tbuckley/cabot-search huggingface dataset:
STUDIES ON THE ACTIVATION OF A PROESTERASE ASSOCIATED WITH PARTIALLY PURIFIED FIRST COMPONENT OF HUMAN COMPLEMENT
Authors: Irwin H. Lepow, Oscar D. Ratnoff, Lawrence R. Levy
Journal: The Journal of Experimental Medicine (1958)

It has been found that under a wide range of physico-chemical conditions a positive correlation exists between the rate of disappearance of hemolytically active, partially purified first component of human complement and the rate of activation of an esterase hydrolyzing N-acetyl-L-tyrosine ethyl ester. Both reactions follow the kinetic equation for second order autocatalysis, with an apparent energy of activation of 31,000 calories per mol. They occur optimally at pH 7.3–7.7 and are inhibited by ionic strengths greater than 0.15, by 5 x 105 M ethylenediaminetetraacetic acid, and by a heat-labile serum inhibitor which appears unrelated to any component of complement. The activation of first component to esterase resembles closely the activation of trypsinogen to trypsin. Partially purified first component, containing plasminogen, may also be activated to esterase by addition of streptokinase. The significance of these data with respect to the postulated existence of first component as a proesterase and its possible role in complement-"fixation" is discussed.
Identification of a specific interleukin 1 inhibitor in the urine of febrile patients.
Authors: Z Liao, R S Grimshaw, D L Rosenstreich
Journal: The Journal of Experimental Medicine (1984)

The urine of febrile patients has been found to contain high concentrations of an inhibitor of interleukin 1 (IL-1)-induced thymocyte proliferation. The inhibitor is specific for IL-1 and does not block the effects of interleukin 2 (IL-2) or phytohemagglutin (PHA) on thymocytes, and it is not nonspecifically toxic for these cells. IL-1 inhibitor can be found in the urine of normal individuals and afebrile patients, but is present in increased concentrations in the urine of patients with fever of diverse etiologies. Preliminary physicochemical characterization indicates that the inhibitor is a 20-40-kdalton protein.
A Comparison of Prediction Equations for Estimating Glomerular Filtration Rate in Adults without Kidney Disease
Authors: Julie Lin, Eric L. Knight, Mary Lou Hogan, Ajay K. Singh
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The ability of the Modification of Renal Disease (MDRD) equation to predict GFR when compared with multiple other prediction equations in healthy subjects without known kidney disease was analyzed. Between May 1995 and December 2001, a total of 117 healthy individuals underwent 125I-iothalamate or 99mTc-diethylenetriamine-pentaacetic acid (DTPA) renal studies as part of a routine kidney donor evaluation at either Brigham and Women’s Hospital or Boston Children’s Hospital. On chart review, 100 individuals had sufficient data for analysis. The MDRD 1, MDRD 2 (simplified MDRD equation), Cockcroft-Gault (CG), Cockcroft-Gault corrected for GFR (CG-GFR), and other equations were tested. The median absolute difference in ml/min per 1.73 m2 between calculated and measured GFR was 28.7 for MDRD 1, 18.5 for MDRD 2, 33.1 for CG, and 28.6 for CG-GFR in the 125I-iothalamate group and was 31.1 for MDRD 1, 38.2 for MDRD 2, 22.0 for CG, and 31.1 for CG-GFR in the 99mTc-DTPA group. Bias was −0.5, −3.3, 25.6, and 5.0 for MDRD 1, MDRD 2, CG, and CG-GFR, respectively, in subjects who received 125I-iothalamate and −33.2, −36.5, 6.0, and −15.0 for MDRD 1, MDRD 2, CG, and CG-GFR, respectively, in those who received 99mTc-DTPA studies. Precision testing, as measured by linear regression, yielded R2 values of 0.04 for CG, 0.05 for CG-GFR, 0.15 for MDRD 1, and 0.14 for MDRD in those who underwent 125I-iothalamate studies and 0.18 for CG, 0.21 for CG-GFR, 0.40 for MDRD 1, and 0.38 for MDRD 2 for those who underwent 99mTc-DTPA studies. The MDRD equations were more accurate within 30 and 50% of the measured GFR compared with the CG and CG-GFR equations. When compared with the CG equation, the MDRD equations are more precise and more accurate for predicting GFR in healthy adults. The MDRD equations, however, consistently underestimate GFR, whereas the CG equations consistently overestimate measured GFR in people with normal renal function. In potential kidney donors, prediction equations may not be sufficient for estimating GFR; radioisotope studies may be needed for a better assessment of GFR. Further studies are needed to derive and assess GFR prediction equations in people with normal or mildly impaired renal function. E-mail: [email protected]
Specific diving training-induced arterial circulation changes
Authors: Y Gole, P Louge, A Boussuges
Journal: British Journal of Sports Medicine (2007)

