tbuckley/cabot-search huggingface dataset:
Pharmacologic Actions of Tetrodotoxin Studied by Direct Perfusion of the Sinus Node
Authors: JOHN C. TOMLINSON, THOMAS N. JAMES
Journal: Circulation Research (1968)

The effects of tetrodotoxin on sinus node activity were studied by direct perfusion through its nutrient artery. Tetrodotoxin suppresses action potentials by blocking sodium entry into the cell. In the open-chest anesthetized dog, direct perfusion of the sinus node artery with tetrodotoxin, 1.0 µg/ml, caused immediate sinus slowing lasting 12 to 60 minutes. This slowing was not affected by intranodal atropinization. Tetrodotoxin also produced complete blockade of sinus node response to vagal stimulation. Blockade of sinus node responses to stellate stimulation was less profound. Tetrodotoxin had no effect on chronotropic responses to intranodal acetylcholine and norepinephrine. These findings suggest that blockade of transmembrane sodium transport (or the rapid entry channel) has a negative chronotropic effect which is not cholinergic and during which response to neurotransmitter substances is normal. Concomitant with this effect there is blockade of neurotransmitter release (or synthesis) in the sinus node.
A molecular basis for the association of the <i>HLA-DRB1</i> locus, citrullination, and rheumatoid arthritis
Authors: Stephen W. Scally, Jan Petersen, Soi Cheng Law, Nadine L. Dudek, Hendrik J. Nel, Khai Lee Loh, Lakshmi C. Wijeyewickrema, Sidonia B.G. Eckle, Jurgen van Heemst, Robert N. Pike, James McCluskey, Rene E. Toes, Nicole L. La Gruta, Anthony W. Purcell, Hugh H. Reid, Ranjeny Thomas, Jamie Rossjohn
Journal: The Journal of Experimental Medicine (2013)

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine–containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.
Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil
Authors: B C Creagh-Brown, A G Nicholson, R Showkathali, J S R Gibbs, L S G E Howard
Journal: Thorax (2008)

Pulmonary veno-occlusive disease (PVOD) is a disorder which causes progressive pulmonary hypertension, usually presenting with worsening dyspnoea and right heart failure. Pulmonary oedema induced by pulmonary vasodilator therapy to reduce pulmonary arterial pressure has been well described in PVOD, but here we describe a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil.
Autosomal recessive congenital ichthyoses in the Czech Republic
Authors: H. Bučková, H. Nosková, R. Borská, K. Réblová, B. Pinková, E. Zapletalová, L. Kopečková, O. Horký, J. Němečková, R. Gaillyová, Z. Nagy, K. Veselý, M. Hermanová, K. Stehlíková, L. Fajkusová
Journal: British Journal of Dermatology (2015)

