tbuckley/cabot-search huggingface dataset:
Application of in vivo and ex vivo magnetic resonance imaging for evaluation of tranilast on neointima formation following balloon angioplasty of the rat carotid artery
Authors: E Ohlstein
Journal: Cardiovascular Research (2000)

Recent studies suggest that tranilast inhibits a variety of agents implicated in neointimal growth and restenosis in experimental animal models and humans. We report here a study evaluating the efficacy of tranilast in the rat carotid artery balloon angioplasty model, a model that mimics many aspects of the percutaneous transluminal angioplasty procedure in humans. Efficacy was determined based on in vivo and ex vivo magnetic resonance imaging (MRI) as well as by histomorphometry. The utility of this study, using a reverse paradigm, is to investigate if agents successful in the clinic can demonstrate efficacy in this animal model primary screen as measured by MRI and histomorphometry.Tranilast (300 mg/kg/day, p.o.) was administered to Sprague-Dawley rats 3 days prior to balloon injury and continued for 14 days after injury. Three methods of measuring the vascular injury that occurs in this model were employed: (1) in vivo MRI, used to measure in vivo lumen volumes for the carotid artery once at baseline (pre-surgery) and again at 14 days post angioplasty; (2) ex vivo MRI (and histomorphometry), used to evaluate the total arterial wall thickness and the intima-to-media ratio; and (3) analysis of collagen density, used to evaluate the efficacy of tranilast to abrogate collagen synthesis and deposition following vascular injury.Tranilast provided 33% protection (P<0.05) from angioplasty-induced lumen narrowing as measured by MRI in vivo. The results of the ex vivo MR analysis of total wall thickness showed a 14% protection of angioplasty-induced narrowing (P<0.05), and the mean intima-to-media ratio showed a 39% (P<0.006) protection for the tranilast-treated rats. Histological analysis of the mean intima-to-media ratio demonstrated that tranilast provided 36% (P<0. 01) protection in the intima-to-media ratio. Further, treatment with tranilast showed a 52% reduction in collagen density of the intimal layer and a 70% reduction in collagen density of the medial layer of the injured arteries.The data obtained by in vivo MRI, ex vivo MRI, histology and collagen analysis demonstrate that tranilast provided significant beneficial effects in inhibiting neointimal formation in the rat carotid artery model. Also this study, to the best of our knowledge, is the first to harness complimentary information from various technologies, including lumen patency by in vivo MRI, neointimal formation by ex vivo MRI and conventional histomorphometry, and histological analysis for collagen density, to provide a comprehensive understanding of the pathology in this disease model.
Asymptomatic primary biliary cirrhosis
Authors: R. A. Fox, P. J. Scheuer, S. Sherlock
Journal: Gut (1973)

Four asymptomatic patients are described with raised serum alkaline phosphatase values and a positive serum mitochondrial antibody test. In all four needle liver biopsy showed destructive bile duct lesions. Lymphocyte transformation to phytohaemagglutinin was normal in three and impaired in one who also suffered from rheumatoid arthritis. Two patients showed normal skin and serological test responses to dinitrochlorobenzene and haemocyanin. These four patients are believed to be suffering from asymptomatic primary biliary cirrhosis.
The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR
Authors: J. Pfisterer, A. du Bois, J. Sehouli, S. Loibl, S. Reinartz, A. Reuß, U. Canzler, A. Belau, C. Jackisch, R. Kimmig, K. Wollschlaeger, V. Heilmann, F. Hilpert
Journal: Annals of Oncology (2006)
Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study
Authors: Daniel M Green, Wei Liu, William H Kutteh, Raymond W Ke, Kyla C Shelton, Charles A Sklar, Wassim Chemaitilly, Ching-Hon Pui, James L Klosky, Sheri L Spunt, Monika L Metzger, DeoKumar Srivastava, Kirsten K Ness, Leslie L Robison, Melissa M Hudson
Journal: The Lancet Oncology (2014)
Multiple inflammatory hits and the pathogenesis of severe airway disease: Fig. 1—
Authors: I. D. Pavord, S. S. Birring, M. Berry, R. H. Green, C. E. Brightling, A. J. Wardlaw
Journal: European Respiratory Journal (2006)

Refractory or difficult-to-control asthma is associated with some clinical and pathological features normally associated with chronic obstructive pulmonary disease (COPD), raising the possibility that there are similarities in their pathogenesis. It is suggested that the coexistence of two or more inflammatory stimuli to the airway (multiple hits) is a key factor leading to the development of more severe airway disease. Airway inflammation in response to chronic inflammatory conditions elsewhere may be a particularly important additional inflammatory stimulus. The “multiple hit” hypothesis for the origins of severe airway disease has important implications for treatment and prevention, since identification and removal of additional inflammatory stimuli may delay progression of the underlying airway disease.
The effect of prolonged pancreatic secretion on blood acid-base balance in the conscious dog
Authors: A. N. Fawcett, C. A. Newman
Journal: Gut (1971)

