tbuckley/cabot-search huggingface dataset:
Complement Receptor 1/Cd35 Is a Receptor for Mannan-Binding Lectin
Authors: Ionita Ghiran, Sergi F. Barbashov, Lloyd B. Klickstein, Sander W. Tas, Jens C. Jensenius, Anne Nicholson-Weller
Journal: The Journal of Experimental Medicine (2000)

Mannan-binding lectin (MBL), a member of the collectin family, is known to have opsonic function, although identification of its cellular receptor has been elusive. Complement C1q, which is homologous to MBL, binds to complement receptor 1 (CR1/CD35), and thus we investigated whether CR1 also functions as the MBL receptor. Radioiodinated MBL bound to recombinant soluble CR1 (sCR1) that had been immobilized on plastic with an apparent equilibrium dissociation constant of 5 nM. N-acetyl-d-glucosamine did not inhibit sCR1–MBL binding, indicating that the carbohydrate binding site of MBL is not involved in binding CR1. C1q inhibited MBL binding to immobilized sCR1, suggesting that MBL and C1q might bind to the same or adjacent sites on CR1. MBL binding to polymorphonuclear leukocytes (PMNs) was associated positively with changes in CR1 expression induced by phorbol myristate acetate. Finally, CR1 mediated the adhesion of human erythrocytes to immobilized MBL and functioned as a phagocytic receptor on PMNs for MBL–immunoglobulin G opsonized bacteria. Thus, MBL binds to both recombinant sCR1 and cellular CR1, which supports the role of CR1 as a cellular receptor for the collectin MBL.
Noninvasive <i>In vivo</i> Detection of Glutathione Metabolism in Tumors
Authors: Peter E. Thelwall, Avner Y. Yemin, Theresa L. Gillian, Nicholas E. Simpson, Mohit S. Kasibhatla, Zahid N. Rabbani, Jeffrey M. Macdonald, Stephen J. Blackband, Michael P. Gamcsik
Journal: Cancer Research (2005)

Abstract Magnetic resonance spectroscopic imaging has been used to follow glutathione metabolism and evaluate glutathione heterogeneity in intact tumor tissue. Stable isotope-labeled glutathione was detected in s.c. implanted fibrosarcoma tumors in anesthetized rats following infusion of [2-13C]glycine. Using 1H-decoupled 13C magnetic resonance spectroscopy, the appearance of [2-13C]glycine at 42.4 ppm and the subsequent incorporation of this isotope label into the glycyl residue of glutathione at 44.2 ppm can be detected. The identity and relative concentrations of labeled metabolites observed in the in vivo spectrum were confirmed in studies of tissue extracts. The high level of isotopic enrichment and the concentration of glutathione in tumor tissue allow for collection of spatially localized spectra using 13C chemical shift imaging methods. These data provide the first direct images of glutathione in intact tumor tissue and show metabolic heterogeneity. This method may lead to the ability to monitor changes in tumor tissue redox state that may ultimately affect diagnosis, monitoring, and treatment.
Development and Use of Integral Assays in Clinical Trials
Authors: Richard L. Schilsky, James H. Doroshow, Michael LeBlanc, Barbara A. Conley
Journal: Clinical Cancer Research (2012)