Autosomal recessive congenital ichthyosis (ARCI) represents a
heterogeneous group of disorders of epidermal cornification.
Nine genes have been identified to be causative of ARCI,
including TGM1 1,2 , ABCA12 3 , NIPAL4 4 , CYP4F22 5 , ALOX12B,
ALOXE3 6 , PNPLA1 7 , LIPN 8 , and CERS3 9 . ARCI is rare, with
a reported prevalence 1 in 200,000 in European and northern
American populations 10 . We started DNA analysis of ARCI in
2012 when PCR-direct sequencing of the TGM1, ALOX12B, ALOXE3,
NIPAL4, and CYP4F22 genes was introduced and patients were
analysed step by step for mutations in these genes.
PPARα Gene Expression in the Developing Rat Kidney
Authors: FATIMA DJOUADI, JEAN BASTIN
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The α isoform of peroxisome proliferator-activated receptor (PPARα), which is highly expressed in the kidney, can stimulate the expression of genes that are involved in fatty acid catabolism and therefore might be involved in the control of renal fatty acid β-oxidation. PPARα expression and its regulation in the immature kidney are not well documented. This study delineated the developmental pattern of PPARα expression in the rat kidney cortex and the medulla between postnatal days 10 and 30 and investigated the role of glucocorticoids in regulating PPARα expression. In the cortex, PPARα mRNA and protein increased 2- and 1.8-fold, respectively, from 10 to 21 d and then decreased 1.5- and 2.4-fold from 21 to 30 d. In the medulla, PPARα mRNA and protein increased continuously 3.3- and 2.4-fold, respectively. It is shown here that acute treatment by dexamethasone of 10-d-old rats precociously induced a 4- to 6-fold increase in PPARα mRNA and a 1.8-fold increase in protein within 6 h in each part of the kidney. Chronic injection of dexamethasone for 3 d also increased PPARα mRNA 3.8- and 2.2-fold in the cortex and the medulla, respectively, with a 1.5- and 2-fold increase in protein. Furthermore, adrenalectomy prevented the increases in PPARα mRNA and protein in both the cortex and the medulla between postnatal days 16 and 21, and these could be restored by dexamethasone treatment. Finally, with the use of an established renal cell line, it was shown that glucocorticoids stimulate gene expression of PPARα and of medium chain acyl-CoA dehydrogenase (MCAD, a PPARα target gene) 2- to 4-fold and 1.5-fold, respectively, and that addition of fatty acids in the culture media led to a 2.2-fold increase in MCAD mRNA. Altogether, these results demonstrated that glucocorticoids are potent regulators of PPARα development in the immature kidney and that these hormones act in concert with fatty acids to regulate MCAD gene expression in renal cells.
Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm
Authors: Elisa R. Zanier, Giovanna Brandi, Giuseppe Peri, Luca Longhi, Tommaso Zoerle, Mauro Tettamanti, Cecilia Garlanda, Anna Sigurtà, Serenella Valaperta, Alberto Mantovani, Maria Grazia De Simoni, Nino Stocchetti
Journal: Intensive Care Medicine (2010)
Comparison of Urokinase and Video-assisted Thoracoscopic Surgery for Treatment of Childhood Empyema
Authors: Samatha Sonnappa, Gordon Cohen, Catherine M. Owens, Carin van Doorn, John Cairns, Sanja Stanojevic, Martin J. Elliott, Adam Jaffé
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Despite increasing incidence and morbidity, little evidence exists to inform the best management approach in childhood empyema.To compare chest drain with intrapleural urokinase and primary video-assisted thoracoscopic surgery (VATS) for the treatment of childhood empyema.Children were prospectively randomized to receive either percutaneous chest drain with intrapleural urokinase or primary VATS. The primary outcome was the number of hospital days after intervention. Secondary end points were number of chest drain days, total hospital stay, failure rate, radiologic outcome at 6 mo, and total treatment costs.Sixty children were recruited. The two groups were well matched for demographics; baseline characteristics; and hematologic, biochemical, and bacteriologic parameters. No significant difference was found in length of hospital stay after intervention between the two groups: VATS (median [range], 6 [3-16] d) versus urokinase (6 [4-25] d) (p = 0.311; 95% confidence interval, -2 to 1). No difference was demonstrated in total hospital stay: VATS versus urokinase (8 [4-17] d and 7 [4-25] d) (p = 0.645); failure rate: 5 (16.6%); and radiologic outcome at 6 mo after intervention in both groups. The mean (median) treatment costs of patients in the urokinase arm US dollars 9,127 (US dollars 6,914) were significantly lower than those for the VATS arm US dollars 11,379 (US dollars 10,146) (p < 0.001).There is no difference in clinical outcome between intrapleural urokinase and VATS for the treatment of childhood empyema. Urokinase is a more economic treatment option compared with VATS and should be the primary treatment of choice. This study provides an evidence base to guide the management of childhood empyema.
Treating latent tuberculosis with rifampin: is it the cheaper option?
Authors: J. E. Stout, D. P. Holland
Journal: Thorax (2010)

Treatment of latent tuberculosis infection (LTBI) is an important measure for tuberculosis control in the developed world. A recent study estimated that between 291 000 and 433 000 persons started LTBI treatment in the USA in 2002 and that between 4000 and 11 000 cases of active tuberculosis were prevented by this treatment.1 However, many persons for whom LTBI treatment is recommended fail to initiate or complete treatment. Another recent cross-sectional survey of clinics in the USA and Canada showed that fewer than 50% of persons prescribed LTBI treatment completed the prescribed course.2 Key barriers to successful completion of treatment include the length and suboptimal tolerability of the 9-month course of isoniazid that is most frequently used for LTBI treatment. Shorter better-tolerated regimens are clearly needed.

