tbuckley/cabot-search huggingface dataset:
Milrinone, a cyclic AMP-phosphodiesterase inhibitor, has differential effects on regional myocardial work and oxygen consumption in experimental left ventricular hypertrophy
Authors: W. C Chiu, J. Kedem, H. R Weiss, J. Tse, B. V Cheinberg, P. M Scholz
Journal: Cardiovascular Research (1994)

The aim was to test the hypothesis that local myocardial work and O2 consumption would respond differentially to milrinone, a selective cyclic AMP-phosphodiesterase inhibitor, in left ventricular hypertrophy due to differences in myocardial cyclic AMP-phosphodiesterase activity.The effect of milrinone on regional segment work and regional O2 consumption was measured in 12 open chest anaesthetised dogs with left ventricular hypertrophy induced by valvular aortic stenosis and in 10 age matched control dogs. Regional myocardial work was calculated as the integrated product of instantaneous force development (miniature transducer) and segment shortening (sonomicrometer). Regional O2 consumption was calculated from coronary blood flow (radiolabelled microspheres) and O2 saturations in small regional vessels (microspectrophotometry). Low Km phosphodiesterase activity was assayed by measuring the hydrolysis of radiolabelled cyclic AMP.Milrinone increased left ventricular dP/dtmax by approximately 60-70% in both control [2808(SEM 314) to 4584(660) mm Hg.s-1] and left ventricular hypertrophy [3279(258) to 5589(470) mm-Hg.s-1]. Regional work increased significantly in control [612(88) to 955(101) g.mm.min-1], while the increase was not significant in left ventricular hypertrophy [859(139) to 974(172) g.mm.min-1]. Regional O2 consumption increased significantly with milrinone in left ventricular hypertrophy [8.1(1.2) to 13.1(2.4) ml O2.min-1.100 g-1], but the increase was not significant in control [6.9(1.2) to 7.4(1.0) ml O2.min-1.100 g-1]. Myocardial stiffness during ejection was increased by milrinone to a significantly greater extent in animals with left ventricular hypertrophy. These effects were not related to differences in cyclic AMP-phosphodiesterase activity between control hearts and hearts with left ventricular hypertrophy [393(45) v 402(36) pmol.mg protein-1.1].Differences between the hypertrophied and normal canine myocardium in response to milrinone are either due to altered levels of cyclic AMP production in left ventricular hypertrophy, to effects of milrinone that are unrelated to cyclic AMP-phosphodiesterase inhibition, or to other differences in hypertrophied hearts. The greater stiffness of the myocardium in left ventricular hypertrophy may require a greater energy expenditure to increase the amount of work it performs.
Radiotherapy in Lung Adenocarcinoma with Brain Metastases: Effects of Activating Epidermal Growth Factor Receptor Mutations on Clinical Response
Authors: Chien-Hung Gow, Chun-Ru Chien, Yih-Leong Chang, Yueh-Hsia Chiu, Sung-Hsin Kuo, Jin-Yuan Shih, Yeun-Chung Chang, Chong-Jen Yu, Chih-Hsin Yang, Pan-Chyr Yang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Whole-brain radiation therapy (WBRT) has been applied to inoperable brain metastases in lung adenocarcinoma. Recently, an in vitro study showed reduced clonogenic survival of mutant epidermal growth factor receptor (EGFR) lung cancer cell lines in response to ionizing radiation compared with that of the wild type. To elucidate the role of EGFR mutations in radiation treatment, we evaluated the clinical response to WBRT and survival of lung adenocarcinoma patients with brain metastases. Experimental Design: This was a retrospective analysis of 63 patients with brain metastases from lung adenocarcinoma who were treated with WBRT. Demographic data, EGFR mutation status, response to WBRT, and survival data were collected. Clinical response was assessed 1 month after the start of WBRT. Univariate and logistic regression models were used to test potential predictive factors associated with clinical response. Log-rank test and Cox regression were analyzed to identify factors that affected survival. Results: Clinical response to WBRT was observed in 29 patients (46%), with 34 nonresponder patients (54%). Patients with EGFR mutations had higher response rates to WBRT compared with those with the wild-type (54% versus 24%; P = 0.045). Both the administration of EGFR tyrosine kinase inhibitor (P = 0.034) and EGFR mutation (P = 0.029) were independently associated with response to WBRT. In Cox regression analysis, WBRT responder (P = 0.010) and absence of extracranial metastases (P = 0.002) were associated with better survival. Conclusions: Both the EGFR mutations and the administration of EGFR TKI during WBRT were independent predictors of response to WBRT in brain metastases of lung adenocarcinoma.
Growth factors and the mesangium.
Authors: H E Abboud
Journal: Journal of the American Society of Nephrology (1992)