Abstract Clinical trials that include integral biomarkers to determine eligibility, assign treatment, or assess outcome must employ robust assays to measure the molecular analyte of interest. The decision to develop a biomarker assay into a test suitable for use in humans should be driven by clinical need, that is, there should be a clear clinical purpose for undertaking the test development. Supporting in vitro or in vivo research on the ability of the marker to distinguish subgroups of patients with a given characteristic is necessary. The magnitude of the difference in treatment effect expected with use of the marker should be sufficient to support differential treatment prescription for marker-positive and -negative patients. Analytical and clinical validation of the marker assay should be completed before the clinical trial is initiated to ensure that the assay is stable enough for clinical use throughout the trial. Clinical use of the assay requires that it be performed in a Clinical Laboratory Improvement Amendments–accredited laboratory, and the need to apply for an Investigational Device Exemption from the U.S. Food and Drug Administration should be considered. In this article we elaborate on the steps required to get a biomarker assay ready for use as an integral component of a clinical trial and give an example of the use of an integral assay in a phase III trial. Clin Cancer Res; 18(6); 1540–6. ©2012 AACR.
[18F]Fluoro-2-deoxy-<scp>d</scp>-glucose Positron Emission Tomography Detects Gastric Carcinoma in an Early Stage in an Asymptomatic E-Cadherin Mutation Carrier
Authors: Mariette C. A. van Kouwen, Joost P. H. Drenth, Wim J. G. Oyen, Joyce H. F. M. de Bruin, Marjolijn J. Ligtenberg, J. J. (Han) Bonenkamp, J. Han J. M. van Krieken, Fokko M. Nagengast
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Autosomal dominant hereditary diffuse gastric cancer (HDGC) is caused by germ-line E-cadherin (CDH1) gene mutations. Early detection of cancer in carriers is difficult because HDGC escapes endoscopic detection. We hypothesized that the glucose metabolism is enhanced in HDGC and that this can be detected with [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET). Experimental Design and Results: An asymptomatic twenty-eight year-old female was seen at our outpatient clinic because of a request for screening on HDGC. Her father and younger sister died of diffuse gastric cancer, at the ages of 52 and 27, respectively. Mutational analysis of the CDH1 gene in this patient demonstrated a novel heterozygous splice-site mutation in exon 8 (1135delACGGTAATinsTTAGA). Upper gastrointestinal endoscopies revealed no macroscopic abnormalities, but one of the 40 random biopsy specimens showed well-differentiated signet-cell carcinoma. A FDG-PET scan demonstrated two spots of FDG accumulation, one located in the proximal part of the stomach and the second in the region of the pylorus. A total gastrectomy was performed and microscopic examination showed focal localization of intramucosal adenocarcinoma of the signet-cell type in the cardiac and antrum area. Most notably, the localization of the FDG accumulation matched the localization of the carcinoma. Conclusions: We present an asymptomatic patient from a HDGC family carrying a novel CDH1 mutation in whom FDG-PET scanning facilitated early detection of HDGC. This calls for further investigation of the role of FDG-PET scan as a screening modality in HDGC.
Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2
Authors: C. Celum, A. Wald, J.R. Lingappa, A.S. Magaret, R.S. Wang, N. Mugo, A. Mujugira, J.M. Baeten, J.I. Mullins, J.P. Hughes, E.A. Bukusi, C.R. Cohen, E. Katabira, A. Ronald, J. Kiarie, C. Farquhar, G.J. Stewart, J. Makhema, M. Essex, E. Were, K.H. Fife, G. de Bruyn, G.E. Gray, J.A. McIntyre, R. Manongi, S. Kapiga, D. Coetzee, S. Allen, M. Inambao, K. Kayitenkore, E. Karita, W. Kanweka, S. Delany, H. Rees, B. Vwalika, W. Stevens, M.S. Campbell, K.K. Thomas, R.W. Coombs, R. Morrow, W.L.H. Whittington, M.J. McElrath, L. Barnes, R. Ridzon, L. Corey
Journal: New England Journal of Medicine (2010)

Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study)
Authors: G. Folprecht, T. Gruenberger, W. Bechstein, H.-R. Raab, J. Weitz, F. Lordick, J.T. Hartmann, J. Stoehlmacher-Williams, H. Lang, T. Trarbach, T. Liersch, D. Ockert, D. Jaeger, U. Steger, T. Suedhoff, A. Rentsch, C.-H. Köhne
Journal: Annals of Oncology (2014)
Intensive practical lifestyle intervention improves endothelial function in metabolic syndrome independent of weight loss: a randomized controlled trial
Authors: Beatriz G.S. Seligman, Carisi A. Polanczyk, Angela S.B. Santos, Murilo Foppa, Mauricio Junges, Laisa Bonzanini, Gabriela Nicolaidis, Suzi Camey, André L. Lopes, Paulo Sehl, Bruce B. Duncan, Nadine Clausell
Journal: Metabolism (2011)
Risk-adapted FDG–PET/CT-based follow-up in patients with diffuse large B-cell lymphoma after first-line therapy
Authors: U. Petrausch, P. Samaras, S.R. Haile, P. Veit-Haibach, J.D. Soyka, A. Knuth, T.F. Hany, A. Mischo, C. Renner, N.G. Schäefer
Journal: Annals of Oncology (2010)
Functional disturbance in hiatal hernia in infants and children
Authors: A. R. Chrispin, G. W. Friedland
Journal: Thorax (1967)