The study by Aspler et al 3 in this issue of Thorax ( see page 582 ) examines one such regimen—namely, 4 months of daily rifampin. This regimen, while recommended as an alternative option for LTBI treatment by the Centers for Disease Control and Prevention,4 has not been widely adopted in the USA. Major barriers to adoption include the possibility of inadvertent treatment of active tuberculosis with rifampin resulting in rifampin-monoresistant disease, concerns about effectiveness and the increased cost of rifampin compared with isoniazid. Aspler et al addressed the latter concern …
Effects of inflammation and fibrosis on pulmonary function in diffuse lung fibrosis.
Authors: T Chinet, F Jaubert, D Dusser, C Danel, J Chretien, G J Huchon
Journal: Thorax (1990)

To investigate the relation between lung function and inflammation and fibrosis in patients with diffuse lung fibrosis, a study was made of untreated patients without appreciable airway obstruction (14 patients with cryptogenic fibrosing alveolitis and seven with pneumoconiosis). Quantitative assessment of inflammatory infiltration and fibrosis was carried out on open lung biopsy specimens and compared with lung volumes, carbon monoxide transfer factor (TLCO), TLCO corrected for alveolar volume (TLCO/VA), and arterial blood gases at rest and during exercise. The degree of fibrosis and the degree of cellular infiltration were positively correlated. Lung volumes and TLCO were correlated with the grades of fibrosis and cellular infiltration of alveoli; arterial blood gases during exercise tended to correlate with both fibrosis and infiltration (p less than 0.06). In contrast, morphological data were not correlated with gas exchange at rest or with TLCO/VA. It is concluded that, in untreated patients with diffuse lung fibrosis, lung volumes, TLCO, and arterial blood gases during exercise reflect the lung lesions, and that the pulmonary function tests used cannot discriminate between fibrosis and infiltration of the lung by inflammatory cells.
Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice
Authors: Douglas Osei-Hyiaman, Jie Liu, Liang Zhou, Grzegorz Godlewski, Judith Harvey-White, Won-il Jeong, Sándor Bátkai, Giovanni Marsicano, Beat Lutz, Christoph Buettner, George Kunos
Journal: Journal of Clinical Investigation (2008)

Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB1 (CB1–/–) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CB1 receptors in the metabolic consequences of a high-fat diet, using liver-specific CB1 knockout (LCB1–/–) mice. LCB1–/– mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1–/– mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CB1 agonist–induced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine palmitoyltransferase–1 and total energy expenditure were absent in both CB1–/– and LCB1–/– mice. We conclude that endocannabinoid activation of hepatic CB1 receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CB1 receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB1 blockade during treatment of obesity-associated conditions.
CARDIAC BIOMARKERS IN PATIENTS WITH TRANSTHYRETIN AMYLOIDOSIS AS DOCUMENTED IN THAOS: THE TRANSTHYRETIN AMYLOIDOSIS SURVEY
Authors: Mathew S. Maurer, Arnt Kristen, Claudio Rapezzi, Ole Suhr, Sheela Kolluri, Thibaud Damy
Journal: Journal of the American College of Cardiology (2013)
Differentiation of malignant pleural mesothelioma from other pleural diseases
Authors: R Bhardwaj
Journal: Thorax (2011)

