tbuckley/cabot-search huggingface dataset:
Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes
Authors: Ling Xiao, Pierre Coutu, Louis R. Villeneuve, Artavazd Tadevosyan, Ange Maguy, Sabrina Le Bouter, Bruce G. Allen, Stanley Nattel
Journal: Circulation Research (2008)

Transient outward K+ current (I to) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiac I(to) and underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37 degrees C) were paced continuously at 1 or 3 Hz for 24 hours. I to was recorded with whole-cell patch clamp. The 3-Hz pacing reduced I to by 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by approximately 30% and approximately 40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca2+ loading with nimodipine or calmodulin inhibition with W-7, A-7, or W-13 eliminated 3-Hz pacing-induced I to downregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II with KN93, or calcineurin with cyclosporin A, also prevented I to downregulation. CaMKII-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced CaMKII activity, with functional significance suggested by acceleration of the Ca2+i transient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na+/Ca2+ exchange and sarcoplasmic reticulum Ca2+-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT prevented I to reduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing. CaMKII inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulates I to expression, with the Ca2+/calmodulin-dependent CaMKII and calcineurin/NFAT systems playing key Ca2+-sensing and signal-transducing roles in rate-dependent I to control.
How Lymphocytes Kill
Authors: L H Y Young, C C Liu, S Joag, S Rafii, J D E Young
Journal: Annual Review of Medicine (1990)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway <i>S</i>-Nitrosothiols
Authors: Harvey E. Marshall, Erin N. Potts, Zachary T. Kelleher, Jonathan S. Stamler, W. Michael Foster, Richard L. Auten
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

S-Nitrosothiols (SNO) inhibit immune activation of the respiratory epithelium and airway SNO levels are decreased in inflammatory lung disease. Ethyl nitrite (ENO) is a gas with chemical properties favoring SNO formation. Augmentation of airway SNO by inhaled ENO treatment may decrease lung inflammation and subsequent injury by inhibiting activation of the airway epithelium.To determine the effect of inhaled ENO on airway SNO levels and LPS-induced lung inflammation/injury.Mice were treated overnight with inhaled ENO (10 ppm) or air, followed immediately by exposure to aerosolized LPS or saline. Parameters of inflammation and lung injury were quantified 1 hour after completion of the aerosol exposure and correlated to lung airway and tissue SNO levels.Aerosolized LPS induced a decrease in airway and lung tissue SNO levels including S-nitrosylated NF-kappaB. The decrease in lung SNO was associated with an increase in lung NF-kappaB activity, cytokine/chemokine expression (keratinocyte-derived chemokine, tumor necrosis factor-alpha, and IL-6), airway neutrophil influx, and worsened lung compliance. Pretreatment with inhaled ENO restored airway SNO levels and reduced LPS-mediated NF-kappaB activation thereby inhibiting the downstream inflammatory response and preserving lung compliance.Airway SNO serves an antiinflammatory role in the lung. Inhaled ENO can be used to augment airway SNO and protect from LPS-induced acute lung injury.
Lecture Notes on Rheumatology
Authors: A. Young
Journal: Annals of the Rheumatic Diseases (1987)

The newer cytotoxic drugs used in connective tissue disorders (J H Klippel) and the role of radiotherapy (A J Calin) are dealt with in two useful chapters.In the former, the available information on the use of cyclophosphamide, azathioprine, methotrexate, and cyclosporin is presented together with information on the potential risks, including that of malignancy.The sacroiliac joint, always a subject of much debate, receives detailed attention by N Bellamy who certainly provides a very comprehensive account of our current knowledge about this joint but rather avoids answering the question of how much this joint contributes to low back pain syndromes.The clinical reviews are well rounded off with useful reviews of dermatology and rheumatology (L G Millard), sports medicine (F Murray Leslie), and rehabilitation of the rheumatic patient (J Winfield).
Malignant Transformation and Antineoplastic Actions of Nonsteroidal Antiinflammatory Drugs (Nsaids) on Cyclooxygenase-Null Embryo Fibroblasts
Authors: Xinping Zhang, Scott G. Morham, Robert Langenbach, Donald A. Young
Journal: The Journal of Experimental Medicine (1999)