Growth factors are prime candidates to mediate and modulate the functions of the mesangium. Mesangial cells are effector cells producing a number of growth factors that act in an autocrine manner to regulate their own function. Mesangial cells are also targets for growth factors released from neighboring glomerular cells or infiltrating cells and platelets. Growth factors may promote hypertrophy, proliferation, matrix metabolism, and immune-inflammatory and vasoactive properties of mesangial cells. These peptides represent important mediators of mesangial cell responses to injury. Platelet-derived growth factor mediates predominantly cell proliferation, whereas transforming growth factor beta mediates mesangial cell matrix expansion. Mesangial cells may also modulate some of the hemodynamic effects of growth factors, such as the increased renal vascular resistance in response to platelet-derived growth factor and epidermal growth factor or the increased RBF and GFR in response to insulin-like growth factor-1. Changes in the expression of growth factors of their receptors during the course of glomerular injury point to a potential role in mediating some of the pathologic changes in vivo. Several agents appear to antagonize the mitogenic and perhaps other effects of growth factors in mesangial cells. Such agents include adenylate cyclase as well as guanylate cyclase agonists. Recent studies also suggest that some traditional vasoactive agents may activate metabolic processes in mesangial cells similar to peptide growth factors. Collectively, these studies point to the interaction of both hemodynamic and metabolic factors in the response and contribution of glomerular and specifically mesangial cells to injury.
Single photon emission computed tomography in the identification of new variant Creutzfeldt-Jakob disease: case reports
Authors: R. de Silva, J. Patterson, D. Hadley, A. Russell, M. Turner, M. Zeidler
Journal: BMJ (1998)

New variant Creutzfeldt-Jakob disease may be associated with exposure to the causative agent of bovine spongiform encephalopathy. 1 Currently, a reliable diagnosis is possible only after neuropathological examination of the brain, which is risky for patients and diagnosticians. 2 The sensitivity and specificity of recently developed techniques are not known for new variant Creutzfeldt-Jakob disease, and they are available only in highly specialised centres. 3 4 Single photon emission computed tomography is a readily available neuroimaging technique that uses intravenously administered radioactive ligands to map different aspects of brain function.We report the findings on this technique using the cerebral perfusion tracer hexamethylpropyleneamineoxime (HMPAO) in two patients with neuropathologically confirmed new variant Creutzfeldt-Jakob disease.
IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1
Authors: Hitoshi Suzuki, Zina Moldoveanu, Stacy Hall, Rhubell Brown, Huong L. Vu, Lea Novak, Bruce A. Julian, Milan Tomana, Robert J. Wyatt, Jeffrey C. Edberg, Graciela S. Alarcón, Robert P. Kimberly, Yasuhiko Tomino, Jiri Mestecky, Jan Novak
Journal: Journal of Clinical Investigation (2008)

Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by β1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine–specific α2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in β1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine–specific α2,6-sialyltransferase activity. Also, expression of β1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine–specific α2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target.
Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts1
Authors: Yoji Yamashita, Michal T. Krauze, Tomohiro Kawaguchi, Charles O. noble, Daryl C. Drummond, John W. Park, Krystof S. Bankiewicz
Journal: Neuro-Oncology (2006)

Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in singleagent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas.
Prevalence, diagnosis and relation to tobacco dependence of chronic obstructive pulmonary disease in a nationally representative population sample
Authors: L Shahab, M J Jarvis, J Britton, R West
Journal: Thorax (2006)

Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death worldwide. It is caused primarily by cigarette smoking. Given its importance, it is remarkable that reliable national prevalence data are lacking for most countries. This study provides estimates of the national prevalence of COPD in England, the extent of under-detection of the disorder, and patterns of cigarette smoking, dependence, and motivation to stop smoking in those with the disease.Data from 8215 adults over the age of 35 who participated in the Health Survey for England were analysed. Information was obtained on self-reported and cotinine validated smoking status, cigarette dependence, motivation to stop smoking, COPD defined by spirometry using joint American Thoracic Society and European Respiratory Society criteria, and self-reports of diagnosis with respiratory disorders.Spirometry-defined COPD was present in 13.3% (95% CI 12.6 to 14.0) of participants, over 80% of whom reported no respiratory diagnosis. Even among people with severe or very severe COPD by spirometric assessment, only 46.8% (95% CI 39.1 to 54.6) reported any diagnosed respiratory disease. A total of 34.9% (95% CI 32.1 to 37.8) of people with spirometry-defined COPD were smokers compared with 22.4% (95% CI 21.4 to 23.4) of those without, and smoking prevalence increased with disease severity. Smokers with spirometry-defined COPD were more cigarette dependent but had no greater desire to quit than other smokers.COPD is common among adults in England and is predominantly undiagnosed. In smokers it is associated with higher degrees of cigarette dependence but not with a greater motivation to stop smoking.
Double tracer gas single-breath washout: reproducibility in healthy subjects and COPD
Authors: Kim Husemann, Nina Berg, Jennifer Engel, Johannes Port, Christoph Joppek, Ziran Tao, Florian Singer, Holger Schulz, Martin Kohlhäufl
Journal: European Respiratory Journal (2014)

