tbuckley/cabot-search huggingface dataset:
Negative-Feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-Dependent Regulation of Transient Receptor Potential Vanilloid 4
Authors: Jun Yin, Julia Hoffmann, Stephanie M. Kaestle, Nils Neye, Liming Wang, Joerg Baeurle, Wolfgang Liedtke, Songwei Wu, Hermann Kuppe, Axel R. Pries, Wolfgang M. Kuebler
Journal: Circulation Research (2008)

Although the formation of hydrostatic lung edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. In combining real-time optical imaging of the endothelial Ca(2+) concentration ([Ca(2+)](i)) and NO production with filtration coefficient (K(f)) measurements in the isolated perfused lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of lung microvascular pressure was shown to increase endothelial [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](i) transient increased K(f) via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca(2+)](i), NO synthesis, and lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca(2+)](i) response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) influx via TRPV4 channels increases lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca(2+)](i) response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic lung edema.
Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane
Authors: F.J. Mercier, E. Naline, M. Bardou, O. Georges, A. Denjean, D. Benhamou, C. Advenier
Journal: European Respiratory Journal (2002)

Volatile anaesthetics relax airway smooth muscle in vitro . The amount of relaxation might depend on the type and concentration of volatile anaesthetics, the calibre and precontraction level of the bronchi, and also on the species considered. These effects were investigated on isolated human bronchi. Isometric relaxations produced by halothane, isoflurane and desflurane bubbled on human bronchial rings precontracted with carbachol were recorded and compared with time controls. Volatile anaesthetics induced a concentration-dependent relaxation at 0.66, 1.33 and 2 minimum alveolar concentration (MAC). The relaxation was greater in mildly (carbachol 3×10 −7 M) than in highly (carbachol 2×10 −6 M) precontracted bronchi. Halothane was more potent in relaxing distal as compared to proximal bronchi; this differential effect was less pronounced with isoflurane and not observed with desflurane. While the three volatile anaesthetics induced similar relaxation on proximal bronchi, halothane was significantly more potent than desflurane on distal bronchi, with isoflurane being intermediate. The relaxation induced by 1.33 MAC of halothane, isoflurane and desflurane on moderately precontracted distal bronchi (carbachol 1×10 −6 M) was attenuated by pretreatment with glibenclamide 1×10 −5 M. In conclusion, halothane, isoflurane and desflurane exert direct but differential relaxant effects on human isolated bronchial smooth muscle. This may provide supplemental bronchodilation during anaesthesia. Although adenosine triphosphate-sensitive K + channels are involved in these relaxant effects, they are unlikely to explain the observed differences between the three volatile anaesthetics.
Acute asthma during pregnancy.
Authors: B S Stenius-Aarniala, J Hedman, K A Teramo
Journal: Thorax (1996)

<h3>Background:</h3> Care coordinators are increasingly featured in patient-centered medical home (PCMH) projects, yet little research examines how coordinators themselves define and experience their role. This is the first study describing experiences of care coordinators across the US from their own perspectives. <h3>Methods:</h3> This qualitative study used a 5-month private, online discussion forum to gather data from 25 care coordinators from PCMH practices representing diversity in practice size, setting, and type. Participants answered questions and interacted with one another, creating an online social learning collaborative while allowing for data collection for research. <h3>Results:</h3> Coordinators identified barriers and facilitators in their work at the organization/system level, the interpersonal level, and the individual level. Some factors emerged as both barriers and facilitators, including the functionality of clinical information technology; the availability of community resources; interactions with clinicians and other health care facilities; interactions with patients; and self-care practices for mental health and wellness. Colocation and full integration into practices were other key facilitators, whereas excessive case loads and data management responsibilities were felt to be important barriers. <h3>Conclusions:</h3> While all the barriers and facilitators were important to performing coordinators9 roles, relationship building materialized as key to effective care coordination, whether with clinicians, patients, or outside organizations. We discuss implications for practice and provide suggestions for further research.
Effect of Increasing the Intensity of Implementing Pneumonia Guidelines
Authors: Donald M. Yealy, Thomas E. Auble, Roslyn A. Stone, Judith R. Lave, Thomas P. Meehan, Louis G. Graff, Jonathan M. Fine, D. Scott Obrosky, Maria K. Mor, Jeff Whittle, Michael J. Fine
Journal: Annals of Internal Medicine (2005)

