tbuckley/cabot-search huggingface dataset:
Selective response of human airway epithelia to luminal but not serosal solution hypertonicity. Possible role for proximal airway epithelia as an osmolality transducer.
Authors: N J Willumsen, C W Davis, R C Boucher
Journal: Journal of Clinical Investigation (1994)

The response of cultured human nasal epithelia to hypertonic bathing solutions was tested using ion-selective microelectrode and quantitative microscopy. Raised luminal, but not serosal, osmolality (+/- 150 mM mannitol) decreased Na+ absorption but did not induce Cl- secretion. Raised luminal osmolality increased cell Cl- activity, Na+ activity, and transepithelial resistance and decreased both apical and basolateral membrane potentials and the fractional resistance of the apical membrane; equivalent circuit analysis revealed increases in apical, basolateral, and shunt resistances. Prolonged exposure (10 min) to 430 mosM luminal solution elicited no regulation of any parameter. Optical measurements revealed a reduction in the thickness of preparations only in response to luminal hypertonic solutions. We conclude that (a) airway epithelial cells exhibit asymmetric water transport properties, with the apical membrane water permeability exceeding that of the basolateral membrane; (b) the cellular response to volume loss is a deactivation of the basolateral membrane K+ conductance and the apical membrane Cl- conductance; (c) luminal hypertonicity slows the rate of Na+ absorption but does not induce Cl- secretion; and (d) cell volume loss increases the resistance of the paracellular path. We speculate that these properties configure human nasal epithelium to behave as an osmotic sensor, transducing information about luminal solutions to the airway wall.
Acute vascular effects of the selective estrogen receptor modulator EM-652 (SCH 57068) in the rat mesenteric vascular bed
Authors: R Tatchum-Talom
Journal: Cardiovascular Research (2003)

Selective estrogen receptor modulators (SERMs) represent a class of compounds that act as either estrogen receptor agonist or antagonist in a tissue-selective manner. SERMs exert beneficial effects on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. 17beta-estradiol (E2) and SERMs such as raloxifene and tamoxifen acutely relax coronary arteries. EM-652 (SCH 57068) is a 4th generation SERM acting as pure antiestrogen in the mammary gland and endometrium. The effects of SERMs on the mesenteric vasculature are unknown. In the present study, the vascular effects of EM-652 and E2 on the rat mesentery were investigated.Isolated perfused (5 ml/min) mesenteric vascular bed (MVB) was preconstricted with methoxamine. Increasing doses (0.1-10 microM) of EM-652 or E2 were infused into the perfusate.EM-652 and E2 relaxed MVBs removed from intact and gonadectomized female and male rats. The amplitude of EM-652 responses was consistently greater than those of E2 and its potency was similar or greater than that of other SERMs. EM-652 and E2 relaxed MVB by an endothelium-independent mechanism. The estrogen receptor (ER) antagonist ICI 182,780 attenuated E2-induced relaxations but only partially block the effects of EM-652. Inhibition of the nitric oxide synthase/cGMP pathway with N(G)-nitro-arginine-methyl-ester (L-NAME) and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one (ODQ) or of prostanoid synthesis with indomethacin failed to reduce EM-652 responses. The vascular effects of EM-652 were also unaffected by potassium channels blockers or inhibitors/scavengers of reactive oxygen species. EM-652 attenuated the vasoconstrictor responses induced by adrenergic agonists and endothelin-1.EM-652 acutely relaxes the mesenteric vasculature by an endothelium-independent pathway which is partly mediated by ER, providing a novel mechanism by which this SERM may exert beneficial actions on the vascular system.
Invasive Acute Hemodynamic Response to Guide Left Ventricular Lead Implantation Predicts Chronic Remodeling in Patients Undergoing Cardiac Resynchronization Therapy
Authors: Simon G. Duckett, Matthew Ginks, Anoop K. Shetty, Julian Bostock, Jaswinder S. Gill, Shoaib Hamid, Stam Kapetanakis, Eliane Cunliffe, Reza Razavi, Gerry Carr-White, C. Aldo Rinaldi
Journal: Journal of the American College of Cardiology (2011)
Effect of simulated intragastric haemorrhage on gastric acid secretion, gastric motility, and serum gastrin.
Authors: G M Fullarton, E J Boyd, G P Crean, T E Hilditch, K E McColl
Journal: Gut (1990)