In this study, we use primary embryonic fibroblasts derived from cyclooxygenase-deficient transgenic embryos to further investigate the role of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), in the process of neoplastic transformation. Cells with either, neither, or both of the cyclooxygenases were transformed by Ha-ras and/or SV40. Our results show that when a cyclooxygenase enzyme is present, the transformed cells have marked increases in COX-2 and/or COX-1 expression. Nevertheless, each type of cell, deficient in either or both cyclooxygenases, can be readily transformed at almost equal efficiency. Different nonsteroidal antiinflammatory drugs (NSAIDs) were used to examine their possible antineoplastic effects on the transformed cells, which have various levels of expression of COX-1 or COX-2. Our results show that NSAIDs suppress the colony formation in soft agar in a dosage-dependent manner in the absence of the cyclooxygenase(s). Thymidine incorporation and apoptosis analyses further demonstrate that the NSAIDs are effective in the cyclooxygenase-null cells. Our findings with cyclooxygenase knockout cells confirm recent reports that some of the antiproliferative and antineoplastic effects of NSAIDs are independent of the inhibition of either COX-1 or COX-2. They also show that transformation is independent of the status of cyclooxygenase expression, suggesting that the involvement of the cyclooxygenases in tumorigenesis may occur at later steps.
Assessing Tumor Angiogenesis
Authors: Cristina Rabascio, Elisabetta Muratori, Patrizia Mancuso, Angelica Calleri, Valentina Raia, Thomas Foutz, Saverio Cinieri, Giulia Veronesi, Giancarlo Pruneri, Pietro Lampertico, Massimo Iavarone, Giovanni Martinelli, Aron Goldhirsch, Francesco Bertolini
Journal: Cancer Research (2004)

Abstract No markers are currently available to indicate the angiogenic profile of a specific malignant disease nor to predict response to antiangiogenic therapies. Nevertheless, many different antiangiogenic drugs are presently being tested in many clinical trials, with an obvious scarcity of useful endpoints for treatment outcome beside survival. By means of a quantitative reverse transcription-PCR approach, we measured VE-cadherin (VE-C), Tie-2, vascular endothelial growth factor receptor 2 and CD133 RNA in the blood of 14 healthy controls, 3 pregnant women, and 84 newly diagnosed (or relapsed) cancer patients. Circulating VE-C RNA was increased in pregnant women and cancer patients (P = 0.0002). VE-C RNA was particularly increased in patients affected by hematological malignancies and decreased to normal values in patients achieving complete remission. Conversely, circulating RNA levels of other endothelial or progenitor cell-specific markers Tie-2, vascular endothelial growth factor receptor 2, and CD133 were not significantly increased in either pregnant women or cancer patients. Comparison of various surrogate angiogenesis markers indicated a switch toward increased plasma vascular endothelial growth factor (VEGF) levels, viable circulating endothelial cells, and circulating VE-C RNA levels in patients affected by hematological malignancies. Taken together, our data indicate that the quantitative evaluation of circulating VE-C RNA is a specific and highly promising tool with which to investigate the angiogenic phenotype of cancer patients.
The Shared Genome Is a Pervasive Constraint on the Evolution of Sex-Biased Gene Expression
Authors: R. M. Griffin, R. Dean, J. L. Grace, P. Ryden, U. Friberg
Journal: Molecular Biology and Evolution (2013)