Retrograde flow from the stomach into the oesophagus in infants and children is prevented by the mucosal choke and muscle cuff of the normally located oesophageal vestibule (Chrispin, Friedland, and Wright, 1967). When a hiatal hernia is present the cardinal functional abnormality is the retrograde flow of gastric content into the oesophagus. An analysis of the factors permitting such flow in these patients is presented in this paper. The important anatomical features are (1) the location of the oesophageal vestibule in the thorax, (2) the phreno-oesophageal membrane with its attachment to both the diaphragm and the vestibule, and (3) the size of the hiatus in the diaphragm. When the oesophageal vestibule lies entirely in the thorax its whole length lies in a zone of subatmospheric pressure. The sharp falls of intrathoracic pressure associated with crying are related to opening of the vestibule. Reduction in tension in the muscle cuff following a dry swallow may also result in vestibular opening with retrograde flow. Inefficient secondary stripping waves may fail to empty the refluxed gastric content from the oesophagus, permitting peptic oesophagitis to develop. The increased tendency to open and the increased difficulty in closing the oesophageal vestibule, because of tension in the abnormally located phreno-oesophageal membrane, are considered. The paradox of free retrograde flow with a small hernia and small retrograde flow with a large hernia is resolved. Basic radiological criteria for establishing the diagnosis of hiatal hernia in this age group are given. The objectives of surgery and the means by which they may be achieved are discussed.
Outcome in the 2 years following a course of exclusive enteral nutrition in a cohort of &gt;100 paediatric crohn's disease patients
Authors: F. L. Cameron, R. K. Russell, K. Gerasimidis, E. Buchanan, T. Cardigan, D. Missiou, P. McGrogan, A. Papangelou
Journal: Gut (2011)