The majority of upper gastrointestinal bleeds stop spontaneously despite the low pH and proteolytic activity of gastric juice which inhibit coagulation and platelet aggregation. In order to investigate this paradox six healthy male volunteers received intragastric infusions of 160 ml autologous venous blood or 160 ml egg white acting as control in random order on separate days. Basal acid output was calculated before infusion, net acid secretion and gastric volume emptied were calculated after intragastric infusions. Serum gastrin concentrations were also measured before and after intragastric infusions and expressed as the integrated gastrin response. Basal acid output (mmol/h) was 4.7 (1.9) (mean (SEM)) before egg white infusion and 5.9 (2.6) before venous blood infusion. After egg white infusion net acid secretion (mmol/20 min) increased to 5.6 (3.1) compared with 2.3 (1.3) after venous blood infusion (p less than 0.05). The gastric volume emptied (ml/20 min) was less after venous blood infusion at 105 (28) compared with 321 (66) after egg white infusion (p less than 0.03). Integrated gastrin response was similar after venous blood and egg white infusion. When compared with an equivalent protein meal intragastric blood stimulates less acid secretion and delays gastric emptying. This effect may facilitate haemostasis after gastric bleeding.
TLR4 stresses the liver: Figure 1
Authors: Hacer Sahin, Christian Trautwein, Hermann E Wasmuth
Journal: Gut (2012)

Most types of chronic liver disease are characterised by hepatocellular necrosis, inflammation and tissue remodelling, ultimately resulting in progressive fibrosis and cirrhosis in a significant number of cases. Evidence from mouse and human studies implicates Toll-like receptors (TLRs) as central mediators of the inflammatory response and a crucial link between inflammation and fibrosis in chronic liver diseases. TLRs are members of the pattern-recognition receptor superfamily, which plays an important role in pathogen recognition and the subsequent activation of the innate immune system.1 To date, 10 functional TLRs have been identified in humans and each of these responds to specific microbial products. TLR4 is the main receptor for lipopolysaccharide, which appears to be a key mediator of liver inflammation associated with several different liver diseases.2 ,3 The interaction of TLR4 with lipopolysaccharide, a specific cell wall component of Gram-negative bacteria, leads to liver fibrosis triggered by proinflammatory cytokines, transforming growth factor β signalling and oxidative stress.4 Notably, TLR4 may also recognise endogenous ligands released by activated or necrotic cells during tissue injury and matrix degradation.3 Within the liver, TLR4 is expressed on diverse cell types, including Kupffer cells (KCs), hepatic stellate cells and hepatocytes (figure 1).5 Activation of TLR4 directly stimulates stellate …
Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension
Authors: Benoît Rondelet, François Kerbaul, Sophie Motte, Ronald van Beneden, Myriam Remmelink, Serge Brimioulle, Kathleen McEntee, Pierre Wauthy, Isabelle Salmon, Jean-Marie Ketelslegers, Robert Naeije
Journal: Circulation (2003)

Background— The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. Methods and Results— Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET B receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET A receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. Conclusions— Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.
Cancer Angiogenesis Induced by Kaposi Sarcoma–Associated Herpesvirus Is Mediated by EZH2
Authors: Meilan He, Wei Zhang, Thomas Bakken, Melissa Schutten, Zsolt Toth, Jae U. Jung, Parkash Gill, Mark Cannon, Shou-Jiang Gao
Journal: Cancer Research (2012)

Abstract EZH2 is a component of the epigenetic regulator PRC2 that suppresses gene expression. Elevated expression of EZH2 is common in human cancers and is associated with tumor progression and poor prognosis. In this study, we show that EZH2 elevation is associated with epigenetic modifications of Kaposi sarcoma–associated herpesvirus (KSHV), an oncogenic virus that promotes the development of Kaposi sarcoma and other malignancies that occur in patients with chronic HIV infections. KSHV induction of EZH2 expression was essential for KSHV-induced angiogenesis. High expression of EZH2 was observed in Kaposi sarcoma tumors. In cell culture, latent KSHV infection upregulated the expression of EZH2 in human endothelial cells through the expression of vFLIP and LANA, two KSHV-latent genes that activate the NF-κB pathway. KSHV-mediated upregulation of EZH2 was required for the induction of Ephrin-B2, an essential proangiogenic factor that drives endothelial cell tubule formation. Taken together, our findings indicate that KSHV regulates the host epigenetic modifier EZH2 to promote angiogenesis. Cancer Res; 72(14); 3582–92. ©2012 AACR.
Recurrent bowel infarction in paroxysmal nocturnal haemoglobinuria
Authors: J Ramus, G A D McPherson
Journal: Journal of the Royal Society of Medicine (2003)

