the participation of FAN in HR-induced cardiomyocyte cell death has not been elucidated. We therefore investigated the expression and role of FAN in rat cardiomyocytes. A cDNA was isolated from rat heart encoding putative rat FAN. Reverse transcriptase-polymerase chain reaction, immunoelectron microscopy, and immunofluorescence demonstrated for the first time the expression of FAN specifically in rat cardiomyocytes. FAN expression was confirmed by the finding that expression of a dominant-negative FAN almost completely abrogated HR-induced cell death, whereas overexpression of wild-type FAN led to an increase. Treatment of FAN and dominant-negative FAN--expressing cells with C2-ceramide produced substantial cell death, indicating dominant-negative FAN exerts its protective action by interfering with the activation of the sphingolipid cascade. Taking these results together, we conclude that FAN is a previously undescribed and important HR signaling component in the heart and that inhibition of FAN may provide a novel intervention point for reducing ischemia/reperfusion injury.
Microflora reactive IL-10 producing regulatory T cells are present in the colon of IL-2 deficient mice but lack efficacious inhibition of IFN-gamma and TNF-alpha production
Authors: M Waidmann
Journal: Gut (2002)

<h3>Abstract</h3> Nervous tissue metabolism is mainly supported by the dense thread of blood vessels which mainly provides fast supplies of oxygen and glucose. Recently, the supplying role of the brain vascular system has been examined in major neurological conditions such as the Alzheimer’s and Parkinson’s diseases. However, to date, fast and reliable methods for the fine level microstructural extraction of whole brain vascular systems are still unavailable. We present a methodological framework suitable for reconstruction of the whole mouse brain cerebral microvasculature by X-ray tomography with the unprecedented pixel size of 0.65 μm. Our measurements suggest that the resolving power of the technique is better than in many previous studies, and therefore it allows for a refinement of current measurements of blood vessel properties. Relevant insights emerged from analyses characterizing the regional morphology and topology of blood vessels. Specifically, vascular diameter and density appeared non-homogeneously distributed among the brain regions suggesting preferential sites for high-demanding metabolic requirements. Also, topological features such as the vessel branching points were non-uniformly distributed among the brain districts indicating that specific architectural schemes are required to serve the distinct functional specialization of the nervous tissue. In conclusion, here we propose a combination of experimental and computational method for efficient and fast investigations of the vascular system of entire organs with submicrometric precision.
Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives
Authors: J Tack, M van Outryve, G Beyens, R Kerstens, L Vandeplassche
Journal: Gut (2008)

<h3>Objective:</h3> To determine the efficacy, impact on quality of life (QOL) and safety of prucalopride, a selective, high-affinity 5-HT<sub>4</sub> receptor agonist, in patients with chronic constipation. <h3>Methods:</h3> In this multicentre, randomised, placebo controlled, parallel-group, phase III study, patients with chronic constipation (two or fewer spontaneous complete bowel movements (SCBM)/week) received 2 mg or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching three or more SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of one or more SCBM/week. The primary QOL endpoint was the patient assessment of constipation QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values and cardiovascular events. <h3>Results:</h3> Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p&lt;0.01), 4 mg (23.6%; p&lt;0.001) had three or more SCBM/week (or normalisation of bowel function) compared with placebo (9.6%). Similar results were seen in the subgroup (83%) of patients dissatisfied with previous laxative treatment. Both doses of prucalopride also significantly improved secondary efficacy and QOL endpoints, including the proportion of patients with an increase of one or more SCBM/week, evacuation completeness, perceived disease severity and treatment effectiveness and QOL. Prucalopride 4 mg significantly reduced the need for straining versus placebo (p&lt;0.05). The most frequent treatment-related adverse events were headache and diarrhoea. Both doses of prucalopride were safe and well tolerated. <h3>Conclusion:</h3> Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients. <h3>Trial registration number:</h3> NCT00488137.
D-Dimer and Exhaled CO<sub>2</sub>/O<sub>2</sub> to Detect Segmental Pulmonary Embolism in Moderate-Risk Patients
Authors: Jeffrey A. Kline, Melanie M. Hogg, D. Mark Courtney, Chadwick D. Miller, Alan E. Jones, Howard A. Smithline, Nicole Klekowski, Randy Lanier
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Pulmonary embolism (PE) decreases the exhaled end-tidal ratio of carbon dioxide to oxygen (etCO(2)/O(2)).To test if the etCO(2)/O(2) can produce clinically important changes in the probability of segmental or larger PE on computerized tomography multidetector-row pulmonary angiography (MDCTPA) in a moderate-risk population with a positive D-dimer.Emergency department and hospitalized patients with one or more predefined symptoms or signs, one or more risk factors for PE, and 64-slice MDCTPA enrolled from four hospitals. D-dimer greater than 499 ng/ml was test(+), and D-dimer less than 500 ng/ml was test(-). The median etCO(2)/O(2) less than 0.28 from seven or more breaths was test(+) and etCO(2)/O(2) greater than 0.45 was test(-). MDCTPA images were read by two independent radiologists and the criterion standard was the interpretation of acute PE by either reader. PE size was then graded.We enrolled 495 patients, including 60 (12%) with segmental or larger, and 29 (6%) with subsegmental PE. A total of 367 (74%) patients were D-dimer(+), including all 60 with segmental or larger PE (posterior probability 16%). The combination of D-dimer(+) and etCO(2)/O(2)(+) increased the posterior probability of segmental or larger PE to 28% (95% confidence interval [CI] for difference of 12%, 3.0-22%). The combination of D-dimer(+) and etCO(2)/O(2)(-) was observed in 40 patients (8%; 95% CI, 6-11%), and none (0/40; 95% CI, 0-9%) had segmental or larger PE on MDCTPA. No strategy changed the prevalence of subsegmental PE.In moderate-risk patients with a positive D-dimer, the et etCO(2)/O(2) less than 0.28 significantly increases the probability of segmental or larger PE and the etCO(2)/O(2) greater than 0.45 predicts the absence of segmental or larger PE on MDCTPA.
Rosiglitazone Improves Exercise Capacity in Individuals With Type 2 Diabetes
Authors: Judith G. Regensteiner, Timothy A. Bauer, Jane E.B. Reusch
Journal: Diabetes Care (2005)

