tbuckley/cabot-search huggingface dataset:
Store-Operated Channels Mediate Ca <sup>2+</sup> Influx and Contraction in Rat Pulmonary Artery
Authors: Lih Chyuan Ng, Alison M. Gurney
Journal: Circulation Research (2001)

Cation channels activated by Ca 2+ store depletion have been proposed to mediate Ca 2+ influx in vascular smooth muscle cells. The aim of this study was to determine if store-operated channels have a functional role in pulmonary artery smooth muscle cells (PASMCs). In intact rat pulmonary artery rings, cyclopiazonic acid (CPA) produced a sustained contraction that was resistant to inhibition by nifedipine, but abolished in Ca 2+ -free solution and 50% blocked in the presence of 6 μmol/L Cd 2+ , 10 μmol/L Ni 2+ , 600 μmol/L La 3+ , and 7 μmol/L SKF96365. In freshly isolated PASMCs loaded with fura-2, CPA increased the intracellular Ca 2+ concentration by stimulating dihydropyridine-resistant Ca 2+ influx, which was ≈50% blocked by 10 μmol/L Ni 2+ and 7 μmol/L SKF96365. In perforated-patch recordings, CPA activated a sustained inward current at negative membrane potentials, which persisted in cells dialyzed with BAPTA, showed a near linear dependence on membrane potential when Cs + was the main intracellular cation, and was blocked by Ni 2+ , Cd 2+ , and SKF96365 at concentrations preventing contraction. The current showed a bimodal dependence on extracellular Ca 2+ , being enhanced 2-fold in the absence of Ca 2+ and around 10-fold on reducing Ca from 1.8 to 0.2 mmol/L. RT-PCR revealed the expression of Trp1, Trp3, Trp4, Trp5, and Trp6 mRNA, whereas immunostaining identified Trp1, Trp3, Trp4, and Trp6 channel proteins in isolated PASMCs. At least one of these subunits may contribute to cation channels in PASMCs, which are activated by store depletion to bring about Ca 2+ influx and contraction.
Low-Dose vs Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis
Authors: Karthi Nallasamy, Muralidharan Jayashree, Sunit Singhi, Arun Bansal
Journal: JAMA Pediatrics (2014)

The standard recommended dose (0.1 U/kg per hour) of insulin in diabetic ketoacidosis (DKA) guidelines is not backed by strong clinical evidence. Physiologic dose-effect studies have found that even lower doses could adequately normalize ketonemia and acidosis. Lowering the insulin dose may be advantageous in the initial hours of therapy when a gradual decrease in glucose, electrolytes, and resultant osmolality is desired.To compare the efficacy and safety of low-dose insulin against the standard dose in children with DKA.This was a prospective, open-label randomized clinical trial conducted in the pediatric emergency department and intensive care unit of a tertiary care teaching hospital in northern India from November 1, 2011, through December 31, 2012. A total of 50 consecutive children 12 years or younger with a diagnosis of DKA were randomized to low-dose (n = 25) and standard-dose (n = 25) groups.Low-dose (0.05 U/kg per hour) vs standard-dose (0.1 U/kg per hour) insulin infusion.The primary outcome was the rate of decrease in blood glucose until a level of 250 mg/dL or less is reached (to convert to millimoles per liter, multiply by 0.0555). The secondary outcomes included time to resolution of acidosis, episodes of treatment failures, and incidences of hypokalemia and hypoglycemia.The mean (SD) rate of blood glucose decrease until a level of 250 mg/dL or less is reached (45.1 [17.6] vs 52.2 [23.4] mg/dL/h) and the mean (SD) time taken to achieve this target (6.0 [3.3] vs 6.2 [2.2] hours) were similar in the low- and standard-dose groups, respectively. Mean (SD) length of time to achieve resolution of acidosis (low vs standard dose: 16.5 [7.2] vs 17.2 [7.7] hours; P = .73) and rate of resolution of acidosis were also similar in the groups. Hypokalemia was seen in 12 children (48%) receiving the standard dose vs 5 (20%) of those receiving the low dose (P = .07); the tendency was more pronounced in malnourished children (7 [88%] vs 2 [28%]). Five children (20%) and 1 child (4%) receiving standard- and low-dose infusion (P = .17), respectively, developed hypoglycemia. Treatment failure was rare and comparable. One child in the standard-dose group developed cerebral edema, and no deaths occurred during the study period.Low dose is noninferior to standard dose with respect to rate of blood glucose decrease and resolution of acidosis. We advocate a superiority trial with a larger sample size before 0.05 U/kg per hour replaces 0.1 U/kg per hour in the practice recommendations.ctri.nic.in Identifier: CTRI/2012/04/002548.
Inhibition of Synthesis of Fetal Hemoglobin by an Isoleucine Analogue*
Authors: George R. Honig
Journal: Journal of Clinical Investigation (1967)