Background: Despite the development of evidence-based pneumonia guidelines, limited data exist on the most effective means to implement guideline recommendations into clinical practice. Objective: To compare the effectiveness and safety of 3 guideline implementation strategies. Design: Cluster-randomized, controlled trial. Setting: 32 emergency departments in Pennsylvania and Connecticut. Patients: 3219 patients with a clinical and radiographic diagnosis of pneumonia. Interventions: The authors implemented a project-developed guideline for the initial site of treatment based on the Pneumonia Severity Index and performance of evidence-based processes of care at the emergency department level. Guideline implementation strategies were defined as low (n = 8), moderate (n = 12), and high intensity (n = 12). Measurements: Effectiveness outcomes were the rate at which low-risk patients were treated on an outpatient basis and the performance of recommended processes of care. Safety outcomes included death, subsequent hospitalization for outpatients, and medical complications for inpatients. Results: More low-risk patients (n = 1901) were treated as outpatients in the moderate-intensity and high-intensity groups than in the low-intensity group (high-intensity group, 61.9%; moderate-intensity group, 61.0%; low-intensity group, 37.5%; P = 0.004). More outpatients (n = 1125) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 60.9%; moderate-intensity group, 28.3%; low-intensity group, 25.3%; P < 0.001); more inpatients (n = 2076) in the high-intensity group received all 4 recommended processes of care (high-intensity group, 44.3%; moderate-intensity group, 30.1%; low-intensity group, 23.0%; P < 0.001). No statistically significant differences in safety outcomes were observed across interventions. Limitations: Twenty percent of eligible patients were not enrolled, and data on effectiveness outcomes were not collected before the trial. Conclusions: Both moderate-intensity and high-intensity guideline implementation strategies safely increased the proportion of low-risk patients with pneumonia who were treated as outpatients. The high-intensity strategy was most effective for increasing the performance of the recommended processes of care for outpatients and inpatients. *For the names of individuals who served as project coordinators, local study investigators, research staff, and study research nurses, see the Appendix.
Neoadjuvant Concurrent Paclitaxel and Radiation in Stage II/III Breast Cancer
Authors: A. Bapsi Chakravarthy, Mark C. Kelley, Bernadette McLaren, Cristina I. Truica, Dean Billheimer, Ingrid A. Mayer, Ana M. Grau, David H. Johnson, Jean F. Simpson, R. Daniel Beauchamp, Catherine Jones, Jennifer A. Pietenpol
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The aim of this study was to determine the safety and pathologic response rates following neoadjuvant paclitaxel and radiation in patients with stage II/III breast cancer and to evaluate the use of sequential biopsies to allow an in vivo assessment of biological markers as potential predictive markers of response to this regimen. Patients and Methods: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel 175 mg/m2 every 3 weeks, followed by twice-weekly paclitaxel 30 mg/m2 and concurrent radiation. Core biopsies were obtained at baseline and 24 to 72 hours after the first cycle of paclitaxel. After completing neoadjuvant treatment, patients underwent definitive surgery. The primary end point was pathologic complete response, which is defined as the absence of any invasive cancer at surgery. Potential markers of therapeutic response were evaluated including markers of proliferation, apoptosis, p21, HER2, estrogen receptor, and progesterone receptor status. Results: Of the 38 patients enrolled, 13 (34%) had a pathologic complete response. There was no significant difference in baseline Ki-67 between responders (35%) and nonresponders (28%; P = 0.45). There was also no significant change in Ki-67 following paclitaxel administration. Despite this lack of immunohistologic change in proliferative activity, baseline mitotic index was higher for patients with pathologic complete response over nonresponders (27 versus 10, P = 0.003). Moreover, the increase in mitotic index following paclitaxel administration was associated with pathologic complete response. Conclusions: Neoadjuvant paclitaxel/radiation is effective and well tolerated. Tumor proliferation at baseline and response to chemotherapy as measured by mitotic activity may serve as an important indicator of pathologic response to neoadjuvant paclitaxel/radiation.
Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis
Authors: T Ohkusa
Journal: Gut (2002)

