tbuckley/cabot-search huggingface dataset:
Genetic variants in<i>CDC42</i>and<i>NXPH1</i>as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome
Authors: Mira M Wouters, Diether Lambrechts, Michael Knapp, Isabelle Cleynen, Peter Whorwell, Lars Agréus, Aldona Dlugosz, Peter Thelin Schmidt, Jonas Halfvarson, Magnus Simrén, Bodil Ohlsson, Pontus Karling, Sander Van Wanrooy, Stéphanie Mondelaers, Severine Vermeire, Greger Lindberg, Robin Spiller, George Dukes, Mauro D'Amato, Guy Boeckxstaens
Journal: Gut (2013)

The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS.384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes.Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1.Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology.
TGF- signaling is required for the function of insulin-reactive T regulatory cells
Authors: W. Du
Journal: Journal of Clinical Investigation (2006)

We have previously isolated insulin-reactive Tregs from diabetic NOD mice designated 2H6, from which TCR transgenic mice were generated. The T cells from these 2H6 transgenic mice recognize insulin but have suppressive properties in vitro. They protect NOD mice in vivo from spontaneous development of diabetes and adoptive transfer of disease caused by polyclonal diabetogenic spleen cells as well as the highly diabetogenic monoclonal BDC2.5 TCR transgenic T cells that recognize an islet granule antigen. Using cells from both NOD and BDC2.5 mice that express a dominant-negative TGF-β receptor type II (TGF-βDNRII), we show that 2H6 T cells protected from disease by producing TGF-β and that the ability of the target diabetogenic T cells to respond to TGF-β was crucial. We further demonstrate that TGF-β signaling in 2H6 cells was important for their protective properties, as 2H6 cells were unable to protect from adoptive transfer–induced diabetes if they were unable to respond to TGF-β. Thus, our data demonstrate that insulin-specific regulatory cells protect from diabetes by virtue of their production of TGF-β1 that acts in an autocrine manner to maintain their regulatory function and acts in a paracrine manner on the target cells.
Improving survival from sudden cardiac arrest: the "chain of survival" concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association.
Authors: R O Cummins, J P Ornato, W H Thies, P E Pepe
Journal: Circulation (1991)

OverviewMore people can survive sudden cardiac arrest when a particular sequence of events occurs as rapidly as possible.This sequence is 1) recognition of early warning signs, 2) activation of the emergency medical system, 3) basic cardiopulmonary resuscita- tion, 4) defibrillation, 5) intubation, and 6) intrave- nous administration of medications.The descriptive device "chain of survival" communicates this under- standing in a useful way (Figure 1).While separate specialized programs are necessary to develop strength in each link, all of the links must be con- nected.Weakness in any link lessens the chance of survival and condemns the efforts of an emergency medical services (EMS) system to poor results.The chain of survival concept has evolved through several decades of research into sudden cardiac arrest.Effective system interventions have been identified that will allow survivors to remain neurologically intact.While a few urban systems may have ap- proached the current practical limit for survivability from sudden cardiac arrest, most EMS systems, both "Improving Survival From Sudden Cardiac Arrest: The 'Chain of Survival' Concept" was approved by the American Heart Association SAC/Steering Committee on October 17, 1990.
Effects of angiotensin converting enzyme inhibition on sodium excretion in patients with hypoxaemic chronic obstructive pulmonary disease.
Authors: A G Stewart, J C Waterhouse, C G Billings, P Baylis, P Howard
Journal: Thorax (1994)