Reticulocytes from newborn infants with Rh isoimmune hemolytic disease actively incorporated radioactive amino acids in vitro into hemoglobins F and A. Approximately 50% of the reticulocytes appeared capable of synthesis of both of these hemoglobins within the same cell, as demonstrated by the selective elution technique of Betke and Kleihauer. An isoleucine analogue, L-O-methylthreonine, inhibited the incorporation of a variety of amino acids into hemoglobin F, without significantly affecting the synthesis of hemoglobin A. The inhibition was prevented upon concomitant addition of L-isoleucine to the medium. These observations suggest that an independent biosynthetic apparatus is present in the cell for the synthesis of each of these two hemoglobins. Because isoleucine is present only in the gamma chains of hemoglobin F, the inhibitory effect of the analogue on the synthesis of this hemoglobin must represent a selective effect on the production of gamma chains.
Decreased <i>ID2</i> Promotes Metastatic Potentials of Hepatocellular Carcinoma by Altering Secretion of Vascular Endothelial Growth Factor
Authors: Ryouichi Tsunedomi, Norio Iizuka, Takao Tamesa, Kazuhiko Sakamoto, Takashi Hamaguchi, Hideaki Somura, Mamoru Yamada, Masaaki Oka
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We aimed to explore the molecular and biological functions of Inhibitor of DNA binding/differentiation 2 (ID2), which was found to be responsible for portal vein invasion of hepatocellular carcinoma (HCC). Experimental Design: We measured ID2 mRNA levels in 92 HCC patients by real-time reverse transcription-PCR and examined the relation to clinicopathologic features. To clarify the precise roles of ID2, we did in vitro analysis with expression vectors and small interfering RNAs. Effects of ID2 on cell invasive potential and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α were analyzed by Matrigel-coated invasion chamber, ELISA, and Western blot analysis, respectively. Results: ID2 mRNA level correlated inversely with portal vein invasion (P &amp;lt; 0.001), tumor-node-metastasis stage (P &amp;lt; 0.001), tumor size (P &amp;lt; 0.001), and early intrahepatic recurrence (P &amp;lt; 0.05). When limited to a cohort of hepatitis C virus–related HCCs, patients with low levels of ID2 had significantly shorter disease-free survival time than those with high levels of ID2. Invasive potential of cells transfected with ID2 expression vector was lower than that of empty vector–transfected cells. Cells overexpressing ID2 also showed decreased VEGF secretion and hypoxia-inducible factor-1α protein levels. The results of ID2-knockdown experiments were opposite to those of ID2 overexpression experiments. Conclusions: On the basis of our clinical and in vitro data, we suggest that ID2 plays a significant role in the metastatic process during progression of HCC. This action might be explained, at least in part, by altered cell mobility due to decreased secretion of VEGF.
Role of superantigenic strains in the prognosis of community-acquired methicillin-susceptible Staphylococcus aureus bacteraemia
Authors: A. Desachy, G. Lina, P. Vignon, A. Hashemzadeh, F. Denis, J. Etienne, B. Francois, M.C. Ploy
Journal: Clinical Microbiology and Infection (2007)
Chronic alpha-irradiation of the nervous system from thorium dioxide
Authors: E H Jellinek
Journal: Journal of the Royal Society of Medicine (2004)