<b>Background:</b> Bacteria are implicated in certain forms of model chronic colitis but the identity and role of bacteria in human ulcerative colitis (UC) are uncertain. <b>Aims:</b> To isolate pathogenic bacteria from inflamed mucosa of patients with UC, to examine whether the bacteria have a toxin to Vero cells, and to determine whether the toxin induces UC-like lesions in animals. <b>Methods:</b> Bacteria were isolated from UC patients and supernatants from cultures were filtered and tested for cytotoxicity to Vero cells. Bacterial cells producing the cytotoxic supernatants were examined by polymerase chain reaction for verotoxin genes. Culture supernatants of cytotoxic strains were examined by high performance liquid chromatography for organic acid concentrations. Mice were given enemas containing organic acid at the mean concentration in the supernatants of cytotoxic strains to ascertain whether colonic lesions appear in UC. <b>Results:</b> Only supernatants from cultures of <i>Fusobacterium varium</i> killed Vero cells. Bacterial cells lacked verotoxin genes. Bacterial culture supernatants contained high concentrations of <i>n</i>-butyric acid and the mean concentration (32 mmol/l) was cytotoxic to Vero cells. Twenty four hours after mice were given enemas containing either butyric acid or <i>F varium</i> culture supernatants, colonic ulcers with crypt abscesses, inflammatory cell infiltration, and apoptotic changes were observed. <b>Conclusions:</b> Butyric acid in culture supernatants from cultures of <i>F varium</i> caused UC-like lesions in mice. This study indicates that <i>F varium</i> may be one of the elusive pathogenic factors in UC.
Impaired potentiation by endothelin-1 and vasopressin of sympathetic contraction in tail artery from hypertensive rats
Authors: A García-Villalón
Journal: Cardiovascular Research (2000)

Objective: To analyse the effects of endothelin-1 and vasopressin on the sympathetic vasoconstriction during hypertension. Methods: Electrical field stimulation (4 Hz) was applied to isolated, 2 mm segments of the tail artery from spontaneously hypertensive (SHR) and normotensive Wistar–Kyoto (WKY) rats prepared for isometric tension recording. Results: The contraction to electrical stimulation was potentiated by endothelin-1 (10−10–10−8 M) in arteries from WKY but not from SHR, and by vasopressin (10−12–10−10 M) more markedly in arteries from WKY than from SHR. The potentiation by endothelin-1 was reduced more markedly by the antagonist of endothelin ETA receptors BQ-123 (10−5 M) than by the endothelin ETB receptor antagonist BQ-788 (10−5 M). The potentiation by vasopressin was reduced by the antagonist of vasopressin V1 receptors d(CH2)5Tyr(Me)AVP (10−7 M), but not by the vasopressin V2 receptor antagonist d(CH2)5d-Ile2, Ile4AVP (10−7 M). The blocker of L-type calcium channels verapamil (10−5 M) reduced the potentiation by both endothelin-1 and vasopressin in arteries from WKY rats, and increased the potentiation by vasopressin in arteries from SHR. Noradrenaline (10−8–10−4 M) contraction was not modified by endothelin-1 (3×10−9 M) or vasopressin (3×10−11 M), and contraction to endothelin-1 (10−9–10−7 M) and vasopressin (10−10–10−7 M) was lower in arteries from SHR than from WKY rats. Conclusions: (1) the potentiation by endothelin-1 and vasopressin of the sympathetic vasoconstriction, probably due to increased release of noradrenaline, is impaired during hypertension, and (2) this potentiation is mediated mainly by endothelin ETA receptors, and by vasopressin V1 receptors, in both WKY and SHR, and for both peptides it is mediated by L-type calcium channels in arteries from normotensive but not in those from hypertensive animals.
Reexpression of <i>Human Somatostatin Receptor Gene 2</i> Gene Mediated by Oncolytic Adenovirus Increases Antitumor Activity of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand against Pancreatic Cancer
Authors: Zhenwei Zhang, Yangbin Huang, Kam Newman, Jinfa Gu, Xuemei Zhang, Hua Wu, Ming Zhao, Zhiqun Xianyu, Xinyuan Liu
Journal: Clinical Cancer Research (2009)

