tbuckley/cabot-search huggingface dataset:
Regulatory Polymorphisms in Human <i>DBH</i> Affect Peripheral Gene Expression and Sympathetic Activity
Authors: Elizabeth S. Barrie, David Weinshenker, Anurag Verma, Sarah A. Pendergrass, Leslie A. Lange, Marylyn D. Ritchie, James G. Wilson, Helena Kuivaniemi, Gerard Tromp, David J. Carey, Glenn S. Gerhard, Murray H. Brilliant, Scott J. Hebbring, Joseph F. Cubells, Julia K. Pinsonneault, Greg J. Norman, Wolfgang Sadee
Journal: Circulation Research (2014)

Rationale : Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the central nervous system and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. Objective : To characterize regulatory variants in DBH , effect on mRNA expression, and role in modulating sympathetic tone and disease risk. Methods and Results : Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus and adrenal gland, but also in sympathetically innervated organs (liver&gt;lung&gt;heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2- to 11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in locus coeruleus and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes, including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in 3 separate clinical cohorts. Conclusions : We demonstrate profound effects of DBH variants on expression in 2 sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.
Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice
Authors: M. Weller, R. Stupp, M. E. Hegi, M. van den Bent, J. C. Tonn, M. Sanson, W. Wick, G. Reifenberger
Journal: Neuro-Oncology (2012)

Histological subtyping and grading by malignancy are the cornerstones of the World Health Organization (WHO) classification of tumors of the central nervous system. They shall provide clinicians with guidance as to the course of disease to be expected and the choices of treatment to be made. Nonetheless, patients with histologically identical tumors may have very different outcomes, notably in patients with astrocytic and oligodendroglial gliomas of WHO grades II and III. In gliomas of adulthood, 3 molecular markers have undergone extensive studies in recent years: 1p/19q chromosomal codeletion, O6-methylguanine methyltransferase (MGMT) promoter methylation, and mutations of isocitrate dehydrogenase (IDH) 1 and 2. However, the assessment of these molecular markers has so far not been implemented in clinical routine because of the lack of therapeutic implications. In fact, these markers were considered to be prognostic irrespective of whether patients were receiving radiotherapy (RT), chemotherapy, or both (1p/19q, IDH1/2), or of limited value because testing is too complex and no chemotherapy alternative to temozolomide was available (MGMT). In 2012, this situation has changed: long-term follow-up of the Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951 trials demonstrated an overall survival benefit from the addition to RT of chemotherapy with procarbazine/CCNU/vincristine confined to patients with anaplastic oligodendroglial tumors with (vs without) 1p/19q codeletion. Furthermore, in elderly glioblastoma patients, the NOA-08 and the Nordic trial of RT alone versus temozolomide alone demonstrated a profound impact of MGMT promoter methylation on outcome by therapy and thus established MGMT as a predictive biomarker in this patient population. These recent results call for the routine implementation of 1p/19q and MGMT testing at least in subpopulations of malignant glioma patients and represent an encouraging step toward the development of personalized therapeutic approaches in neuro-oncology.
Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line.
Authors: O Kan, S A Baldwin, A D Whetton
Journal: The Journal of Experimental Medicine (1994)

In the absence of a survival stimulus, the interleukin 3 (IL-3)-dependent IC.DP cell line undergoes a process termed programmed cell death or apoptosis. Survival can be induced by IL-3, which can also stimulate proliferation of IC.DP cells. IC.DP cells have been stably transfected with the p160v-abl protein tyrosine kinase, activation of the kinase at the permissive temperature permits cell survival in the absence of IL-3 by suppression of apoptosis, although the growth factor is still required for proliferation. Both IL-3 and activation of the v-ABL tyrosine kinase stimulated glucose transport, which may in part be due to a translocation of transporters to the cell surface. Inhibition of glucose uptake markedly increased the rate of apoptosis in these cells, an effect that could be reversed by the provision of alternative energy sources such as glutamine. Growth factor- or oncogene-mediated increases in glucose uptake may therefore represent an important regulatory point in the suppression of apoptosis.
Physician among surgeons: thoughts on preoperative assessment.
Authors: C Ogilvie
Journal: Thorax (1980)