Prolonged near maximal pancreatic secretion in conscious dogs has been found to result in a metabolic acidosis. This is mild and is accompanied by respiratory and other forms of compensation. Measurements of blood bicarbonate or base-excess changes cannot be used to estimate pancreatic bicarbonate output. The acidosis caused by pancreatic secretion cannot explain the changes in bicarbonate concentration seen in pancreatic juice during prolonged secretion.
B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome
Authors: Maria Carmina Castiello, Samantha Scaramuzza, Francesca Pala, Francesca Ferrua, Paolo Uva, Immacolata Brigida, Lucia Sereni, Mirjam van der Burg, Giorgio Ottaviano, Michael H. Albert, Maria Grazia Roncarolo, Luigi Naldini, Alessandro Aiuti, Anna Villa, Marita Bosticardo
Journal: Journal of Allergy and Clinical Immunology (2015)

Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach.Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration.We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein.After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19(+)CD21(-)CD35(-) and CD21(low) B cells and a reduction in B cell-activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients.We provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS.
CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
Authors: Susanne Svensson, Annelie Abrahamsson, Gabriela Vazquez Rodriguez, Anna-Karin Olsson, Lasse Jensen, Yihai Cao, Charlotta Dabrosin
Journal: Clinical Cancer Research (2015)

Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models.For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish.ER(+) cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment.Our findings shed new light on the mechanisms underlying the progression of ER(+) breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways.
Tryptophan Metabolism in Man *
Authors: Alfred F. Michael, Keith N. Drummond, Doris Doeden, John A. Anderson, Robert A. Good
Journal: Journal of Clinical Investigation (1964)

The amino acid tryptophan is unique because it contains the indole nucleus and because it is metabolized in man through several different bio- chemical pathways to a number of specific prod- ucts.It is the precursor of serotonin and 5-hy- droxyindoleacetic acid.In addition, after cleavage of the indole ring, it may be metabolized by way of the kynurenine pathway to 3-hydroxyanthranilic acid and ultimately to nicotinamide.In mam- malian liver the benzene ring is oxidized and me- tabolized through a number of intermediate reac- tions to glutarate, acetate, and carbon dioxide (1, 2).Tryptophan is also the precursor of in- dolic acids, such as 3-indoleacetic acid.In man this compound is formed both by tissue enzymes and by bacteria in the gut (3).In the intestinal tract, bacteria that contain tryptophanase (4) re- ductively cleave the side chain of tryptophan and form indole, which is absorbed, conjugated in the liver, and excreted as indican (sulfated potassium ester of indoxyl).In addition to the various re- actions involving the indole ring or side chain, tryptophan, like other amino acids, is incorporated into protein.These pathways are schematically shown in Figure 1.The many different enzyme systems and important cofactors, such as pyridoxal phosphate, that take part in these reactions have been ably re- viewed (5-7) and will not be discussed here.In the investigation of tryptophan metabolism in man, a number of variables must be considered.These include not only these enzymes and cofactors, but
Publication of Trials Funded by the National Heart, Lung, and Blood Institute
Authors: David Gordon, Wendy Taddei-Peters, Alice Mascette, Melissa Antman, Peter G. Kaufmann, Michael S. Lauer
Journal: New England Journal of Medicine (2013)

Rapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized.We analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal.As of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan-Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P=0.004) and higher costs of conducting the trial, up to a threshold of approximately $5 million (P<0.001). The 37 trials that focused on clinical events and cost at least $5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative.Results of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.).
Molecular Characterization of Visual Pigments in Branchiopoda and the Evolution of Opsins in Arthropoda
Authors: K. Kashiyama, T. Seki, H. Numata, S. G. Goto
Journal: Molecular Biology and Evolution (2008)