A man of 43 was referred after 24 hours of feeling generally unwell with intermittent rigors. PNH had been diagnosed 18 years previously, and regular blood transfusions for his anaemia had resulted in iron-overload diabetes mellitus. 8 years before the present episode he had had a small-bowel resection for ischaemia secondary to venous thrombosis. On examination his abdomen was distended and slightly tender in the left lower quadrant, without obvious peritonism. Haemoglobin was 6.4 g/dL and platelet count 166109/L. Blood indices were otherwise normal. A plain abdominal X-ray showed dilated small-bowel loops. Adhesional small-bowel obstruction was diagnosed and initial management was conservative. After three days the abdominal distention had not resolved and a CT scan (Figure 1) showed gross small-bowel dilatation with an area of collapsed small bowel distally, highly suggestive of a mechanical obstruction. At laparotomy, with bloodtransfusion and platelet cover, he was found to have a segment of gangrenous small bowel with a stricture. This was resected and the bowel was anastomosed by an extramucosal technique. The patient spent the first three postoperative days on the intensive care unit for close monitoring, and received total parenteral nutrition for five days until enteral feeding was started. No further blood or platelet transfusions were required. Histopathological examination of the operative specimen showed extensive haemorrhagic infarction secondary to venous thrombosis.
No-Scar Transanal Total Mesorectal Excision
Authors: Joël Leroy, Brian Donncha Barry, Armando Melani, Didier Mutter, Jacques Marescaux
Journal: JAMA Surgery (2012)

Because of the concerns over the operative platform, accidental organ injury, and viscerotomy closure, natural orifice transluminal endoscopic surgery (NOTES) currently remains an experimental technique. Transanal NOTES for colorectal surgery overcomes all of these issues; however, all of the reports to date have used hybrid laparoscopic techniques. We demonstrate herein the first case, to our knowledge, of pure transanal NOTES colorectal surgery.Case report.University hospital.The patient was a 56-year-old woman with a midrectal neoplasia.Pure transanal NOTES total mesorectal excision with a coloanal anastomosis and without a diverting stoma. Using a transanal endoscopic operation device as a surgical platform, we created a viscerotomy distal to an endoluminal purse-string suture. We performed a total mesorectal excision using a “bottom-up” approach. The sigmoid colon was mobilized by a posterior, retroperitoneal approach and the colon was divided intraperitoneally. A hand-sewn, side-to-end, coloanal anastomosis was performed. Because the viscerotomy was incorporated into the anastomosis, the concerns of both accidental organ damage and viscerotomy closure were abrogated.The procedure was completed entirely by a transanal fashion. We successfully mobilized the rectum, mesorectum, and sigmoid colon. The specimen length was more than 20 cm. The patient required minimal analgesia and her pain was nonabdominal.To our knowledge, the first pure transanal NOTES total mesorectal excision with retroperitoneal sigmoid mobilization and coloanal, side-to-end anastomosis was successfully performed using what we called a peri-rectal oncologic gateway for retroperitoneal endoscopic single site surgery (PROGRESSS). This monumental case could pave the way for a new era in pure transanal NOTES for colorectal surgery.
Diagnostic yield and safety of ultrasound-assisted biopsies in superior vena cava syndrome
Authors: C. F. N. Koegelenberg, C. T. Bolliger, D. Plekker, C. A. Wright, K. Brundyn, M. Louw, P. Schubert, M. M. van den Heuvel, A. H. Diacon
Journal: European Respiratory Journal (2009)

The yield and safety of ultrasound (US)-assisted transthoracic fine needle aspirations (TTFNA) and cutting needle biopsies (CNB) in the setting of superior vena cava (SVC) syndrome are unknown. The aims of the present prospective study were to asses the diagnostic yield and safety of US-assisted TTFNA and CNB in SVC syndrome with an associated mass lesion abutting the chest wall. Over a 3-yr period, the present authors screened 59 patients with SVC syndrome, and enrolled 25 patients who had an associated mass lesion that extended to the chest wall. US-assisted TTFNA with rapid on-site evaluation (ROSE) was performed in all cases. CNBs were performed where a provisional diagnosis of bronchogenic carcinoma could not be established, and in 57.1% of patients with bronchogenic carcinoma (limited due to safety constraints). ROSE of US-assisted TTFNA confirmed diagnostically useful material in 24 patients, and cytological diagnoses were ultimately made in all of these cases (diagnostic yield 96%). US-assisted CNB had a diagnostic yield of 87.5%. Minor haemorrhage occurred in one out of 25 TTFNA and three out of 16 CNB. Neither procedure resulted in major haemorrhage nor pneumothoraces. US-assisted TTFNA and CNB have a high diagnostic yield and are safe in the setting of SVC syndrome with an associated mass lesion abutting the chest wall.
Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet
Authors: Iris Shai, Dan Schwarzfuchs, Yaakov Henkin, Danit R. Shahar, Shula Witkow, Ilana Greenberg, Rachel Golan, Drora Fraser, Arkady Bolotin, Hilel Vardi, Osnat Tangi-Rozental, Rachel Zuk-Ramot, Benjamin Sarusi, Dov Brickner, Ziva Schwartz, Einat Sheiner, Rachel Marko, Esther Katorza, Joachim Thiery, Georg Martin Fiedler, Matthias Blüher, Michael Stumvoll, Meir J. Stampfer
Journal: New England Journal of Medicine (2008)

Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates.In this 2-year trial, we randomly assigned 322 moderately obese subjects (mean age, 52 years; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 31; male sex, 86%) to one of three diets: low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, non-restricted-calorie.The rate of adherence to a study diet was 95.4% at 1 year and 84.6% at 2 years. The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat (P<0.05 for all comparisons among treatment groups). The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat, protein, and cholesterol and had the highest percentage of participants with detectable urinary ketones (P<0.05 for all comparisons among treatment groups). The mean weight loss was 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-diet group, and 4.7 kg for the low-carbohydrate group (P<0.001 for the interaction between diet group and time); among the 272 participants who completed the intervention, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20% in the low-carbohydrate group and 12% in the low-fat group (P=0.01). Among the 36 subjects with diabetes, changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet (P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels).Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. The more favorable effects on lipids (with the low-carbohydrate diet) and on glycemic control (with the Mediterranean diet) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions. (ClinicalTrials.gov number, NCT00160108.)
Role of Microvascular Permeability on Physiologic Differences in Asthma and Eosinophilic Bronchitis
Authors: Hiroshi Kanazawa, Saeko Nomura, Junichi Yoshikawa
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Asthma and eosinophilic bronchitis are characterized by a similar type of eosinophilic inflammation. However, eosinophilic bronchitis differs from asthma in that there is no variable airflow obstruction or airway hyperresponsiveness. We evaluated the roles of vascular endothelial growth factor (VEGF) and microvascular permeability in causing these differences between the two diseases. Inflammatory indexes in induced sputum, exhaled nitric oxide levels, and vascular permeability index were examined in 11 normal control subjects, 19 beclomethasone dipropionate (BDP)-treated subjects with asthma, 20 non-BDP-treated subjects with asthma, and 17 patients with eosinophilic bronchitis. The percentage of eosinophils in sputum and exhaled nitric oxide levels were significantly higher in non-BDP-treated subjects with asthma and patients with eosinophilic bronchitis than in other two groups; however, VEGF levels and vascular permeability index were significantly higher in non-BDP-treated (VEGF: mean; 4,710 [SD; 1,150] pg/ml, p < 0.0001; vascular permeability index: 0.028 [0.009], p < 0.0001) and BDP-treated (2,560 [1,070] pg/ml, p = 0.0002; 0.016 [0.006], p = 0.004) subjects with asthma than in patients with eosinophilic bronchitis (1,120 [800] pg/ml; 0.01 [0.005]) and normal control subjects (1,390 [1,280] pg/ml; 0.008 [0.003]). We found significant correlations between the VEGF level and the airway vascular permeability index in all patient groups. Thus, interaction between airway microcirculation and VEGF may be a key element in differences in airway function between asthma and eosinophilic bronchitis.
Ciliate Pellicular Proteome Identifies Novel Protein Families with Characteristic Repeat Motifs That Are Common to Alveolates
Authors: S. B. Gould, L. G. K. Kraft, G. G. van Dooren, C. D. Goodman, K. L. Ford, A. M. Cassin, A. Bacic, G. I. McFadden, R. F. Waller
Journal: Molecular Biology and Evolution (2010)

The pellicles of alveolates (ciliates, apicomplexans, and dinoflagellates) share a common organization, yet perform very divergent functions, including motility, host cell invasion, and armor. The alveolate pellicle consists of a system of flattened membrane sacs (alveoli, which are the defining feature of the group) below the plasma membrane that is supported by a membrane skeleton as well as a network of microtubules and other filamentous elements. We recently showed that a family of proteins, alveolins, are common and unique to this pellicular structure in alveolates. To identify additional proteins that contribute to this structure, a pellicle proteome study was conducted for the ciliate Tetrahymena thermophila. We found 1,173 proteins associated with this structure, 45% (529 proteins) of which represented novel proteins without matches to other functionally characterized proteins. Expression of four newly identified T. thermophila pellicular proteins as green fluorescent protein-fusion constructs confirmed pellicular location, and one new protein located in the oral apparatus. Bioinformatic analysis revealed that 21% of the putative pellicular proteins, predominantly the novel proteins, contained highly repetitive regions with strong amino acid biases for particular residues (K, E, Q, L, I, and V). When the T. thermophila novel proteins were compared with apicomplexan genomic data, 278 proteins with high sequence similarity were identified, suggesting that many of these putative pellicular components are shared between the alveolates. Of these shared proteins, 126 contained the distinctive repeat regions. Localization of two such proteins in Toxoplasma gondii confirmed their role in the pellicle and in doing so identified two new proteins of the apicomplexan invasive structure—the apical complex. Screening broadly for these repetitive domains in genomic data revealed large and actively evolving families of such proteins in alveolates, suggesting that these proteins might underpin the diversity and utility of their unique pellicular structure.