Physician among surgeons: thoughts on preoperative assessment Some of my best friends are surgeons.A few drive fast cars, shoot birds, hunt foxes, write inadequate case notes, throw things when provoked and gen- erally prefer action to thought-but an equal number of my physician friends do the same.Between physician and surgeon today there is surely no real difference of outlook or purpose.
Nuclear Calcium Signaling in Spinal Neurons Drives a Genomic Program Required for Persistent Inflammatory Pain
Authors: Manuela Simonetti, Anna M. Hagenston, Daniel Vardeh, H. Eckehard Freitag, Daniela Mauceri, Jianning Lu, Venkata P. Satagopam, Reinhard Schneider, Michael Costigan, Hilmar Bading, Rohini Kuner
Journal: Neuron (2013)
More on compulsory registration of clinical trials: GSK has created useful register
Authors: Ronald Krall, Frank Rockhold
Journal: BMJ (2005)

EDITOR—The editorial by Abbasi and letters in response illustrate the considerable interest in the registration of clinical trials.1 2 As a pharmaceutical company that has created a register to communicate the results of clinical trials of our marketed products, GlaxoSmithKline would like to bring to your attention the decisions we have taken to make our register worthwhile and meaningful to the medical profession and …
Selecting culprits in type 1 diabetes β-cell killing
Authors: ′«ke Lernmark
Journal: Journal of Clinical Investigation (1999)

Type 1 diabetes is by several measures a remarkable disorder. Diabetes appears when 80‐90% of the islet β-cells have been lost after being killed in a process strongly associated with autoimmune phenomena (1, 2). The rate of β-cell destruction before the clinical diagnosis of diabetes is made is not understood. Once the disease process has resulted in hyperglycemia that needs to be corrected with daily insulin injections, the point of no return has been reached; patients remain insulin-dependent for the rest of their lives. The disease may occur at any age and in individuals throughout the world. The incidence rate is increasing steadily in the developed countries. Individuals from developing countries moving to Western societies often expe
Grape Seed Proanthocyanidins Inhibit the Growth of Human Non-Small Cell Lung Cancer Xenografts by Targeting Insulin-Like Growth Factor Binding Protein-3, Tumor Cell Proliferation, and Angiogenic Factors
Authors: Suhail Akhtar, Syed M. Meeran, Nandan Katiyar, Santosh K. Katiyar
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Lung cancer is a leading cause of cancer-related deaths worldwide. Here, we assessed the chemotherapeutic effect of grape seed proanthocyanidins (GSPs) on human non-small cell lung cancer (NSCLC) cells in vitro and in vivo using a tumor xenograft model. Experimental Design: The effects of GSPs on human NSCLC cell lines in terms of cellular proliferation were determined. The chemotherapeutic effects of a GSP- supplemented AIN76A control diet fed to nude mice bearing tumor xenografts (A549 and H1299) were evaluated in terms of biomarkers of cell proliferation and angiogenesis and on insulin-like growth factor binding protein-3 using immunohistochemical detection, ELISA, and Western blotting. Results: In vitro treatment of NSCLC cells with GSPs resulted in inhibition of cellular proliferation. Administration of GSPs (0.1%, 0.2%, and 0.5%, w/w) as a supplement of an AIN76A control diet resulted in a dose-dependent inhibition of the growth of NSCLC (A549 and H1299) tumor xenografts in athymic nude mice (25-76%; P &amp;lt; 0.05-0.001). The growth-inhibitory effect of GSPs on the NSCLC xenograft tumors was associated with the enhancement of the levels of insulin-like growth factor binding protein-3 in the tumor microenvironment and plasma and antiproliferative, antiangiogenic, and proapoptotic effects. Conclusions: This preclinical study reveals for the first time that dietary GSPs have the ability to inhibit the growth of human NSCLC tumor xenografts grown in vivo in athymic nude mice. More studies are needed to develop GSPs as a pharmacologically safe agent for the prevention of lung cancer in humans.
Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis
Authors: Mark L. Bassett, June W. Halliday, Lawrie W. Powell
Journal: Hepatology (1986)