Males and females share most of their genomes, and differences between the sexes can therefore not evolve through sequence divergence in protein coding genes. Sexual dimorphism is instead restricted to occur through sex-specific expression and splicing of gene products. Evolution of sexual dimorphism through these mechanisms should, however, also be constrained when the sexes share the genetic architecture for regulation of gene expression. Despite these obstacles, sexual dimorphism is prevalent in the animal kingdom and commonly evolves rapidly. Here, we ask whether the genetic architecture of gene expression is plastic and easily molded by sex-specific selection, or if sexual dimorphism evolves rapidly despite pervasive genetic constraint. To address this question, we explore the relationship between the intersexual genetic correlation for gene expression (rMF), which captures how independently genes are regulated in the sexes, and the evolution of sex-biased gene expression. Using transcriptome data from Drosophila melanogaster, we find that most genes have a high rMF and that genes currently exposed to sexually antagonistic selection have a higher average rMF than other genes. We further show that genes with a high rMF have less pronounced sex-biased gene expression than genes with a low rMF within D. melanogaster and that the strength of the rMF in D. melanogaster predicts the degree to which the sex bias of a gene's expression has changed between D. melanogaster and six other species in the Drosophila genus. In sum, our results show that a shared genome constrains both short- and long-term evolution of sexual dimorphism.
Serum Matrix Metalloproteinase-9:Tissue Inhibitor of Metalloproteinase-1 Ratio Correlates with Steroid Responsiveness in Moderate to Severe Asthma
Authors: MARC BOSSÉ, JAMILA CHAKIR, MAHMOUD ROUABHIA, LOUIS-PHILIPPE BOULET, MARIE AUDETTE, MICHEL LAVIOLETTE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Asthma presents a variable clinical response to corticosteroids (CS). Because CS more likely act on inflammation than on tissue remodeling, the presence of bronchial structural changes in certain asthmatics may explain their limited clinical response to CS. Matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), are, respectively, involved in tissue inflammatory processes and fibrogenic processes. Previous reports have suggested that MMP-9:TIMP-1 ratio may reflect the balance between these two processes in various diseases. This study evaluated the relation of this ratio and the response to CS in severe asthma. Twenty asthmatics with low baseline FEV1 (59 ± 4% predicted) and ⩾ 30 % increase with β2-agonist were recruited. Serum MMP-9 and TIMP-1 levels were measured and correlated with response to an oral CS trial (methylprenisolone 40 mg/d for 14 d). With oral CS, FEV1 changes ( Δ FEV1) ranged from − 15 to + 43%. The Δ FEV1 closely correlated with the MMP-9:TIMP-1 ratios (rho = 0.79, p = 0.0006). In conclusion, serum MMP-9: TIMP-1 ratio could predict the response of oral CS therapy in asthma. The low MMP-9:TIMP-1 ratio observed in subjects with little or no FEV1 improvement with CS supports the hypothesis that, in these asthmatic subjects, bronchial fibrogenesis predominates over inflammation.
Medical pleuroscoy, role in undiagnosed pleural effusion and therapy for pneumothorax and recurrent pleural effusion
Authors: Varun Patel, Mukesh Patel, Harjit Dumra, Amrish Patel, Gopal Raval, Tushar Patel
Journal: European Respiratory Journal (2013)

Introduction: Pleuroscopy has received renewed interest in the recent past for diagnostic as well as therapeutic uses. It is a minimally invasive procedure to inspect and perform a biopsy of the pleural space as well as to perform chemical Pleurodesis. Aim and Objective: To find the diagnostic yield of a pleuroscopic pleural biopsy of undiagnosed effusion, therapeutic effectiveness of chemical pleurodesis in recurrent effusion and Pneumothorax. Material & Methods: It is prospective observation study conducted at tertiary care center over a span of 4 years. Patients with undiagnosed exudative pleural effusions defined as effusion with adenosine deaminase levels less than 70 IU/L and negative pleural fluid cytology for malignancy and recurrent pneumothorax and recurrent pleural effusion were recruited for diagnostic evaluations and therapeutic interventions, respectively after inform consent. Rusult:Results: 250 patients with 71.26% were men and mean age of cohort was 54.51 years, and mean amount of effusion was 1252 ml. 27.9% patients were diagnosed malignant mesothelioma (MM), 22.42% patients were having granulomatous inflammation, 16.96% were diagnosed as metastatic adenocarcinoma, rest biopsies were diagnosed as inflammation, 3 biopsies were reported as normal pleura. 100% success rate achieved with chemical pleurodesis. Higher prevalence rate of MM was seen in metros. Complication rates are low (2%-5%) and are typically minor. Conclusion: Pleuroscopy using a semi-rigid instrument is a safe and efficacious procedure for the management of pleural disease in suitable patients. Mesothelioma is increased in western part of country needs to be investigated properly.
Recent Horizontal Transfer of Mellifera Subfamily Mariner Transposons into Insect Lineages Representing Four Different Orders Shows that Selection Acts Only During Horizontal Transfer
Authors: D. J. Lampe
Journal: Molecular Biology and Evolution (2003)