BACKGROUND--Some patients with hypoxaemic chronic obstructive pulmonary disease (COPD) develop cor pulmonale with sodium and water retention. The sodium retention has been explained as a result of increased plasma levels of aldosterone. If this was true angiotensin converting enzyme (ACE) inhibition would be expected to lower plasma levels of aldosterone and improve the renal excretion of sodium. METHODS--Six patients with stable hypoxaemic COPD (PaO2 &lt; 8.0 kPa) and a history of an oedematous exacerbation received an intravenous hypertonic saline load (6 ml/kg body weight of 2.7% saline over one hour) before and while taking 4 mg/day perindopril, an ACE inhibitor, for one month. Aldosterone, antidiuretic hormone (ADH), plasma and urine electrolyte levels, osmolality, and volume were measured over four hours. The repeatability of the saline load test was assessed in six patients with a similar severity of hypoxaemic COPD. For comparison the saline load test was also performed in six patients with mild COPD. RESULTS--The hypertonic saline load test results were repeatable. Perindopril reduced the mean (SD) plasma level of aldosterone from 142 (88) pg/ml to 54 (24) pg/ml at 0 minutes before the saline infusion, and from 64 (35) pg/ml to 30 (17) pg/ml after the infusion without improving the urinary volume or sodium excretion. Before starting treatment with perindopril 43.7 (6.9) mmol (20%) of the sodium load was excreted compared with 49.6 (7.9) mmol (22% of load) when taking perindopril. Patients with mild COPD excreted more sodium (77.6 (21.4) mmol (38.7% of load)) despite having similar plasma aldosterone levels to those in the patients receiving perindopril. CONCLUSIONS--Patients with stable hypoxaemic COPD have an impaired ability to excrete sodium which is not improved by the administration of an ACE inhibitor. ACE inhibition lowered the plasma level of aldosterone without improving sodium excretion. This suggests that the inability of patients with hypoxaemic COPD to excrete sodium is not caused by their increased plasma levels of aldosterone.
Nocturnal oxygen saturation in advanced chronic obstructive pulmonary disease after a moderate dose of ethanol
Authors: PE Brander, T Kuitunen, T Salmi, M Partinen
Journal: European Respiratory Journal (1992)

The effect of a moderate oral dose of ethanol/(0.5 g.kg-1 body weight) on nocturnal arterial oxygen saturation (SaO2) was evaluated in nine male patients with advanced chronic obstructive pulmonary disease (COPD), (median forced expiratory volume in one second (FEV1) 0.9 l, arterial oxygen tension (PaO2) 9.3 kPa, arterial carbon dioxide tension (PaCO2) 5.3 kPa). During the four study nights (two after alcohol and two after placebo intake), the patients were monitored by whole-night computerized recordings of SaO2 (Biox-oximeter), airflow (thermistors) and respiratory as well as body movements (static charge sensitive bed). After alcohol intake, the mean blood ethanol concentration (SEM) in the evening was 42(2.3) mg.100 ml-1. Alcohol intake was associated with a marginal deterioration of nocturnal oxygenation; the mean (SEM) nocturnal SaO2 was 88.4(2.0) % after alcohol ingestion and 89.1(1.6) % after placebo ingestion, respectively. Only during the first 2 h in bed was there a statistically significant difference in SaO2 in favour of placebo (p less than 0.05). It is concluded that moderate alcohol intake in the evening, corresponding to "social" drinking, did not substantially aggravate nocturnal oxygenation in our patients with advanced COPD and mild to moderate daytime hypoxaemia.
Putting cholesterol in its place: apoE and reverse cholesterol transport
Authors: R. W. Mahley
Journal: Journal of Clinical Investigation (2006)

To avoid toxic overload of cholesterol in peripheral cells, the reverse cholesterol transport pathway directs excess cholesterol through HDL acceptors to the liver for elimination. In this issue of the JCI, a study by Matsuura et al. reveals new features of this pathway, including the importance of the ATP-binding cassette transporter G1 in macrophages and apoE in cholesteryl efflux from cells to cholesterol ester–rich (CE-rich) HDL2 acceptors (see the related article beginning on page 1435). One proposal for boosting reverse cholesterol transport has been to elevate plasma HDL levels by inhibiting CE transfer protein (CETP), which transfers CE from HDL to lower-density lipoproteins. However, there has been concern that large, CE-rich HDL2 generated by CETP inhibition might impair reverse cholesterol transport. ApoE uniquely facilitates reverse cholesterol transport by allowing CE-rich core expansion in HDL. In lower species, these large HDLs are not atherogenic. Thus, CETP might not be essential for reverse cholesterol transport in humans, raising hope of using a CETP inhibitor to elevate HDL levels.
THE OCCURRENCE OF CHANGES RESEMBLING THE INFLAMMATORY IN SKIN INJURED AND INCUBATED AFTER EXCISION
Authors: Jean V. Cooke, David Goldring, Lawrence I. Kahn
Journal: The Journal of Experimental Medicine (1953)