<h3>Introduction</h3> EEN is an effective 1st line treatment for active paediatric Crohn9s disease (CD). We explored the short &amp; long term effects of EEN including anthropometric parameters and evaluated factors that predicted subsequent disease outcomes. <h3>Methods</h3> A retrospective case note review in newly diagnosed CD (&lt;16 years) who completed 8 weeks of EEN. Demographics, anthropometry, disease characteristics and inflammatory markers were taken at EEN initiation and then at 1,2, 6, 12 &amp; 24 months post diagnosis. Clinical response to EEN was characterised according to the global physician assessment. <h3>Results</h3> 110 patients were included (Males 68; Median age: 11.2 years). At diagnosis 34% were thin (BMI ≤−2SD), 1% obese (BMI ≥2SD), 10% had short stature (height ≤ −2SD) and 25% were underweight (weight ≤−2SD). By 4 weeks of EEN weight and BMI z-score increased significantly (−1.1 cf. −0.6 and −1.3 cf. −0.4 respectively, p&lt;0.02) with a smaller increase between 4 and 8 weeks (−0.6 cf. −0.4 and −0.4 cf. −0.05 respectively, p&lt;0.05). Children with active disease (n=12) gained less weight than those in remission (2.2 vs 5.0 kg respectively, p&lt;0.05). There was a strong negative correlation between weight/BMI z-score at diagnosis and magnitude of change at the end of EEN (r=−0.76, p&lt;0.0001). Compared to baseline albumin, CRP and platelets significantly improved and weeks 4 and 8 (Albumin (g/L): 31±6.4 vs 36±4.7; CRP (mg/L): 44.1±48.8 vs 16.1±13.9; platelets (×10<sup>9</sup>): 525±147 vs 471±165; all p&lt;0.01) but not between weeks 4 and 8. ESR improved significantly between 0 and 4 ((ESR (mm/h): 43.5±23.2 vs 24.3±20.7, p &lt;0.00001) and continuing to fall to 18.8 at 4–8 weeks (p&lt;0.01 cf. 4 weeks). 44 patients completed a 2<sup>nd</sup> course of EEN; median weight gain improved but was less than the initial course (3.3 vs 5.1 kg, p&lt;0.05). Of these children, 19 achieved remission after both courses and 2 children who had active disease after the first course went on to achieve remission after the second course. BMI z-score at diagnosis was the strongest predictor of BMI z-score at any time point of the follow-up. The size of weight or BMI z-score change at the end of the primary EEN did not predict time to subsequent clinical relapse or anthropometry at follow-up. Median height z-score did not change compared to diagnosis. <h3>Conclusion</h3> Anthropometry improves with EEN but the change is smaller in the second half of the initial course or in secondary courses. Weight gain is not a predictor of time to relapse or anthropometry at follow-up to 2 years. Systemic inflammatory markers improve during the 1<sup>st</sup> 4 weeks of treatment with little improvement at the second half.
Evidence In Vivo Showing Increase of Baseline Nitric Oxide Generation and Impairment of Endothelium-Dependent Vasodilation in Normotensive Patients on Chronic Hemodialysis
Authors: JENS PASSAUER, ECKHART BÜSSEMAKER, URSULA RANGE, MARIA PLUG, PETER GROSS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD; n = 11) and in matched control subjects ( n = 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 ± 20 [SEM], 246 ± 26, and 338 ± 29%; HD patients: 161 ± 7, 206 ± 12, and 262 ± 24%; baseline = 100% for each group, P = 0.032 by ANOVA). All subsequent data were corrected for this decreased response to defined doses of NO in HD patients. L-arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 ± 4%; HD patients: 103 ± 4%; P = NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 ± 32, 340 ± 40, and 465 ± 52%; HD patients: 251 ± 55, 244 ± 36, and 318 ± 50%; P = 0.002). N -monomethyl-L-arginine (LMA 1:1 μmol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control subjects: 90 ± 2, 83 ± 2, and 74 ± 4%; HD patients: 84 ± 3, 73 ± 3, and 64 ± 4%; P = 0.037). Vascular response to three doses of norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive HD patients, ( 1 ) vasodilation to defined doses of exogenous NO was reduced, ( 2 ) there was no evidence of substrate deficiency of NOS, and ( 3 ) stimulation of NOS was impaired; however, ( 4 ) baseline NO generation was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.
Anti-oxidant action of metronidazole: a possible mechanism of action in rosacea
Authors: Y. MIYACHI, S. IMAMURA, Y. NIWA
Journal: British Journal of Dermatology (1986)

To elucidate the mechanism of action of metronidazole in the treatment of rosacea, the effect of metronidazole on the generation of reactive oxygen species was examined both in neutrophil and xanthine-xanthine oxidase systems. Metronidazole had anti-oxidant action which was not exerted by the scavenging of reactive oxygen species, but by having an effect on neutrophil cell functions. Beneficial effects of metronidazole in the treatment of papulopustular rosacea can in part be attributable to this anti-inflammatory effect.
β-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+: Na+ selectivity
Authors: R Chandra
Journal: Cardiovascular Research (1999)