In this study, pleural effusion samples from 101 patients with suspected or newly diagnosed malignant pleural mesothelioma (MPM) or metastatic adenocarcinoma (ADCA) were collected between 1998 and 2010. Of the 101 patients, 65 were diagnosed with MPM, 25 with ADCA and 15 with benign pleural effusion. Cancer cells isolated from pleural effusion samples were …
Decreased fibrocyte number is associated with atherosclerotic plaque instability in man
Authors: Lu Fang, Xiao-Lei Moore, William Chan, David A White, Jaye Chin-Dusting, Anthony M Dart
Journal: Cardiovascular Research (2012)

Plaque rupture partly results from inadequate collagen synthesis due to lower smooth muscle cell numbers in fibrous caps. Fibrocytes are bone-marrow-derived circulating mesenchymal progenitors and have recently been identified in fibrous caps. This study hypothesized that reduced fibrocyte numbers would be associated with plaque instability. Patients with acute myocardial infarction (MI) (n = 22), stable angina (SA) (n = 20), or healthy controls (n = 22) were recruited. Circulating fibrocytes (CD45+/CD34+/collagen I+) were measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from blood and cultured for 2 weeks, and fibrocytes were quantified by morphology (spindle-shaped) and flow cytometry (CD45+/collagen I+). Another set of PBMCs was stimulated with macrophage colony-stimulating factor (M-CSF) for 72 h and the expression of several macrophage markers was measured by flow cytometry. Acute MI patients had decreased circulating fibrocyte numbers compared with healthy controls or SA patients. Following 2 weeks' culture, both the number of spindle-shaped fibrocytes counted under the microscope and the percentage of fibrocytes of the remaining adherent cells in culture measured by flow cytometry were reduced in acute MI patients. Expression of macrophage markers CD68, CD36, and EMR in M-CSF-stimulated PBMCs was enhanced in acute MI patients compared with the other two groups. SA patients with previous MI had decreased circulating fibrocyte numbers and a lower yield of fibrocytes from PBMCs than those without previous MI. This is the first report of decreased fibrocyte numbers in patients with MI. Reduced fibrocytes and preferential differentiation of PBMCs into macrophages may contribute to plaque instability.
Purifying Selection in Mammalian Mitochondrial Protein-Coding Genes Is Highly Effective and Congruent with Evolution of Nuclear Genes
Authors: K. Y. Popadin, S. I. Nikolaev, T. Junier, M. Baranova, S. E. Antonarakis
Journal: Molecular Biology and Evolution (2012)

The mammalian mitochondrial genomes differ from the nuclear genomes by maternal inheritance, absence of recombination, and higher mutation rate. All these differences decrease the effective population size of mitochondrial genome and make it more susceptible to accumulation of slightly deleterious mutations. It was hypothesized that mitochondrial genes, especially in species with low effective population size, irreversibly degrade leading to decrease of organismal fitness and even to extinction of species through the mutational meltdown. To interrogate this hypothesis, we compared the purifying selections acting on the representative set of mitochondrial (potentially degrading) and nuclear (potentially not degrading) protein-coding genes in species with different effective population size. For 21 mammalian species, we calculated the ratios of accumulation of slightly deleterious mutations approximated by Kn/Ks separately for mitochondrial and nuclear genomes. The 75% of variation in Kn/Ks is explained by two independent variables: type of a genome (mitochondrial or nuclear) and effective population size of species approximated by generation time. First, we observed that purifying selection is more effective in mitochondria than in the nucleus that implies strong evolutionary constraints of mitochondrial genome. Mitochondrial de novo nonsynonymous mutations have at least 5-fold more harmful effect when compared with nuclear. Second, Kn/Ks of mitochondrial and nuclear genomes is positively correlated with generation time of species, indicating relaxation of purifying selection with decrease of species-specific effective population size. Most importantly, the linear regression lines of mitochondrial and nuclear Kn/Ks's from generation times of species are parallel, indicating congruent relaxation of purifying selection in both genomes. Thus, our results reveal that the distribution of selection coefficients of de novo nonsynonymous mitochondrial mutations has a similar shape with the distribution of de novo nonsynonymous nuclear mutations, but its mean is five times smaller. The harmful effect of mitochondrial de novo nonsynonymous mutations triggers highly effective purifying selection, which maintains the fitness of the mammalian mitochondrial genome.
Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma
Authors: F Maire
Journal: Gut (2002)