Observations are reported on the changes which occurred in excised rabbit and human skin after mild trauma and incubation at body temperature. These changes resembled those of chronic inflammation, in that perivascular and diffuse infiltration by histiocytes occurred in the corium and subcutaneous tissue, but they developed within a few hours. The experiments have shown that even after removal from the body certain tissue elements may retain the ability to react with proliferative changes in response to tissue injury if kept under artificially simulated physiological conditions. The possible significance of these changes in relation to the inflammatory process is discussed.
Topical glycopyrrolate for patients with facial hyperhidrosis
Authors: W.O. Kim, H.K. Kil, K.B. Yoon, D.M. Yoon
Journal: British Journal of Dermatology (2008)

Facial hyperhidrosis may negatively impact the quality of life. Although various conservative modalities have been suggested, the condition is not often treated successfully.To examine whether topical glycopyrrolate could be an effective and safe treatment for facial hyperhidrosis.Twenty-five patients with facial hyperhidrosis were enrolled and treated with 2% topical glycopyrrolate on one half of the forehead while the other half of the forehead was treated with a placebo.The sweat production rate of the half of the forehead treated with topical glycopyrrolate was significantly reduced to 37.6+/-2.8 mg min(-1) (mean+/-SEM) compared with 102.2+/-5.5 mg min(-1) at the placebo-treated half of the forehead (P<0.001). Patients evaluated their degree of anhidrosis as excellent in six (24%) patients, good in 16 (64%), fair in two (8%) and poor in one (4%). Twenty-four patients (96%) were partially or fully satisfied with their fair to excellent anhidrosis; only one patient (who developed a transient headache after treatment) was dissatisfied with its therapeutic effect. Only seven patients (28%) experienced recurrence within 1 day while 17 patients (68%) had recurrence within 2 days. One patient (4%) remained stable for up to 4 days.Topical glycopyrrolate application appears to be effective and safe for the treatment of excessive facial sweating in primary craniofacial and secondary gustatory hyperhidrosis following sympathectomy.
Downregulation of FOXP1 is required during germinal center B-cell function
Authors: Ainara Sagardoy, Jose I. Martinez-Ferrandis, Sergio Roa, Karen L. Bunting, María Angela Aznar, Olivier Elemento, Rita Shaknovich, Lorena Fontán, Vicente Fresquet, Ignacio Perez-Roger, Eloy F. Robles, Linde De Smedt, Xavier Sagaert, Ari Melnick, Jose A. Martinez-Climent
Journal: Blood (2013)
Enhanced protein phosphorylation in hypertensive hypertrophy
Authors: P Bokník
Journal: Cardiovascular Research (2001)