The discoveries by A H Becquerel of the radioactivity of uranium ore in 1895 and of X-rays by W Ro ¨ntgen in 1896 were soon followed by the appreciation of biological effects, initially on the skin of the physicists themselves.Pierre Curie reported animal experiments in 1904, 1 shortly before his death in a road accident; his wife, Marie, was to succumb to radiation damage 30 years later.The hazards of the deeply penetrating X-rays (gamma radiation) led to appropriate measures by physicists, physicians and governments, 2,3 but the very short-range (Figure 1) and slower effects of alpha particles from thorium dioxide, an excellent radiological contrast medium introduced in 1928/9, 4 were treated more cavalierly until half-way into the twentieth century, long after the tragedy from alpha radiation of the luminous watch-dial painters in New York in 1925. 5horium dioxide (Thorotrast) was still marketed in 1967 for radiodiagnosis. 6 The long delayed and insiduously fatal effects of alpha radiation, with postmortem findings, are described here in two men who had Thorotrast ventriculography in 1937 and in 1938, 44 and 30 years before they died.Case 2 was reported intra vitam in 1952.
Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man.
Authors: J D Veldhuis, A D Rogol, E Samojlik, N H Ertel
Journal: Journal of Clinical Investigation (1984)

We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectively reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-17 beta, opiate receptor blockade significantly augments LH pulse frequency and increases LH peak amplitude to control levels. Thus, the present studies in normal men demonstrate for the first time that the selective inhibitory action of a pure androgen on LH pulse frequency is effectively antagonized by opiate-receptor blockade. This pivotal observation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-releasing hormone (GnRH)
Inhibition of collagen deposition in the extracellular matrix prevents the establishment of a stroma supportive of hematopoiesis in long-term murine bone marrow cultures.
Authors: K S Zuckerman, R K Rhodes, D D Goodrum, V R Patel, B Sparks, J Wells, M S Wicha, L A Mayo
Journal: Journal of Clinical Investigation (1985)

Long-term production of murine hematopoietic cells in vitro is dependent on establishment of a complex microenvironment consisting of a variety of stromal cells and an extensive extracellular matrix which includes collagen, fibronectin, laminin, proteoglycans, and other undefined components adherent to the culture dishes. Cis-4-hydroxyproline (CHP), a relatively specific inhibitor of collagen secretion, was used to examine the role of extracellular collagen deposition in supporting hematopoiesis in long-term C57B1/6J mouse bone marrow cell cultures. Throughout the 10-wk culture period, all culture dishes contained either 0, 10, 25, or 50 micrograms/ml of CHP. All medium and nonadherent cells were removed at weekly intervals and replaced with fresh medium containing the previous concentrations of CHP. Nonadherent cells were assayed weekly for total cells and pluripotent, erythroid, megakaryocytic, and granulocytic-macrophage progenitor cells. Dishes were killed at selected intervals to assess protein and collagen synthesis in the adherent layer. Adherent cell numbers, as judged by microscopic examination and DNA assays, correlated inversely with CHP concentrations used and paralleled degree of collagen synthesis inhibition. The decreased hemopoietic progenitor cell production correlated closely with percent inhibition of collagen synthesis and stromal cellularity. The CHP concentrations tested were not directly toxic to hemopoietic progenitor cells. These studies demonstrate that collagen deposition in the extracellular matrix of murine bone marrow cell cultures is essential to the establishment of a functional stromal microenvironment that is supportive of long-term hematopoiesis.
Vitamin K in hand osteoarthritis: results from a randomised clinical trial
Authors: T Neogi, D T Felson, R Sarno, S L Booth
Journal: Annals of the Rheumatic Diseases (2008)