OBJECTIVE—Although exercise is recommended as a cornerstone of treatment for type 2 diabetes, it is often poorly adopted by patients. We have noted that even in the absence of apparent cardiovascular disease, persons with type 2 diabetes have an impaired ability to carry out maximal exercise, and the impairment is correlated with insulin resistance and endothelial dysfunction. We hypothesized that administration of a thiazolidinedione (TZD) agent would improve exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS—Twenty participants with uncomplicated type 2 diabetes were randomly assigned in a double-blind study to receive either 4 mg/day of rosiglitazone or matching placebo after baseline measurements to assess endothelial function (brachial artery diameter by brachial ultrasound), maximal oxygen consumption ([Vdot]o2max), oxygen uptake ([Vdot]o2) kinetics, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Measurements were reassessed after 4 months of treatment. RESULTS—Participant groups did not differ at baseline in any measure. Rosiglitazone-treated participants (n = 10) had significantly improved [Vdot]o2max (19.8 ± 5.3 ml · kg−1 · min−1 before rosiglitazone vs. 21.2 ± 5.1 ml · kg−1 · min−1 after rosiglitazone, P &amp;lt; 0.01), insulin sensitivity, and endothelial function. A change in [Vdot]o2max correlated with improved insulin sensitivity measured by clamp (r = 0.68, P &amp;lt; 0.05) and with improved brachial artery diameter (r = 0.70, P &amp;lt; 0.05). Placebo-treated participants (n = 10) showed no changes in [Vdot]o2max (19.4 ± 5.2 ml · kg−1 · min−1 before rosiglitazone vs. 18.1 ± 5.3 ml · kg−1 · min−1 after rosiglitazone, NS) or brachial artery diameter. CONCLUSIONS—This is the first known report showing that a TZD improved exercise function in type 2 diabetes. Whether this is due to the observed improvements in insulin sensitivity and/or endothelial function or to another action of the TZD class requires further exploration.
<i>In vivo</i>Biological Activity of the Histone Deacetylase Inhibitor LAQ824 Is detectable with 3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography
Authors: Julius Leyton, John P. Alao, Marco Da Costa, Alexandra V. Stavropoulou, John R. Latigo, Meg Perumal, Radhakrishna Pillai, Qimin He, Peter Atadja, Eric W.-F. Lam, Paul Workman, David M. Vigushin, Eric O. Aboagye
Journal: Cancer Research (2006)