Objective: Chronic pressure overload in spontaneously hypertensive rats (SHR) is accompanied by heart hypertrophy and signs of heart failure. Since there is growing evidence for a possible pathophysiological role of altered protein phosphorylation in heart hypertrophy and failure, we studied here cardiac regulatory phosphoproteins and the kinases and phosphatases which regulate their phosphorylation state. Methods: The experiments were performed in ventricles of SHR (12–13 weeks old) and age-matched normotensive Wistar–Kyoto rats (WKY). Results: Basal as well as isoproterenol (Iso)-stimulated force of contraction (FOC) was markedly decreased in isolated electrically driven papillary muscles of SHR. Iso (3 μmol/l, 10 min) increased FOC by 0.91±0.20 mN in SHR and by 3.88±0.52 mN in WKY, respectively. Ca2+-uptake by sarcoplasmic reticulum (SR) at low ionized Ca2+-concentration was increased in homogenates from SHR. This was not due to altered expression of phospholamban (PLB), SR-Ca2+-ATPase and calsequestrin. However, PLB-phosphorylation at threonine-17 (PLB-PT-17) and the activity of Ca2+/calmodulin dependent protein kinase (Ca2+/Cam-PK) was increased in SHR. In addition, we found an enhanced protein kinase A (PKA)-dependent phosphorylation of the inhibitory subunit of troponin (TnI). In contrast, there was no difference in the activity or expression (protein- and mRNA-level) of protein phosphatases type 1 or type 2A between SHR and WKY. Conclusions: It is suggested that increased Ca2+/Cam-PK-activity with resulting increase of PLB-PT-17 enhanced SR-Ca2+-uptake in SHR and might contribute to the pathophysiological changes in cardiac hypertrophy of SHR.
Mutations in the DNMT3A exon 23 independently predict poor outcome in older patients with acute myeloid leukemia: a SWOG report
Authors: F Ostronoff, M Othus, P A Ho, M Kutny, D E Geraghty, S H Petersdorf, J E Godwin, C L Willman, J P Radich, F R Appelbaum, D L Stirewalt, S Meshinchi
Journal: Leukemia (2012)
Lithium in Breast Milk and Nursing Infants: Clinical Implications
Authors: Adele C. Viguera, D. Jeffrey Newport, James Ritchie, Zachary Stowe, Theodore Whitfield, Juliana Mogielnicki, Ross J. Baldessarini, Amanda Zurick, Lee S. Cohen
Journal: American Journal of Psychiatry (2007)

Objective: Current practice guidelines discourage use of lithium during breast-feeding, despite limited data. This study aimed to quantify lithium exposure in nursing infants. Method: In 10 mother-infant pairs, the authors obtained assays of lithium in maternal serum, breast milk, and infant serum and indices of infant renal and thyroid function. Results: Maternal serum, breast milk, and infant serum daily trough concentrations of lithium averaged 0.76, 0.35, and 0.16 meq/liter, respectively, each lithium level lower than the preceding level by approximately one-half. No serious adverse events were observed, and elevations of thyroid-stimulating hormone, blood urea nitrogen, and creatinine were few, minor, and transient. Conclusions: Serum lithium levels in nursing infants were low and well tolerated. No significant adverse clinical or behavioral effects in the infants were noted. These findings encourage reassessment of recommendations against lithium during breast-feeding and underscore the importance of close clinical monitoring of nursing infants.
Acute Abnormalities of Sensory Nerve Function Associated With Oxaliplatin-Induced Neurotoxicity
Authors: Susanna B. Park, David Goldstein, Cindy S.-Y. Lin, Arun V. Krishnan, Michael L. Friedlander, Matthew C. Kiernan
Journal: Journal of Clinical Oncology (2009)

Purpose Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction. Patients and Methods Measures of sensory axonal excitability were recorded before and after infusion over 88 treatment cycles in 25 patients with colorectal cancer, who received a total oxaliplatin dose of 766 ± 56 mg/m 2 . Neurologic assessment, clinical rating scales, and routine nerve conduction studies were performed. Results By completion of treatment, 16% of patients had developed severe (grade 3) neurotoxicity, and oxaliplatin dose reduction or cessation as a result of neurotoxicity was required in 40% of patients. Changes in axonal excitability occurred after infusion and could be explained on the basis of alterations in axonal membrane sodium (Na + ) channel function (refractoriness: 7.6% ± 1.7% before infusion v 4.5% ± 1.4% after infusion; P = .03; superexcitability: −22.8% ± 0.8% before infusion v −20.1% ± 1.1% after infusion; P = .0002). Changes became less pronounced in later treatment cycles, suggesting that chronic nerve dysfunction and sensory loss masked acute effects at higher cumulative doses. Importantly, patients who demonstrated reductions in superexcitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity. The findings suggest that the degree of acute nerve dysfunction may relate to the development of chronic neurotoxicity. Conclusion Sensory axonal excitability techniques may facilitate identification of Na + channel dysfunction in oxaliplatin-induced neurotoxicity and thereby provide a method to identify patients at risk for neurotoxicity to target those most likely to benefit from future neuroprotective strategies.
Effect of spironolactone on stool electrolyte losses during human cholera
Authors: R. L. Guerrant, L. C. Chen, J. E. Rohde
Journal: Gut (1972)