Vitamin K has bone and cartilage effects, and previously shown to be associated with radiographic osteoarthritis. We evaluated vitamin K's effect on hand osteoarthritis in a randomised controlled trial.
Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis
Authors: Nathan P. Young, Denise Crowley, Tyler Jacks
Journal: Cancer Research (2011)

It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-ras(G12D) with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-ras(G12D) activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell-cycle arrest as an extremely potent tumor suppressor mechanism.
Serious Shortcomings in the Management of Children with Anaphylaxis in Scottish Schools
Authors: Kirsty E Rankin, Aziz Sheikh
Journal: PLoS Medicine (2006)

Background The United Kingdom incidence of anaphylaxis has increased very sharply over the last decade, with the highest rates of hospital admissions occurring in school-aged children. This raises concerns about the extent to which schools are aware of approaches to the prevention and treatment of anaphylaxis. Methods and Findings We undertook a national postal survey of 250 Scottish schools enquiring about approaches to managing children considered to be at risk of anaphylaxis. We obtained responses from 148 (60%) schools, 90 (61%) of which reported having at least one at risk child. Most (80%) schools with children considered to be at risk reported having personalised care plans and invariably reported having at least one member of staff trained in the emergency treatment of anaphylaxis. Access to adrenaline was available on-site in 97% of these schools. However, significantly fewer schools without children considered to be at risk reported having a trained member of staff (48%, p < 0.001), with access to adrenaline being very poor (12%, p < 0.001). Overall, 59% of respondents did not feel confident in their school's ability to respond in an emergency situation. Conclusions Most schools with children considered to be at risk of anaphylaxis report using personal care plans and having a member of staff trained in the use of, and with access to, adrenaline. The picture is, however, less encouraging in schools without known at risk children, both in relation to staff training and access to adrenaline. The majority of schools with at risk children have poorly developed strategies for preventing food-triggered anaphylaxis reactions. There is a need for detailed national guidelines for all schools, which the Scottish Executive must now ensure are developed and implemented.
Expression of<i>ZNF804A</i>in Human Brain and Alterations in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder
Authors: Ran Tao, Helena Cousijn, Andrew E. Jaffe, Philip W. J. Burnet, Freya Edwards, Sharon L. Eastwood, Joo Heon Shin, Tracy A. Lane, Mary A. Walker, Brady J. Maher, Daniel R. Weinberger, Paul J. Harrison, Thomas M. Hyde, Joel E. Kleinman
Journal: JAMA Psychiatry (2014)

The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706.To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder.Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder.Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype.ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P = .02). In contrast, full-length ZNF804A showed no association with genotype (P > .05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P = .006) and increased in those with major depressive disorder (P < .001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P = .002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P > .05).rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor.
Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders
Authors: Marco Ladetto, Mara Compagno, Irene Ricca, Marco Pagano, Alberto Rocci, Monica Astolfi, Daniela Drandi, Paola Francia di Celle, Maria Dell'Aquila, Barbara Mantoan, Sonia Vallet, Gloria Pagliano, Federica De Marco, Roberto Francese, Loredana Santo, Alessandra Cuttica, Carlo Marinone, Mario Boccadoro, Corrado Tarella
Journal: Blood (2004)
Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcome in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial
Authors: Edith A. Perez, E. Aubrey Thompson, Karla V. Ballman, S. Keith Anderson, Yan W. Asmann, Krishna R. Kalari, Jeanette E. Eckel-Passow, Amylou C. Dueck, Kathleen S. Tenner, Jin Jen, Jian-Bing Fan, Xochiquetzal J. Geiger, Ann E. McCullough, Beiyun Chen, Robert B. Jenkins, George W. Sledge, Eric P. Winer, Julie R. Gralow, Monica M. Reinholz
Journal: Journal of Clinical Oncology (2015)

Purpose To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene–enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P &lt; .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64). Conclusion Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.