Pancreatic cancer continues to pose an enormous challenge to clinicians and cancer scientists. Clinical studies show that tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) exerts a potent and tumor-specific proapoptotic activity. However, most pancreatic cancer cells are resistant to TRAIL therapy. Human somatostatin receptor gene 2 (hSSTr2) is lost in 90% of pancreatic carcinoma. Oncolytic viruses are able to selectively lyse cancer cells and represent a promising novel anticancer therapy. Here, we investigated whether oncolytic adenovirus-mediated reexpression of hSSTr2 would enhance TRAIL-induced antitumor efficacy against pancreatic cancer.The antitumor efficacies of combined or single treatment of hSSTr2 and TRAIL mediated by oncolytic adenovirus were compared in pancreatic cancer cell culture and xenografts. The mechanisms involved in hSSTr2-induced sensitization to TRAIL were studied.Oncolytic adenovirus-mediated reexpression of hSSTr2 potentiated TRAIL-induced tumor growth inhibition in vitro and in vivo. Reexpression of hSSTr2 augmented TRAIL-induced apoptosis against pancreatic cancer cells via up-regulation of death receptor 4 and down-regulation of Bcl-2.hSSTr2 restoration mediated by oncolytic adenovirus enhances TRAIL-induced antitumor efficacy against pancreatic cancer. Combined treatment with oncolytic adenovirus-mediated hSSTr2 and TRAIL gene provides the rationale for a clinical trial in pancreatic cancer.
Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death
Authors: Claus-Detlev Klemke, Dirk Brenner, Eva-Maria Weiβ, Marc Schmidt, Martin Leverkus, Karsten Gülow, Peter H. Krammer
Journal: Cancer Research (2009)

Restimulation of previously activated T cells via the T-cell receptor (TCR) leads to activation-induced cell death (AICD), which is, at least in part, dependent on the death receptor CD95 (APO-1, FAS) and its natural ligand (CD95L). Here, we characterize cutaneous T-cell lymphoma (CTCL) cells (CTCL tumor cell lines and primary CTCL tumor cells from CTCL patients) as AICD resistant. We show that CTCL cells have elevated levels of the CD95-inhibitory protein cFLIP. However, cFLIP is not responsible for CTCL AICD resistance. Instead, our data suggest that reduced TCR-proximal signaling in CTCL cells is responsible for the observed AICD resistance. CTCL cells exhibit no PLC-gamma1 activity, resulting in an impaired Ca(2+)release and reduced generation of reactive oxygen species upon TCR stimulation. Ca(2+) and ROS production are crucial for up-regulation of CD95L and reconstitution of both signals resulted in AICD sensitivity of CTCL cells. In accordance with these data, CTCL tumor cells from patients with Sézary syndrome do not up-regulate CD95L upon TCR-stimulation and are therefore resistant to AICD. These results show a novel mechanism of AICD resistance in CTCL that could have future therapeutic implications to overcome apoptosis resistance in CTCL patients.
Antibiotic prophylaxis in gastrointestinal endoscopy
Authors: M C Allison, J A T Sandoe, R Tighe, I A Simpson, R J Hall, T S J Elliott
Journal: Gut (2009)

Bacteraemia is common following some forms of gastrointestinal endoscopic therapy, such as dilatation or injection sclerotherapy, and can occur with diagnostic endoscopy alone. Fortunately complications resulting from dissemination of endogenous bacteria are uncommon, and infective endocarditis is an extremely rare complication. Furthermore, for most diagnostic and therapeutic procedures there is scant evidence that antibiotic prophylaxis can reduce the incidence of infective complications.

The area that has attracted the most controversy in recent years has been the use of antibiotics to prevent infective endocarditis. The recommendations by the American Heart Association (AHA)1 have traditionally guided the advice of the national bodies representing endoscopic practice,2 3 including the British Society of Gastroenterology (BSG).4 The traditional guidance has been that patients at high risk of endocarditis, such as those with a prosthetic (ie, tissue or mechanical) valve and/or a past history of endocarditis should receive antibiotics for all endoscopic procedures. More recently the European Society of Cardiology recommended antibiotic prophylaxis to cover therapeutic endoscopy in patients with acquired valvular heart disease,5 and the British Cardiovascular Society went even further, advising antibiotic prophylaxis for patients at moderate risk of endocarditis undergoing any endoscopic procedure.6