This study demonstrated that endogenous aldosterone, as determined by its transient competitive block by spironolactone, caused significant sodium and chloride retention during naturally acquired cholera. This beneficial effect of the hormone is accompanied, however, by a deleterious depletion of potassium. In addition, it was found that stool rate significantly altered the sodium and potassium concentrations in cholera stool despite minimal or absent aldosterone activity.
Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma
Authors: Amanda Lassen, Mohammad Atefi, Lidia Robert, Deborah JL Wong, Michael Cerniglia, Begonya Comin-Anduix, Antoni Ribas
Journal: Molecular Cancer (2014)

The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro. Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures. More than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 < 1.5 μM). The combination of dabrafenib and AKTi synergistically potentiated growth inhibition in the majority of cell lines with IC50 > 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line. AKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations.
Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations
Authors: Panagiotis Baliakas, Andreas Agathangelidis, Anastasia Hadzidimitriou, Lesley-Ann Sutton, Eva Minga, Athina Tsanousa, Lydia Scarfò, Zadie Davis, Xiao-Jie Yan, Tait Shanafelt, Karla Plevova, Yorick Sandberg, Fie Juhl Vojdeman, Myriam Boudjogra, Tatiana Tzenou, Maria Chatzouli, Charles C. Chu, Silvio Veronese, Anne Gardiner, Larry Mansouri, Karin E. Smedby, Lone Bredo Pedersen, Denis Moreno, Kirsten Van Lom, Véronique Giudicelli, Hana Skuhrova Francova, Florence Nguyen-Khac, Panagiotis Panagiotidis, Gunnar Juliusson, Lefteris Angelis, Achilles Anagnostopoulos, Marie-Paule Lefranc, Monica Facco, Livio Trentin, Mark Catherwood, Marco Montillo, Christian H. Geisler, Anton W. Langerak, Sarka Pospisilova, Nicholas Chiorazzi, David Oscier, Diane F. Jelinek, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Paolo Ghia, Richard Rosenquist, Kostas Stamatopoulos
Journal: Blood (2015)
Comparison of the Reflexes Elicited from Combined or Separate Stimulation of the Aortic and Carotid Chemoreceptors on Myocardial Contractility, Cardiac Output and Systemic Resistance
Authors: SHLOMO STERN, ELLIOT RAPAPORT
Journal: Circulation Research (1967)

Changes in left ventricular performance, stroke volume, and peripheral vascular resistance were studied in dogs after combined and separate stimulation of the aortic and carotid chemoreceptors. Selective stimulation of the aortic chemoreceptors produced an immediate increase in myocardial contractility as judged by the force developed by a strain gauge arch sewn into the left ventricular myocardium and by changes in the first derivative of the left ventricular pressure. Similar results were seen when heart rate changes were prevented by prior administration of atropine, when changes in outflow impedance were prevented by previous blockade of the alpha-adrenergic receptors, and when there was combined chemoreceptor stimulation. Beta-adrenergic blockade prevented the increase in myocardial contractility observed after chemoreceptor stimulation. With selective carotid chemoreceptor stimulation there was no significant change in contractility. Aortic chemoreceptor stimulation increased the heart rate and peripheral vascular resistance, while stroke volume decreased; carotid chemoreceptor stimulation slowed the heart rate and increased the stroke volume, but not change peripheral vascular resistance.