Several stressors such as cold water immersion, hyperoxic exposure and decompression-induced circulating bubbles can alter arterial circulation after a dive. The aim of this study was to investigate the arterial modifications induced by a specific diving training including repeated hyperbaric exposures and physical training.Arterial pressure measurement and pulse wave velocity (PWV) recordings were performed in 12 student military divers before and after 15 weeks' training. The results were compared with the same investigations performed in 12 non-diver healthy subjects.A decrease in systolic blood pressure and pulse pressure was observed at both upper and lower limbs in student military divers after the training. Non-significant decreases in both carotido-femoral PWV and carotido-pedal PWV were found after the training. When the pulse time transit was divided by the cardiac cycle length between two R peaks ((RR) interval), a significant increase was observed between the carotid and femoral sensors. On the other hand, some differences were noticed between military divers and controls. Controls and divers were matched appropriately according to age and height, although the divers had a higher aerobic capacity as well as lower resting heart rate and lower pulse wave velocity.In trained military subjects, a training which includes repeated diving exposures and endurance exercises leads to vascular modifications suggesting an increase in central arterial compliance. There was no sign of arterial alteration induced by repeated diving exposures.
Widening participation: say no to nepotism
Authors: T. Greenhalgh
Journal: BMJ (2010)

I’ve just lost a friend. I bumped into him recently, having not seen him for years. Actually, he said, he needed a favour. He had a teenage son who was keen to apply for medicine. The boy had already spent time with doctors from various specialties who were friends of the family. It wasn’t that he really needed more work experience, but his medical school application would look better for it. Could I help?

I explained that I was a …
Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells
Authors: Yannick D. Benoit, Borhane Guezguez, Allison L. Boyd, Mickie Bhatia
Journal: Clinical Cancer Research (2014)

Aberrant regulation of the canonical Wnt signaling pathway (Wnt-β-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-β-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-β-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.
Eotaxin-2 in sputum cell culture to evaluate asthma inflammation
Authors: M. E. Scheicher, M. M. Teixeira, F. Q. Cunha, A. L. Teixeira, J. T. Filho, E. O. Vianna
Journal: European Respiratory Journal (2006)

The aim of the present study was to elucidate whether the culture of cells recovered from induced sputum may represent a suitable model to evaluate cytokine and chemokine production by airway inflammatory cells. Sputum induction was performed in 21 normal subjects and 30 asthmatic patients. A total of 21 out of the 30 asthmatic patients were taking inhaled corticosteroids, while the remaining nine were steroid-naive asthmatics. The steroid-naive group was evaluated before and after a 14-day treatment with oral prednisone (40 mg·day −1 ). The supernatant of lysed and centrifuged sputum and the supernatant of sputum cell culture were analysed. Tumour necrosis factor-α, interleukin (IL)-8 (CXCL8), IL-1β, IL-13 and eotaxin-2 (CCL24) concentrations were determined by specific ELISA. Eotaxin-2 production by cell culture was higher in the asthma group (131±108 pg·mL −1 ) than in the control group (36±41 pg·mL −1 ) and treatment with oral corticosteroids eliminated this difference. In addition, reduction of eotaxin-2 levels by corticosteroid treatment was greater in cell culture (81.3% reduction) than in sputum (26.4%). There was correlation between the decrease in eotaxin-2 production and the decrease in blood eosinophil number and between eotaxin-2 and eosinophils in sputum. Eotaxin-2 may play an important role in asthma and the response to corticosteroid treatment suggests that analysis of sputum cell culture is relevant as an inflammatory parameter.
Effects of obesity and caloric intake on biliary lipid metabolism in man.
Authors: L J Bennion, S M Grundy
Journal: Journal of Clinical Investigation (1975)