We report the isolation and sequencing of genomic copies of mariner transposons involved in recent horizontal transfers into the genomes of the European earwig, Forficula auricularia; the European honey bee, Apis mellifera; the Mediterranean fruit fly, Ceratitis capitata; and a blister beetle, Epicauta funebris, insects from four different orders. These elements are in the mellifera subfamily and are the second documented example of full-length mariner elements involved in this kind of phenomenon. We applied maximum likelihood methods to the coding sequences and determined that the copies in each genome were evolving neutrally, whereas reconstructed ancestral coding sequences appeared to be under selection, which strengthens our previous hypothesis that the primary selective constraint on mariner sequence evolution is the act of horizontal transfer between genomes.
Effect of vitamin B6 supplementation on plasma oxalate and oxalate removal rate in hemodialysis patients.
Authors: J F Costello, M C Sadovnic, M Smith, C Stolarski
Journal: Journal of the American Society of Nephrology (1992)

Whether pyridoxine (B6) supplements decrease plasma oxalate concentrations in patients on maintenance dialysis is unresolved. The effect of two dose levels of B6, 0.59 mmol/day (100 mg/day) over 6 months and 4.43 mmol (750 mg) after each dialysis treatment for 4 wk, on plasma oxalate and oxalate removal rate (dialysis plus urinary excretion) was studied in patients on maintenance hemodialysis. In both studies, a control group unsupplemented with B6, who remained on their regular diet, was also studied. The vitamin B6 status of the patients was assessed by the erythrocyte glutamate pyruvate transaminase activity and index before and during supplementation. No decrease in plasma oxalate or oxalate removal rate was found in either study. The plasma oxalate and oxalate removal rates of the unsupplemented hemodialysis patients were not different from those receiving B6 either before or after supplementation. These studies demonstrate that high-dose B6 supplementation does not decrease plasma oxalate concentration in a population of hemodialysis patients.
The Cooling of the Body after Death
Authors: J. W. Burman
Journal: BMJ (1874)

the contents of the bowels were pale, the gall-bladder empty, and the biliary ducts coated -with a greyish mucus, notwithstaniding which the skin was of a chalky paleniess, anid the urine contained no bile-pigment.* Similar observations have beeni made by Budd in cases of waxy disease and cancer of the liver,e and several instances of a like nature have come un(ler rrm own notice.If bile-pigment be formed in the circulating blood, it is diffic 'lt to account for whlat becomes of it in these cases.4. If the constituents of bile be formed in the blood, intense jaundice ought at once to follow the extirpation of the liver in any of the lower animals, in like manner as urea acctumulates in the blood after removal of the kidneys.But, so far from this being the case, Muller, Kunde, Lehmanni, and Moleschott have repeatedly extirpated the liver of frogs, and have invariably failed to find a tr-ace of the biliary acids, or of the colouring matter of the bile, in the blood, the urine, or the muscular tissue.The supposition that bile-pigment is formed in the blood appears to me for these reasons to be ulntenable.
Potential difference across the normal and the abnormal gastric mucosa in man.
Authors: A Hossenbocus, P Fitzpatrick, D G Colin-Jones
Journal: Gut (1976)

The mucosal potential difference in the body of the stomach was measured in 18 patients with gastric ulcers, five with gastritis, and three with pernicious anaemia. The results were compared with those of 12 normal volunteers. Significantly lower than normal levels were found in the groups of patients with gastric ulcers and gastritis. The patients with pernicious anaemia had even lower potential differences. In an additional 25 subjects, measurements were made in the duodenal bulb and at five sites in the stomach under direct vision at endoscopy. Biopsies were taken from each site for histology. Subjects with gastritis at the high lesser curve had a significantly lower potential difference at that site than those without gastritis. In the latter group, the potential difference at the high lesser curve was as low as in the antrum, and invariably lower than at the high greater curve.
Diagnosis of pulmonary disease in human immunodeficiency virus infection: role of transbronchial biopsy and bronchoalveolar lavage.
Authors: M H Griffiths, G Kocjan, R F Miller, P Godfrey-Faussett
Journal: Thorax (1989)