<b>Background:</b> Although the prognosis in malignant resectable intraductal papillary mucinous tumours of the pancreas (IPMT) is often considered more favourable than for ordinary pancreatic ductal adenocarcinoma, the long term outcome remains ill defined. <b>Aims:</b> To assess prognostic factors in patients with malignant IPMT after surgical resection, and to compare long term survival rates with those of patients surgically treated for ductal adenocarcinoma. <b>Methods:</b> Seventy three patients underwent surgery for malignant IPMT in four French centres. Clinical, biochemical, and pathological features and follow up after resection were recorded. Patients with invasive malignant IPMT were matched with patients with pancreatic ductal adenocarcinoma, according to age and TNM stages; survival rates after resection were compared. <b>Results:</b> Surgical treatment for IPMT were pancreaticoduodenectomy (n=46), distal (n=14), total (n=11), or segmentary (n=2) pancreatectomy. The operative mortality rate was 4%. IPMT corresponded to in situ (n=22) or invasive carcinoma (n=51). In the latter group, 17 had lymph node metastases. Overall median survival was 47 months. Five year survival rates in patients with in situ and invasive carcinoma were 88% and 36%, respectively. On univariate analysis, abdominal pain, preoperative high serum carbohydrate antigen 19.9 concentrations, caudal localisation, invasive carcinoma, lymph node metastases, peripancreatic extension, and malignant relapse were associated with a fatal outcome. Using multivariate analysis, lymph node metastases were the only prognostic factor (OR 7.5; 95% CI: 3.4 to 16.4). Overall five year survival rate was higher in patients with malignant invasive IPMT compared with those with pancreatic ductal carcinoma (36 <i>v</i> 21%, p=0.03), but was similar in the subset of stage II/III tumours. <b>Conclusions:</b> The prognosis of patients with resected in situ/invasive stage I malignant IPMT is excellent. In contrast, prognosis of locally advanced forms is as poor as in patients with pancreatic ductal adenocarcinoma.
Genomic Divergence during Speciation Driven by Adaptation to Altitude
Authors: Mark A. Chapman, Simon J. Hiscock, Dmitry A. Filatov
Journal: Molecular Biology and Evolution (2013)

Even though Darwin's "On the Origin of Species" implied selection being the main driver of species formation, the role of natural selection in speciation remains poorly understood. In particular, it remains unclear how selection at a few genes can lead to genomewide divergence and the formation of distinct species. We used a particularly attractive clear-cut case of recent plant ecological speciation to investigate the demography and genomic bases of species formation driven by adaptation to contrasting conditions. High-altitude Senecio aethnensis and low-altitude S. chrysanthemifolius live at the extremes of a mountain slope on Mt. Etna, Sicily, and form a hybrid zone at intermediate altitudes but remain morphologically distinct. Genetic differentiation of these species was analyzed at the DNA polymorphism and gene expression levels by high-throughput sequencing of transcriptomes from multiple individuals. Out of ≈ 18,000 genes analyzed, only a small number (90) displayed differential expression between the two species. These genes showed significantly elevated species differentiation (FST and Dxy), consistent with diversifying selection acting on these genes. Genomewide genetic differentiation of the species is surprisingly low (FST = 0.19), while ≈ 200 genes showed significantly higher (false discovery rate < 1%; mean outlier FST > 0.6) interspecific differentiation and evidence for local adaptation. Diversifying selection at only a handful of loci may be enough for the formation and maintenance of taxonomically well-defined species, despite ongoing gene flow. This provides an explanation of why many closely related species (in plants, in particular) remain phenotypically and ecologically distinct despite ongoing hybridization, a question that has long puzzled naturalists and geneticists alike.