The role of the measurement of hepatic iron in the diagnosis of genetic hemochromatosis was studied, with particular reference to the differentiation of early hemochromatosis from alcoholic siderosis and the critical hepatic iron concentration associated with fibrosis in hemochromatosis. Hepatic iron was measured in 30 homozygous relatives of 17 hemochromatosis probands, 8 heterozygous relatives, 51 patients with alcoholic liver disease and 40 control subjects. Hepatic iron concentrations were greatly increased in the majority of homozygous hemochromatosis subjects, and there was little overlapwith the other groups. In the absence of alcoholism, fibrosis or cirrhosis in hemochromatosis was present only with hepatic iron concentrations above a threshold of approximately 400 μmoles per gm (22.3 mg per gm) dry weight. In some heterozygous hemochromatosis subjects and in some alcoholic patients, hepatic iron concentrations were in the range seen in young homozygous subjects. However, an age–related rise in hepatic iron was seen only in hemochromatosis homozygotes, and calculation of an hepatic iron index (hepatic iron/age) resulted in a clear distinction between homozygotes and the other three groups. It is concluded: (a) that chemical measurement of hepatic iron concentration, when corrected for the age of the subject, reliably distinguishes early hemochromatosis from alcoholic siderosis, and (b), that there appears to be a threshold level of hepatic iron above which there is a high risk of fibrosis.
Lymph node perforation into the airway in AIDS-associated tuberculosis
Authors: T Alame, P Dierckx, S Carlier, R Sergysels
Journal: European Respiratory Journal (1995)

A 27 year old African woman infected with the human immunodeficiency virus (HIV) presented with pulmonary complaints. Her sputum smears were positive for acid-fast bacilli (AFB). Chest roentgenogram showed right mediastinal and hilar adenopathy with a right pulmonary infiltrate. At fibreoptic bronchoscopy, mucosal infiltration with perforation and presence of thick caseum was detected in the bronchus intermedius confirming the diagnosis of a perforated lymph node. This case demonstrates that a more liberal indication of bronchoscopy helps in evaluating the impact of enlarged intrathoracic lymph nodes on neighbouring bronchi, leading to earlier detection of endobronchial tuberculosis in patients with the acquired immune deficiency syndrome (AIDS).
Gastrin receptors on isolated canine parietal cells.
Authors: A H Soll, D A Amirian, L P Thomas, T J Reedy, J D Elashoff
Journal: Journal of Clinical Investigation (1984)

The receptors in the fundic mucosa that mediate gastrin stimulation of acid secretion have been studied. Synthetic human gastrin-17-I (G17) with a leucine substitution in the 15th position ( [Leu15]-G17) was iodinated by chloramine T; high saturable binding was found to enzyme-dispersed canine fundic mucosal cells. 127I-[Leu15]-G17, but not 127I-G17, retained binding potency and biological activity comparable with uniodinated G17. Fundic mucosal cells were separated by size by using an elutriator rotor, and specific 125I-[Leu-15]-G17 binding in the larger cell fractions was highly correlated with the distribution of parietal cells. There was, however, specific gastrin binding in the small cell fractions, not accounted for by parietal cells. Using sequential elutriation and stepwise density gradients, highly enriched parietal and chief cell fractions were prepared; 125I-[Leu15]-G17 binding correlated positively with the parietal cell (r = 0.98) and negatively with chief cell content (r = -0.96). In fractions enriched to 45-65% parietal cells, specific 125I-[Leu15]-G17 binding was rapid, reaching a steady state at 37 degrees C within 30 min. Dissociation was also rapid, with the rate similar after 100-fold dilution or dilution plus excess pentagastrin. At a tracer concentration from 10 to 30 pM, saturable binding was 7.8 +/- 0.8% per 10(6) cells (mean +/- SE) and binding in the presence of excess pentagastrin accounted for 11% of total binding. G17 and carboxyl terminal octapeptide of cholecystokinin (26-33) were equipotent in displacing tracer binding and in stimulating parietal cell function ( [14C]aminopyrine accumulation), whereas the tetrapeptide of gastrin (14-17) had a much lower potency. Proglumide inhibited gastrin binding and selectively inhibited gastrin stimulation of parietal cell function. Canine parietal cells have specific receptors for gastrin that mediate stimulation of parietal cell function. Gastrin receptors were undetectable on chief cells, and yet present on another smaller mucosal cell(s).
Evidence for both histamine H1 and H2 receptors on human articular chondrocytes.
Authors: D J Taylor, D E Woolley
Journal: Annals of the Rheumatic Diseases (1987)