The effects of obesity and caloric intake on biliary lipid metabolism were investigated in a series of related studies. The degree of saturation of gallbladder bile with cholesterol was found to be significantly higher in a group of 23 obese healthy subjects than in a group of 23 nonobese controls matched for age, sex, and race. Bile was also significantly more saturated in 11 obese subjects before than after weight reduction. To determine whether supersaturated bile in obesity is due to excessive secretion of cholesterol or to deficient secretion of bile acids and phospholipids, the hepatic outputs of these three lipids were measured during constant duodenal infusion of formula in the same 11 subjects before and after weight reduction. Weight reduction resulted in significant reduction of cholesterol output but not of bile acid or phospholipid output. Moreover, very obese subjects were found to have cholesterol secretion rates markedly higher than less obese subjects previously studied by the same method. In obese subjects, bile was supersaturated with cholesterol despite increased bile acid pool sizes and increased secretion rates of bile acids and phospholipids. Supersaturated bile in the obese could therefore be attributed to a single defect in lipid secretion, namely, an excessive output of cholesterol. To determine whether the rate of caloric intake can account for the effects of obesity on biliary lipid composition and secretion, nine obese white men were studied on a weight maintenance diet and then during weight reduction on a 1,000 cal diet. As compared to weight maintenance, chronic caloric restriction resulted in reduced outputs of cholesterol, bile acids, and phospholipids, reduced bile acid pool size, and reduced synthesis and fecal excretion of cholesterol. Saturation of bile with cholesterol did not decrease during weight reduction, evidently because of the mobilization of cholesterol from adipose stores and the marked reduction in bile acid and phospholipid output observed during chronic caloric restriction. Acute alterations in caloric infusion rates did not fully reproduce the effects of chronic administration of high and low calorie diets. Likewise, chronic intake of hypercaloric diets by nonobese subjects did not reproduce the cholesterol hypersecretion characteristic of the obese. Thus, increased cholesterol secretion in obese subjects could not be fully explained by the amount of calories they ingested to maintain stable weight. It is concluded that obesity is characterized by excessive hepatic secretion of cholesterol which results in supersaturated bile.
Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity
Authors: Annemie Deiteren, Joris G De Man, Nathalie E Ruyssers, Tom G Moreels, Paul A Pelckmans, Benedicte Y De Winter
Journal: Gut (2014)

Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.
Repair of an intercalated long bone defect with a synthetic biodegradable bone-inducing implant
Authors: Masahiro Yoneda, Hidetomi Terai, Yuuki Imai, Takao Okada, Kazutoshi Nozaki, Hikaru Inoue, Shimpei Miyamoto, Kunio Takaoka
Journal: Biomaterials (2005)
Corticotropin Release During ECT in Man
Authors: JOHN P. ALLEN, DUANE DENNEY, JOHN W. KENDALL, PAUL H. BLACHLY
Journal: American Journal of Psychiatry (1974)

The authors studied patterns of corticotropin (ACTH) secretion following single and multiple electrically induced convulsions in the course of treating seven psychiatric patients. All seven patients improved clinically after administration of ECT along with other rehabilitative and therapeutic measures. The pattern of ACTH release during ECT was found to be similar to the pattern during other known physiological stresses. Serial seizures produced sustained high ACTH levels that fell to basal levels at the same rate as the fall after a single convulsion. One patient who had been receiving supraphysiological doses of steroids showed no rise in ACTH during five serial seizures. The authors discuss the clinical and heuristic implications of these results.
PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2
Authors: Dailing Mao, Holly Epple, Brian Uthgenannt, Deborah V. Novack, Roberta Faccio
Journal: Journal of Clinical Investigation (2006)