The value of transbronchial biopsy and bronchoalveolar lavage was assessed in the diagnosis of pulmonary disease in patients infected with the human immunodeficiency virus (HIV). Seventy four transbronchial biopsy and 66 bronchoalveolar lavage specimens (60 paired specimens) from 80 examinations in 64 patients were reviewed. Pneumocystis carinii was the most common pathogen isolated (43 patients). Bronchoalveolar lavage was superior to transbronchial biopsy for the diagnosis of this pathogen, the sensitivities being 90% and 56%. Cytomegalovirus was identified three times by lavage and once by transbronchial biopsy. Neither method detected Kaposi's sarcoma in the one patient shown to have it by open lung biopsy. The complication rate in a concurrent study of bronchoscopy with transbronchial biopsy in 74 consecutive HIV positive patients was 22%. This study does not support the use of transbronchial biopsy in these patients.
Mannose metabolism in the human erythrocyte
Authors: Ernest Beutler, Leslie Teeple
Journal: Journal of Clinical Investigation (1969)

The metabolism of mannose by human erythrocytes has been investigated. Phosphorylation of mannose is achieved by an enzyme with electrophoretic mobility on starch gel indistinguishable from the glucose-phosphorylating enzyme. Mannose phosphorylation is competitively inhibited by glucose; glucose phosphorylation is competitively inhibited by mannose. The K(i) values of inhibition are similar to the K(m) values for uninhibited phosphorylation. The normal average mannose-phosphorylating activity was found to be 0.69 U/g of Hb; the normal average glucose-phosphorylating activity was found to be 0.64 U/g of Hb. The ratio of mannose-phosphorylating activity to glucose-phosphorylating activity of a hemolysate prepared from the red cells of a subject with hexokinase deficiency was found to be within the normal range.Phosphomannose isomerase (PMI) activity of the red cells was found to average 0.064 U/g of Hb at its pH optimum of 5.9 with a mannose-6-phosphate (Man-6-P) concentration of 5 mmoles/liter. The enzyme activity in young cells was greater than activity in old cells. When human erythrocytes are incubated with mannose rapid accumulation of Man-6-P occurs, a finding indicating that PMI and not hexokinase is the limiting enzyme in the over-all conversion of mannose to fructose by the red cell. The ratio of mannose utilization to glucose utilization in hexokinase-deficient cells was greater than normal, as has been reported previously. These cells were found to have greatly increased PMI activity, presumably because of their young mean cell age. Consequently, Man-6-P accumulated only approximately one-third as rapidly as normal in hexokinase-deficient cells incubated with mannose. It is believed that the more rapid utilization of mannose relative to glucose by intact hexokinase-deficient cells may be explained on the basis of the regulatory effect of the PMI reaction on the rate of mannose utilization.
Beneficial effect of omeprazole in a patient with severe bronchial asthma and gastro-oesophageal reflux
Authors: AC Depla, JF Bartelsman, CM Roos, GN Tytgat, HM Jansen
Journal: European Respiratory Journal (1988)

A 25-yr-old man suffered from severe nocturnal asthma, which was shown to be provoked by pathological gastro-oesophageal reflux. A dramatic, immediate improvement of his pulmonary condition was achieved by treatment with omeprazole after failure of other therapeutic measures, including high doses of ranitidine.
Efficient Retroviral Vector Targeting of Carcinoembryonic Antigen-Positive Tumors
Authors: Simon Chowdhury, Kerry A Chester, John Bridgewater, Mary K Collins, Francisco Martin
Journal: Molecular Therapy (2003)

Many gene therapy approaches require specific, efficient gene delivery to cells in vivo. To target colorectal tumors we fused a single-chain variable fragment (scFv) directed against carcinoembryonic antigen (CEA) to the amphotropic murine leukemia virus envelope. A proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two proteins. Following attachment to CEA, MMP cleavage of the envelope at the cell surface removed the scFv and proline-rich hinge, allowing transduction. This allowed selective targeting of CEA-positive cells in vivo after injection of producer cells at the site of the tumor, with up to 10% of cells within a CEA-positive tumor xenograft becoming transduced. Intraperitoneal injection of amphotropic producer cells resulted in transduction of cells in spleen, liver, and kidney, which was not detected when CEA-targeted producer cells were used. These results demonstrate the feasibility of using targeted retroviral vectors for in vivo gene delivery to tumors. Furthermore, the lack of transduction of host cells eliminates the risk of insertional mutagenesis leading to transformation of host hematopoietic cells.