Using specific histamine H1 and H2 receptor antagonists, evidence is presented for the existence of both H1 and H2 receptors on human articular chondrocytes in vitro. Stimulation of the H1 receptor by histamine (range 0.18 to 17.8 mumol/l) significantly increased prostaglandin E (PGE) production, while activation of the histamine H2 receptor increased intracellular cyclic adenosine-59-monophosphate (AMP). The histamine H1 antagonists mepyramine and tripelennamine blocked the histamine induced increase in PGE production, and the H2 antagonists cimetidine and ranitidine prevented the increase in intracellular cyclic AMP. These observations suggest that mast cell-chondrocyte interactions mediated via histamine may contribute to some of the pathophysiological changes observed in joint disease.
Childhood sarcoidosis: long-term follow-up
Authors: N. Milman, A. L. Hoffmann
Journal: European Respiratory Journal (2007)

The aim of the present study was to describe clinical features and long-term survival in childhood sarcoidosis. In total, 46 ethnic Caucasian Danish children (aged &lt;16 yrs, 24 males) with sarcoidosis were identified in 1979–1994. In 33 (72%) children, diagnosis was verified by histology and, in the remaining 13, by clinical and radiological findings. In total, 37 subjects had a follow-up examination. Median (range) age at onset of disease was 14 (0.7–15.8) yrs and median (range) clinical follow-up was 15 (3–23) yrs after onset of disease. The median (range) age at clinical follow-up was 28 (17–30) yrs. At follow-up: 36 (78%) children recovered completely; 30 (65%) showed complete clinical regression at a median (range) 0.7 (0.6–5.9) yrs after onset of disease; two (4%) recovered with organ damage (unilateral loss of vision, abnormal chest radiograph); five (11%) still had chronic active disease with multiorgan involvement and impaired lung function; and three (7%) were deceased, due to central nervous system sarcoidosis and acute myeloid leukaemia probably caused by cytostatics. In Danish children, sarcoidosis had a favourable prognosis; the majority recovered &lt;6 yrs after onset of disease. Some developed chronic active disease and impairment of pulmonary function, demanding continuous medical treatment. Prognosis was not related to the age at onset of disease. Erythema nodosum was associated with a good prognosis, and central nervous system involvement with a poor prognosis.
Deficiency of the Calcium-Sensing Receptor in the Kidney Causes Parathyroid Hormone–Independent Hypocalciuria
Authors: Hakan R. Toka, Khaldoun Al-Romaih, Jacob M. Koshy, Salvatore DiBartolo, Claudine H. Kos, Stephen J. Quinn, Gary C. Curhan, David B. Mount, Edward M. Brown, Martin R. Pollak
Journal: Journal of the American Society of Nephrology (2012)

Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.
Diseases of the liver and biliary system
Authors: A E Read
Journal: Gut (1986)