Abstract Histone deacetylase inhibitors (HDACI) are emerging as growth inhibitory compounds that modulate gene expression and inhibit tumor cell proliferation. We assessed whether 3′-deoxy-3′-[18F]fluorothymidine–positron emission tomography ([18F]FLT-PET) could be used to noninvasively measure the biological activity of a novel HDACI LAQ824 in vivo. We initially showed that thymidine kinase 1 (TK1; EC2.7.1.21), the enzyme responsible for [18F]FLT retention in cells, was regulated by LAQ824 in a drug concentration–dependent manner in vitro. In HCT116 colon carcinoma xenograft–bearing mice, LAQ824 significantly decreased tumor [18F]FLT uptake in a dose-dependent manner. At day 4 of treatment, [18F]FLT tumor-to-heart ratios at 60 minutes (NUV60) were 2.16 ± 0.15, 1.86 ± 0.13, and 1.45 ± 0.20 in vehicle, and 5 and 25 mg/kg LAQ824 treatment groups, respectively (P ≤ 0.05). LAQ825 at 5 mg/kg also significantly reduced both TK1 levels and [18F]FLT uptake at day 10 but not at day 2 (P ≤ 0.05). [18F]FLT NUV60 correlated significantly with cellular proliferation (r = 0.68; P = 0.0019) and was associated with drug-induced histone H4 hyperacetylation. Of interest to [18F]FLT-PET imaging, both TK1 mRNA copy numbers and protein levels decreased in the order vehicle &amp;gt;5 mg/kg LAQ824 &amp;gt; 25 mg/kg LAQ824, providing a rationale for the use of [18F]FLT-PET in this setting. We also observed increases in Rb hypophosphorylation and p21 levels, factors that could have contributed to the alteration in TK1 transcription in vivo. In conclusion, we have shown the utility of [18F]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [18F]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation. (Cancer Res 2006; 66(15): 7621-9)
Heparin modifies the immunogenicity of positively charged proteins
Authors: Shalini L. Chudasama, Benjamin Espinasse, Fred Hwang, Rui Qi, Manali Joglekar, Galyna Afonina, Mark R. Wiesner, Ian J. Welsby, Thomas L. Ortel, Gowthami M. Arepally
Journal: Blood (2010)
Apoptosis Induced by Inhibition of Cyclic AMP Response Element–Binding Protein in Vascular Smooth Muscle Cells
Authors: Tomotake Tokunou, Rei Shibata, Hisashi Kai, Toshihiro Ichiki, Takashi Morisaki, Kae Fukuyama, Hiroki Ono, Naoko Iino, Satoko Masuda, Hiroaki Shimokawa, Kensuke Egashira, Tsutomu Imaizumi, Akira Takeshita
Journal: Circulation (2003)

Background— The balance between apoptosis and proliferation of vascular smooth muscle cells (VSMCs) is believed to contribute to the vascular remodeling process. Cyclic AMP response element–binding protein (CREB) is a critical transcription factor for the survival of neuronal cells and T lymphocytes. However, the role of CREB in blood vessels is incompletely characterized. Methods and Results— Nuclear staining with Hoechst 33258 or propidium iodine showed an increase in apoptotic cells with activation of caspase-3 in VSMCs infected with adenovirus expressing the dominant-negative form of CREB (AdCREBM1). Basal expression of Bcl-2 and Bcl-2 promoter activity were decreased by infection with AdCREBM1. Immunohistochemistry revealed that CREB was mainly induced and activated in the neointimal α-smooth muscle actin–positive cells of rat carotid artery after balloon injury. Infection with AdCREBM1 suppressed neointimal formation (intima-media ratio) by 33.8% after 14 days of injury, which was accompanied by an increase in apoptosis as indicated by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling–positive cells and a decrease in bromodeoxyuridine incorporation. Conclusions— These results suggest that CRE-dependent gene transcription might play an important role in the survival and proliferation of VSMCs. CREB might be a novel transcription factor mediating the vascular remodeling process and a potential therapeutic target for atherosclerotic disease.
A Birth Cohort Study of Subjects at Risk of Atopy
Authors: HELEN L. RHODES, PETER THOMAS, RICHARD SPORIK, STEPHEN T. HOLGATE, JEREMY J. COGSWELL
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

This study describes the natural history of atopic and wheezy disorders from birth to adult life in a cohort at risk of atopy. One hundred subjects born in Poole, England, were selected at birth in 1976 on the basis that at least one parent was atopic. Subjects were examined annually in the preschool years, and at the ages of 11 and 22 yr. Skin prick tests and total serum immunoglobulin E (IgE) were performed at each visit, and at 11 and 22 yr, bronchial hyperresponsiveness (BHR) to inhaled histamine was measured. Sixty-three subjects remained on follow-up at 22 yr. The annual prevalence of both wheeze and atopy increased with age. Twenty-five percent of adults showed both wheeze and BHR (asthma). Remission of wheeze was common in subjects younger than 5 yr of age and likely if wheezing occurred on less than two occasions, but wheeze at 11 yr was likely to persist. Sixty percent of the adult subjects with asthma developed sensitivity to common allergens by the age of 2 yr and were showing BHR by mid-childhood. Sensitization to dietary allergens occurred in infancy and waned after early childhood but predicted the early sensitization to inhalant allergens. In conclusion, adults with asthma can begin wheezing at any age but tend to sensitize early and have abnormal airway characteristics by the age of 11 yr.