Studies on color vision in invertebrates have focused primarily on insect visual pigments, with little attention given to crustacean visual pigments. None of the blue-green-, blue-, or ultraviolet (UV)-sensitive-opsins have been identified in crustaceans. In addition, the discussion of visual pigments has been limited to long-wavelength-sensitive opsins in Pancrustacea. Here, we focused on Branchiopoda (Crustacea), which is a sister group of Hexapoda including insects. In the tadpole shrimp Triops granarius, the visual pigment chromophore was retinal. Multiple opsins were isolated from each of three branchiopod species, T. granarius, Triops longicaudatus, and the fairy shrimp Branchinella kugenumaensis (five, five, and four opsins from these species, respectively). Phylogenetic analyses and the presence of a lysine residue corresponding to position 90 in bovine rhodopsin suggested that three of the branchiopod opsins comprise UV-sensitive pigments. In addition, the phylogenetic relationships between insect and branchiopod UV-sensitive opsins revealed that the divergence of blue- and UV-sensitive pigments predates the Branchiopoda and Insecta divergence. The other branchiopod opsins show distant relationships to other known insect opsins and form novel clusters. The present results strongly suggest that the ancestral arthropod of the Chelicerata-Pancrustacea lineages possessed at least four types of opsins. The ancestors of Pancrustacea and the Insecta-Branchiopoda lineages possessed at least five and six types of opsins, respectively. Our results suggest that in the evolutionary process associated with each lineage, several opsins appeared and diversified with repeated gene duplication, of which some have been lost in some taxa.
Transforming Growth Factor-β<sub>1</sub> Promoter Polymorphism C–509T Is Associated with Asthma
Authors: Eric S. Silverman, Lyle J. Palmer, Venkat Subramaniam, Arlene Hallock, Sheeba Mathew, Joseph Vallone, Debora S. Faffe, Toshiki Shikanai, Benjamin A. Raby, Scott T. Weiss, Stephanie A. Shore
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Transforming growth factor-β1 (TGF-β1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C–509T) in the TGF-β1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case–control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case–control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C–509T polymorphism alters TGF-β1 promoter–reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C–509T is associated with the diagnosis of asthma and may enhance TGF-β1 gene transcription.
The Dream in Contemporary Psychiatry
Authors: Morton F. Reiser
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This article offers selective reviews of cogent sectors of research regarding the dream in contemporary psychiatry. METHOD: First, the author discusses relatively recent research (1953–1999) on the neurobiology and clinical psychophysiology of dreaming sleep; second, he reviews experimental cognitive neuroscientific studies of perception, emotion, and memory and the putative interrelationships among them in generating dream imagery; and third, he interprets psychoanalytic studies (1900–1999) on related aspects of dreams and the dream process. RESULTS: Exploration for interrelationships among information from these three areas entails discussion of the mind/brain problem. These considerations illuminate some of the logical and interpretive dilemmas that enter into debates about Freud's theory of the dream. CONCLUSIONS: The author proposes a preliminary psychobiologic concept of the dream process and discusses, in light of the foregoing considerations, the importance of collaborative research for developing a realistic perspective concerning the proper place of the dream in contemporary psychiatry.
Incidental diagnosis of colonic tumor by PET/CT in infectious endocarditis
Authors: Frédérique Gouriet, Ludivine Saby, Edouard Delaunay, Serge Cammilleri, Yvan le Dolley, Alberto Riberi, Jean-Paul Casalta, Gilbert Habib, Didier Raoult
Journal: Journal of Infection (2013)
Evidence for Load-Dependent and Load-Independent Determinants of Cardiac Natriuretic Peptide Production
Authors: Tsuneo Ogawa, Wolfgang Linz, Michelle Stevenson, Benoit G. Bruneau, Mercedes L. Kuroski de Bold, Jia Hua Chen, Hoda Eid, Bernward A. Schölkens, Adolfo J. de Bold
Journal: Circulation (1996)

In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix.Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels.(1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.
The effect of inhalation duration on lung deposition with a pressurized metered-dose inhaler (pMDI)
Authors: Cedric Van Holsbeke, Jonathan Marshall, Jan De Backer, Wim Vos
Journal: European Respiratory Journal (2014)

Rationale 

Although the guidance for using a pMDI is to inhale 'slow and deeply', many patients inhale fast over a short duration. The ERS/ISAM Task Force suggested 'slowly' equates to inhaling over 4-5 seconds (s) for adults (Laube B.L. et al. ERJ 2011; 37(6):1308–417), a much clearer instruction. This study therefore examined the influence of inhalation time on total lung deposition (TLD) using Functional Respiratory Imaging (FRI).

Methods 

Three-dimensional airway models of 6 asthma patients (mean FEV1 83%), treated with an ICS/LABA combination, were included. The lung deposition characteristics of an HFA-based pMDI (MMAD ∼3.0μm; fine particle fraction (FPF) ∼40%) were assessed using FRI. Simulations were performed on 3 different inhalation profiles matched for the same inspiratory volume (3L) with durations of 1s, 3s and 5s and actuation at start of inhalation.

Results 

For the 1s, 3s and 5s profiles, the TLD values were 22.81±3.71%, 36.13±2.51% and 41.61±3.11% of nominal dose respectively, and were predicted using a concave down quadratic model (R2=0.87, p<0.001). The central to peripheral deposition ratios were 1.58, 0.81 and 0.57 respectively.

Conclusions 

A 5 s inhalation led to highest TLD with greatest peripheral deposition. Increased deposition with longer times mainly reflected increased peripheral deposition, central deposition was less affected by flow rate. These data support ERS/ISAM guidance for inhaling over 4-5 sec to optimize deposition, although similar TLD were achieved with 3s. These data also suggest that high FPF pMDIs can achieve reasonable deposition even with short, fast inhalations.

This study was funded by MundiPharma International.