Use of alpha-tocopherylquinone in ulcerative colitis SIR,-The personal experience reported by J D Bennet (Gut 1986; 27: 695-7) on the use of alpha-tocopherylquinone in the treatment of ulcera- tive colitis appears to be a most valuable contri- bution.Tocopherols and their quinone derivatives are potent inhibitors of fatty-acid oxydation.' There is a striking correlation between consumption of polyun- saturated chemically processed fats -for example, margarine and shortening, and incidence of in- flammatory bowel disease.2 3 Such polyunsaturated fats have a tendency to form peroxides which in turn are potent inhibitors of prostacyclin-synthesis.4The most plausible mode of action for alphatocopherylquinone is a blockade of fatty acid- oxidation and a restoration of host defense mechanisms in the bowel mucosa.
Value of high-sensitivity C-reactive protein for classification of early axial spondyloarthritis: results from the DESIR cohort
Authors: Victoria Navarro-Compán, Désirée van der Heijde, Bernard Combe, Claudine Cosson, Floris A van Gaalen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Abstract</h3> A pandemic caused by the SARS-CoV2 is being experienced by the whole world since December, 2019. A thorough understanding beyond just sequential similarities among the protein coding genes of SARS-CoV2 is important in order to differentiate or relate to the other known CoVs of the same genus. In this study, we compare three genomes namely MT012098 (India-Kerala), MT050493 (India-Kerala), MT358637 (India-Gujrat) from India with NC_045512 (China-Wuhan) to view the spatial as well as molecular arrangements of nucleotide bases of all the genes embedded in these four genomes. Based on different features extracted for each gene embedded in these genomes, corresponding phylogenetic relationships have been built up. Differences in phylogenetic tree arrangement with individual gene suggest that three genomes of Indian origin have come from three different origins or the evolution of viral genome is very fast process. This study would also help to understand the virulence factors, disease pathogenicity, origin and transmission of the SARS-CoV2.
Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data
Authors: Gretchen A Stevens, Mariel M Finucane, Luz Maria De-Regil, Christopher J Paciorek, Seth R Flaxman, Francesco Branca, Juan Pablo Peña-Rosas, Zulfiqar A Bhutta, Majid Ezzati
Journal: The Lancet Global Health (2013)

BackgroundLow haemoglobin concentrations and anaemia are important risk factors for the health and development of women and children. We estimated trends in the distributions of haemoglobin concentration and in the prevalence of anaemia and severe anaemia in young children and pregnant and non-pregnant women between 1995 and 2011.MethodsWe obtained data about haemoglobin and anaemia for children aged 6–59 months and women of childbearing age (15–49 years) from 257 population-representative data sources from 107 countries worldwide. We used health, nutrition, and household surveys; summary statistics from WHO's Vitamin and Mineral Nutrition Information System; and summary statistics reported by other national and international agencies. We used a Bayesian hierarchical mixture model to estimate haemoglobin distributions and systematically addressed missing data, non-linear time trends, and representativeness of data sources. We quantified the uncertainty of our estimates.FindingsGlobal mean haemoglobin improved slightly between 1995 and 2011, from 125 g/L (95% credibility interval 123–126) to 126 g/L (124–128) in non-pregnant women, from 112 g/L (111–113) to 114 g/L (112–116) in pregnant women, and from 109 g/L (107–111) to 111 g/L (110–113) in children. Anaemia prevalence decreased from 33% (29–37) to 29% (24–35) in non-pregnant women, from 43% (39–47) to 38% (34–43) in pregnant women, and from 47% (43–51) to 43% (38–47) in children. These prevalences translated to 496 million (409–595 million) non-pregnant women, 32 million (28–36 million) pregnant women, and 273 million (242–304 million) children with anaemia in 2011. In 2011, concentrations of mean haemoglobin were lowest and anaemia prevalence was highest in south Asia and central and west Africa.InterpretationChildren's and women's haemoglobin statuses improved in some regions where concentrations had been low in the 1990s, leading to a modest global increase in mean haemoglobin and a reduction in anaemia prevalence. Further improvements are needed in some regions, particularly south Asia and central and west Africa, to improve the health of women and children and achieve global targets for reducing anaemia.FundingBill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Medical Research Council.