Objective: Prior studies of the modulation of the Na+ current by sympathetic stimulation have yielded controversial results. Separation of the Na+ and Ca2+ currents poses a problem in myocyte preparations. The gating of cloned Na+ channels is different in oocytes compared with mammalian expression systems. We have examined the sympathetic modulation of the α-subunit of the wild-type human cardiac Na+ channel (hH1) and the long QT-associated mutant, ΔKPQ, expressed in human embryonic kidney cells. Methods: Stable cell lines of hH1 and ΔKPQ were established in human embryonic kidney cells. Whole-cell and single-channel currents were measured with the patch–clamp technique. Sympathetic stimulation was effected by exposure to isoproterenol or 8-bromo-cAMP. Na+ channel activation and inactivation were determined using standard voltage clamp protocols. Ca2+: Na+ permeability ratio was determined under bi-ionic conditions. Results: We observed a qualitatively different effect of sympathetic stimulation on the cardiac Na+ current from that reported in frog oocytes: activation and inactivation kinetics were shifted to more negative potentials. This shift was similar for both hH1 and ΔKPQ. [ΔV0.5 for inactivation: 8.3±1.7 mV, p<0.001 (hH1); 6.8±0.9 mV, p<0.001 (ΔKPQ)]. Increased rate of closed-state inactivation contributed to the shifting of the inactivation–voltage relationship. Open-state inactivation was not affected as mean open times were unchanged. Reversal potential measurement in hH1 suggested a low Ca2+: Na+ permeability ratio of 0.017, uninfluenced by sympathetic stimulation. In ΔKPQ, the size of the persistent relative to the peak current was increased with 8-bromo-cAMP from 3.0±0.7% to 4.3±0.6% (p=0.056). Conclusions: Sympathetic stimulation exerts multiple effects on the gating of hH1. Similar effects are also seen in ΔKPQ which may increase arrhythmia susceptibility in long QT syndrome by modifying the Na+ channel contribution to the action potential.
The clinical role of routine non-invasive parameters in the diagnostic work-up of patients with risk for pulmonary hypertension
Authors: Gabor Kovacs, Vasile Foris, Maria Tscherner, Alexander Avian, Xhylsime Kqiku, Andrea Olschewski, Horst Olschewski
Journal: European Respiratory Journal (2012)

Objective: Pulmonary hypertension (PH) is diagnosed by right heart catheterization. Doppler Echocardiography is the most specific non-invasive screening tool, but the role of other routine measures in the diagnostic work-up of patients is not clearly defined. We hypothesized that a diagnostic algorithm using a combination of simple non-invasive parameters might help to identify patients with PH.

Patients and Methods : We retrospectively analyzed all patients who received a right heart catheterization and a routine non-invasive assessment between 2005 and 2010. The pretest probability for PH was 50%. As first step, the ratio of the S and R waves in lead I of the ECG were determined; a value ≥1 (≥90°) was considered as right axis deviation (RAD). In a second step, further simple non-invasive parameters were analyzed by logistic regression for their association with PH.

Results : We included n=395 patients. RAD was present in n=87 of them. Within these, n=82 had PH, and n=5 did not, revealing a positive predictive value of 94%. In the remaining n=308 patients, we identified n=60 patients with a combination of NT-proBNP 65%, arterial SO2≥95% and Borg dyspnoe score< 3 at the end of six-minute walk test, of which only n=4 suffered from PH revealing a negative predictive value of 93%.

Conclusion : Our retrospective analysis on a large, heterogenous cohort of subjects including patients with and without PH suggests that the combination of simple, non-invasive parameters allows a reliable identification of subjects both with a very high and with very low probability of PH. Further validation in prospective, population based studies is needed.
Effects of Beta-Receptor Blockade and Glucagon on the Atrioventricular Transmission System in the Dog
Authors: LEIGHTON S. WHITSITT, BENEDICT R. LUCCHESI, Barbara Laidlaw
Journal: Circulation Research (1968)

The effects of dl -propranolol, d -propranolol, and ICI 46037, a quaternary analog of propranolol, on the functional refractory period and conduction time of the atrioventricular transmission system were studied in anesthetized dogs. dl -Propranolol, 0.5 mg/kg, prolonged the functional refractory period, increased the conduction time, and reduced the maximum frequency of A-V transmission. Larger doses (5 mg/kg) produced only a small additional depression of A-V transmission. In contrast, neither d -propranolol nor ICI 46037, 0.5 mg/kg, depressed A-V transmission. Larger doses of both drugs prolonged both the functional refractory period and the conduction time, the magnitude of the response being quantitatively similar to that produced by increasing the dose of dl -propranolol from 0.5 mg/kg to 5 mg/kg. The intravenous administration of glucagon, 2 µg/kg, promptly restored normal A-V conduction in animals that had received dl - or d -propranolol, but was ineffective in those which had received ICI 46037. It was concluded that propranolol depresses A-V transmission by both specific (beta-receptor blockade) and nonspecific mechanisms, the former being the more important. In addition, it appears that glucagon is capable of reversing the cardiodepressant action of propranolol on A-V transmission, a finding which may have considerable clinical importance.