The applicability and interpretation of inert tracer gas washout tests is hampered by the lack of feasible protocols and reproducibility data. We assessed feasibility, variability and reproducibility of a new easy to perform double tracer gas (DTG) single-breath washout (SBW) test and compared this with conventional nitrogen washouts. In 40 healthy nonsmokers and 20 patients with stable chronic obstructive pulmonary disease (COPD), we performed three N 2 vital capacity SBWs, three N 2 multiple-breath washouts and three tidal DTG-SBW tests. Follow-up was after 1 week, 1 month and 6 months. Main outcomes were the lung clearance index (LCI) (N 2 multiple-breath washout), slope of phase III (dN 2 ) (N 2 vital capacity SBW) and slope of phase III (SIII DTG ) (DTG-SBW). In healthy subjects, mean± sd LCI at baseline was 6.94±0.61, dN 2 0.99±0.42% N 2 per litre and SIII DTG −0.206±0.108 g·mol −1 ·L −1 . In COPD, LCI and dN 2 were significantly higher (LCI 12.23±2.67, dN 2 7.43±5.38% N 2 per litre; p&lt;0.001) and SIII DTG significantly steeper (−0.653±0.428 g·mol −1 ·L −1 , p&lt;0.001). Reproducibility was high for main outcome parameters: the intraclass correlation coefficient over 6 months was 0.77 (0.86 in COPD) for LCI, 0.82 (0.89) for dN 2 and 0.83 (0.93) for SIII DTG . The tidal DTG-SBW is a reproducible test in healthy and COPD subjects that seems attractive for use in routine clinical settings.
Human lymphocyte metabolism. Effects of cyclic and noncyclic nucleotides on stimulation by phytohemagglutinin
Authors: Jay W. Smith, Alton L. Steiner, Charles W. Parker
Journal: Journal of Clinical Investigation (1971)

The effects of extracellular nucleotides and agents which elevate intracellular cyclic adenosine 3',5'-monophosphate (cyclic AMP) concentrations on human lymphocyte metabolism have been studied. Aminophylline, isoproterenol, and prostaglandins, all of which elevate lymphocyte cyclic AMP levels, inhibited incorporation of (3)H-labeled thymidine, uridine, and leucine into the DNA, RNA, and protein of phytohemagglutinin (PHA)-stimulated lymphocytes. Aminophylline inhibition was maximal only when the inhibitor was added within 1 hr after exposure of cells to PHA, suggesting that a relatively early step in the lymphocyte transformation process may be affected. The addition of various nucleotides to the culture medium also inhibited incorporation of labeled precursors. The best inhibitor, dibutyryl cyclic AMP (DU cyclic AMP), produced maximal inhibition only if present during the 1st hr after initial exposure to PHA. Among the various cyclic nucleotides derivatives of guanosine and adenine were the most effective inhibitors (substantial inhibition at 0.1 mM concentrations). However, the inhibition was not specific for nucleotides containing the cyclic phosphodiester moiety since the tri-, di-, and monophosphates of adenosine and guanosine were equally effective in diminishing thymidine uptake. The above inhibitions were not due to secondary effects of the inhibitors on the interaction of PHA with lymphocytes as judged by (125)I-labeled PHA binding studies.Low concentrations (1-10 mumoles/liter) of cyclic AMP produced slight stimulation of thymidine-(3)H uptake in resting lymphocytes (lymphocytes not stimulated with PHA). However, the effects were quite small as compared with those produced by PHA itself. Attempts to demonstrate increased thymidine uptake 48 hr after pulsing lymphocytes with aminophylline or isoproterenol were unsuccessful. The relationship of these observations to a possible regulatory role for cyclic AMP in PHA-stimulated lymphocytes is discussed.
The Complete Chloroplast and Mitochondrial DNA Sequence of Ostreococcus tauri: Organelle Genomes of the Smallest Eukaryote Are Examples of Compaction
Authors: Steven Robbens, Evelyne Derelle, Conchita Ferraz, Jan Wuyts, Hervé Moreau, Yves Van de Peer
Journal: Molecular Biology and Evolution (2007)