The Endoscopy Committee of the BSG recognised the need for consensus on this issue, and convened a Working Party in the spring of 2006. The membership, comprised doctors with a special interest in gastroenterology, gastroenterologists, cardiologists and microbiologists. The gastroenterologists and microbiologists from this Working Party also took the opportunity to review the evidence underpinning the use of antibiotic prophylaxis in other areas of endoscopic practice, in particular endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous endoscopic gastrostomy (PEG). In view of new guidance from the AHA, and from the National Institute for Health and Clinical Excellence (NICE), the Working Party reconvened in 2008 to reconsider, in …
Antithrombotic Treatment in Patients With Heart Failure and Associated Atrial Fibrillation and Vascular Disease
Authors: Morten Lamberts, Gregory Y H Lip, Martin H Ruwald, Morten Lock Hansen, Cengiz Özcan, Søren L Kristensen, Lars Køber, Christian Torp-Pedersen, Gunnar H Gislason
Journal: Journal of the American College of Cardiology (2014)
USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma
Authors: Pieter J A Eichhorn, Laura Rodón, Alba Gonzàlez-Juncà, Annette Dirac, Magüi Gili, Elena Martínez-Sáez, Claudia Aura, Ignasi Barba, Vicente Peg, Aleix Prat, Isabel Cuartas, Jose Jimenez, David García-Dorado, Juan Sahuquillo, Réné Bernards, José Baselga, Joan Seoane
Journal: Nature Medicine (2012)
Short Sleep Duration Is Associated With a Blood Pressure Nondipping Pattern in Type 1 Diabetes
Authors: Anne-Laure Borel, Pierre-Yves Benhamou, Jean-Philippe Baguet, Isabelle Debaty, Patrick Levy, Jean-Louis Pépin, Jean-Michel Mallion
Journal: Diabetes Care (2009)

OBJECTIVE To assess whether nocturnal blood pressure dipping status in type 1 diabetes is correlated with specific sleep characteristics and differences in nocturnal glycemic profiles. RESEARCH DESIGN AND METHODS Twenty type 1 diabetic adult patients underwent sleep studies with simultaneous 24-h ambulatory blood pressure monitoring and continuous nocturnal glucose monitoring. RESULTS Altogether, 55% of patients exhibited blunted blood pressure dipping. They did not differ from the dipper group in age, BMI, or systolic (SBP) and diastolic (DBP) blood pressure. Total sleep period (TSP) was higher in the dipper group (497 ± 30 vs. 407 ± 44 min for dippers and nondippers, respectively, P &amp;lt; 0.001). TSP was correlated with SBP and DBP day-night differences (r = 0.44 and 0.49, respectively). Periods of nocturnal hypoglycemia (i.e., % of TSP with glycemia &amp;lt;70 mg/dl) were longer in the dipper group (8.1 ± 10.7 vs. 0.1 ± 0.4% for dippers and nondippers, respectively, P = 0.02). CONCLUSIONS Dipping status in type 1 diabetes was associated with longer sleep duration and with hypoglycemia unawareness.
Initiation codon mutation (ATG → ATA) of the β‐globin gene causing β‐thalassemia in a Swedish family
Authors: Britta Landin, Olle Rudolphi, BÖRje Ek
Journal: American Journal of Hematology (1995)

Abstract An initiation codon mutation ATG → ATA of the β‐globin gene was found in seven members of three generations of a family living in northern Sweden. This mutation, which has not previously been described, changes the initiation codon for methionine into a codon for isoleucine and will then result in a β°‐thalassemic phenotype. The affected family members all present hematological findings typical for β‐thalassemic trait, with slight anemia, marked microcytosis, and increased levels of Hb A 2 . ©1995 Wiley‐Liss, Inc.
MRI monitoring of pathological changes in the spinal cord in patients with multiple sclerosis
Authors: Achim Gass, Maria A Rocca, Federica Agosta, Olga Ciccarelli, Declan Chard, Paola Valsasina, Jonathan C W Brooks, Antje Bischof, Philipp Eisele, Ludwig Kappos, Frederik Barkhof, Massimo Filippi
Journal: The Lancet Neurology (2015)