Excessive bone loss in arthritic diseases is mostly due to abnormal activation of the immune system leading to stimulation of osteoclasts. While phospholipase Cγ (PLCγ) isoforms are known modulators of T and B lymphocyte–mediated immune responses, we found that blockade of PLCγ enzymatic activity also blocks early osteoclast development and function. Importantly, targeted deletion of Plcg2 in mice led to an osteopetrotic phenotype. PLCγ2, independent of PLCγ1, was required for receptor activator of NF-κB ligand–induced (RANKL-induced) osteoclastogenesis by differentially regulating nuclear factor of activated T cells c1 (NFATc1), activator protein–1 (AP1), and NF-κB. Specifically, we show that NFATc1 upregulation is dependent on RANKL-mediated phosphorylation of PLCγ2 downstream of Dap12/Fc receptor γ (Dap12/FcRγ) receptors and is blocked by the PLCγ inhibitor U73122. In contrast, activation of JNK and NF-κB was not affected by U73122 or Dap12/FcRγ deletion. Interestingly, we found that in osteoclasts, PLCγ2 formed a complex with the regulatory adapter molecule GAB2, was required for GAB2 phosphorylation, and modulated GAB2 recruitment to RANK. Thus, PLCγ2 mediates RANKL-induced osteoclastogenesis and is a potential candidate for antiresorptive therapy.
Phosphoinositide 3–kinase γ participates in T cell receptor–induced T cell activation
Authors: Isabela Alcázar, Miriam Marqués, Amit Kumar, Emilio Hirsch, Matthias Wymann, Ana C. Carrera, Domingo F. Barber
Journal: The Journal of Experimental Medicine (2007)

Class I phosphoinositide 3–kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase–associated receptors or G protein–coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class IA p85/p110 heterodimers, which are activated by Tyr kinases, and the class IB p110γ isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110γ deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110γ, as well as the consequences of interfering with p110γ expression or function for T cell activation. We found that after TCR ligation, p110γ interacts with Gαq/11, lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation.
Differential Regulation of Collecting Duct Na+,K+-ATPase and K+ Excretion by Furosemide and Piretanide
Authors: Bénédicte Buffin-Meyer, Mauricio Younes-Ibrahim, Ghazi El Mernissi, Lydie Cheval, Sophie Marsy, Michèle Grima, Jean-Pierre Girolami, Alain Doucet
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. In response to chronic treatment with furosemide, collecting ducts adapt their function to the initial loss of Na<sup>+</sup> to prevent further Na<sup>+</sup> loss and extracellular volume decrease. This adaptation, which includes the overexpression of Na<sup>+</sup>,K<sup>+</sup>-ATPase, is thought to account for most of the kaliuretic effect of furosemide. Because piretanide is reported to be less kaliuretic than equidiuretic doses of furosemide, the authors compared the effects of 1-wk treatment with the two loop diuretics on urinary potassium excretion and on Na<sup>+</sup>,K<sup>+</sup>-ATPase activity in the collecting duct. At equidiuretic and equinatriuretic doses, furosemide increased urinary potassium excretion as well as collecting duct Na<sup>+</sup>,K<sup>+</sup>-ATPase activity, whereas piretanide had no effect on either parameter. These effects of furosemide were curtailed by concomitant administration of the angiotensin-converting enzyme inhibitor enalapril, but they were not altered either by clamping changes in plasma aldosterone or by blocking type I angiotensin receptors. Treatment with the antagonist of bradykinin B2 receptors Hoe140 mimicked the two effects of furosemide. In addition, the effects of Hoe140 and furosemide were not additive. Finally, piretanide increased urinary bradykinin excretion, whereas furosemide did not. These results suggest that induction of collecting duct Na<sup>+</sup>,K<sup>+</sup>-ATPase (a) accounts for the kaliuretic effect of furosemide, (b) is independent of the renin/angiotensin/aldosterone system, (c) results from increased Na<sup>+</sup> delivery to the collecting duct and enhanced intracellular Na<sup>+</sup> concentration, and (d) is prevented in piretanide treated rats by increased bradykinin production that may limit apical Na<sup>+</sup> entry in collecting duct principal cells.
Radiographic signs of pulmonary embolism and pulmonary infarction
Authors: S. Talbot, B. S. Worthington, E. J. Roebuck
Journal: Thorax (1973)

A comparative analysis of the radiographic features in a group of patients dying with pulmonary embolism and/or pulmonary infarction, and a group without but suspected of having the conditions before death, showed that two radiologists could diagnose pulmonary infarction correctly in 70% of cases. The most useful radiographic sign was elevation of the diaphragm often with slight atelectasis and a small unilateral effusion. The plain chest radiograph was of little value in diagnosing pulmonary embolism without infarction.
Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG
Authors: Asish K. Ghosh, Neil E. Kay, Charla R. Secreto, Tait D. Shanafelt
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection. Experimental Design: The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated. Results: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 μmol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor κB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection. Conclusions: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.