The complete nucleotide sequence of the mt (mitochondrial) and cp (chloroplast) genomes of the unicellular green alga Ostreococcus tauri has been determined. The mt genome assembles as a circle of 44,237 bp and contains 65 genes. With an overall average length of only 42 bp for the intergenic regions, this is the most gene-dense mt genome of all Chlorophyta. Furthermore, it is characterized by a unique segmental duplication, encompassing 22 genes and covering 44% of the genome. Such a duplication has not been observed before in green algae, although it is also present in the mt genomes of higher plants. The quadripartite cp genome forms a circle of 71,666 bp, containing 86 genes divided over a larger and a smaller single-copy region, separated by 2 inverted repeat sequences. Based on genome size and number of genes, the Ostreococcus cp genome is the smallest known among the green algae. Phylogenetic analyses based on a concatenated alignment of cp, mt, and nuclear genes confirm the position of O. tauri within the Prasinophyceae, an early branch of the Chlorophyta.
Non-Stem Cell Origin for Oligodendroglioma
Authors: Anders I. Persson, Claudia Petritsch, Fredrik J. Swartling, Melissa Itsara, Fraser J. Sim, Romane Auvergne, David D. Goldenberg, Scott R. Vandenberg, Kim N. Nguyen, Stanislava Yakovenko, Jennifer Ayers-Ringler, Akiko Nishiyama, William B. Stallcup, Mitchel S. Berger, Gabriele Bergers, Tracy R. McKnight, Steven A. Goldman, William A. Weiss
Journal: Cancer Cell (2010)
Resistance of Very Young Mice to Inhaled Allergen Sensitization Is Overcome by Coexposure to an Air-Pollutant Aerosol
Authors: KAORU HAMADA, CARROLL-ANN GOLDSMITH, ALEJANDRA GOLDMAN, LESTER KOBZIK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The role of air pollution in the initiation of asthma is controversial. We sought to model the potential effects of air pollution on immune responses to inhaled allergens in developing lungs by using very young mice. Neonatal mice were repeatedly exposed to aerosolized ovalbumin (OVA; 3% in phosphate-buffered saline for 10 min/d, from Days 5 to 15 of age). Some mice were also exposed to leachate of residual oil fly ash (ROFA-s), a surrogate for ambient air particles, for 30 min, on Days 6, 8, and 10 of age). Repeated exposure of very young mice to allergen alone (OVA) or pollutant alone (ROFA-s) had no effect on airway hyperresponsiveness (AHR, measured as enhanced pause (Penh) with noninvasive plethysmography at Day 16 of age), and did not cause inflammation or OVA-specific antibody production. Similar exposures of adult mice to either OVA alone or to OVA + ROFA-s did result in AHR, without evidence of enhancement by combined exposure. In contrast, very young mice exposed to both OVA and ROFA-s showed significantly increased AHR (e.g., Penh with 50 mg/ml methacholine for OVA + ROFA-s versus OVA alone = 2.6 ± 0.4 [mean ± SE], versus 1.2 ± 0.1; p < 0.01, n ⩾ 15), and produced OVA-specific IgE and IgG upon allergen challenge a week later. Immunostaining of airways taken from mice at Day 11 showed a marked increase in Ia+ cells after OVA + ROFA-s exposure. We conclude that exposure to pollutant aerosols can disrupt normal resistance to sensitization to inhaled allergens, and can thereby promote development of airway hypersensitivity in this neonatal/juvenile mouse model.
Prion Protein Devoid of the Octapeptide Repeat Region Restores Susceptibility to Scrapie in PrP Knockout Mice
Authors: Eckhard Flechsig, Doron Shmerling, Ivan Hegyi, Alex J Raeber, Marek Fischer, Antonio Cozzio, Christian von Mering, Adriano Aguzzi, Charles Weissmann
Journal: Neuron (2000)
Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis
Authors: George K Bertsias, Maria Tektonidou, Zahir Amoura, Martin Aringer, Ingeborg Bajema, Jo H M Berden, John Boletis, Ricard Cervera, Thomas Dörner, Andrea Doria, Franco Ferrario, Jürgen Floege, Frederic A Houssiau, John P A Ioannidis, David A Isenberg, Cees G M Kallenberg, Liz Lightstone, Stephen D Marks, Alberto Martini, Gabriela Moroni, Irmgard Neumann, Manuel Praga, Matthias Schneider, Argyre Starra, Vladimir Tesar, Carlos Vasconcelos, Ronald F van Vollenhoven, Helena Zakharova, Marion Haubitz, Caroline Gordon, David Jayne, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2012)

Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. Results Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria &lt;0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IV A or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. Conclusions Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.