tbuckley/cabot-search huggingface dataset:
Alteration of NMDA NR <sub>1</sub> Receptors Within the Paraventricular Nucleus of Hypothalamus in Rats With Heart Failure
Authors: Yi-Fan Li, Kurtis G. Cornish, Kaushik P. Patel
Journal: Circulation Research (2003)

One of the pathophysiological characteristics of chronic heart failure (HF) is elevated sympathetic drive, which is a major factor contributing to the morbidity and mortality of HF. Resent evidence points to a central mechanism that contributes to the sympathetic abnormality in HF. The paraventricular nucleus (PVN) of the hypothalamus is an important site that integrates sympathetic nerve activity. Studies have shown that glutamate elicits excitatory effects on neurons in the PVN through the NMDA receptor. The goal of the present study was to examine the role of NMDA receptors in the altered sympathetic nerve activation during HF. The left coronary ligation-induced heart failure model in the rat was used. In α-chloralose and urethane anesthetized rats, microinjection of NMDA into the PVN (50 to 200 pmol) produced dose-dependent increases in renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR). This response to NMDA was significantly potentiated (27±7%) in HF compared with sham rats. On the other hand, microinjection of the NMDA receptor antagonist AP-5 (4 to 16 nmol) into the PVN caused significant decreases in RSND, BP, and HR only in rats with HF but very slight changes in sham rats. Furthermore, using microdialysis and HPLC in combination with electrochemical detection techniques, we found that the glutamate level in the PVN was not increased significantly in HF compared with sham rats. However, using RT-PCR, Western blot, and immunofluorescence techniques, it was found that NMDA NR 1 subunit mRNA expression and protein level in the PVN were significantly increased in HF compared with sham rats. These data suggest that the increased glutamatergic activity on sympathetic regulation, due to the upregulation of NMDA NR 1 receptor subunits within the PVN may contribute to the elevated sympathoexcitation during HF.
Neighborhood Socioeconomic Change and Diabetes Risk
Authors: Diana S. Grigsby-Toussaint, Rebecca Lipton, Noel Chavez, Arden Handler, Timothy P. Johnson, Jessica Kubo
Journal: Diabetes Care (2010)

OBJECTIVE To examine whether patterns in socioeconomic characteristics in Chicago over a 30-year period are associated with neighborhood distribution of youth diabetes risk. RESEARCH DESIGN AND METHODS Incident cases of diabetes in youth aged 0–17 years were identified from the Chicago Childhood Diabetes Registry between 1994 and 2003. Those with a type 2 diabetes–like clinical course or related indicators were classified as non–type 1 diabetic; the remaining cases were considered to have type 1 diabetes. RESULTS Compared with stable diversity neighborhoods, significant associations for type 1 diabetes were found for younger children residing in emerging low-income neighborhoods (relative risk 0.56 [95% CI 0.36–0.90]) and older children residing in emerging high-income neighborhoods (1.52 [1.17–1.98]). For non–type 1 diabetes, older youth residing in desertification neighborhoods were at increased risk (1.47 [1.09–1.99]). CONCLUSIONS Neighborhood socioeconomic characteristics in Chicago may be associated with the risk of diabetes in youth.
DNA Methylation in Oocytes and Liver of Female Mice and Their Offspring: Effects of High-Fat-Diet–Induced Obesity
Authors: Zhao-Jia Ge, Shi-Ming Luo, Fei Lin, Qiu-Xia Liang, Lin Huang, Yan-Chang Wei, Yi Hou, Zhi-Ming Han, Heide Schatten, Qing-Yuan Sun
Journal: Environmental Health Perspectives (2013)

Background: Maternal obesity has adverse effects on oocyte quality, embryo development, and the health of the offspring.Objectives: To understand the underlying mechanisms responsible for the negative effects of maternal obesity, we investigated the DNA methylation status of several imprinted genes and metabolism-related genes.Methods: Using a high-fat-diet (HFD)-induced mouse model of obesity, we analyzed the DNA methylation of several imprinted genes and metabolism-related genes in oocytes from control and obese dams and in oocytes and liver from their offspring. Analysis was performed using combined bisulfite restriction analysis (COBRA) and bisulfite sequencing.Results: DNA methylation of imprinted genes in oocytes was not altered in either obese dams or their offspring; however, DNA methylation of metabolism-related genes was changed. In oocytes of obese mice, the DNA methylation level of the leptin (Lep) promoter was significantly increased and that of the Ppar-α promoter was reduced. Increased methylation of Lep and decreased methylation of Ppar-α was also observed in the liver of female offspring from dams fed the high-fat diet (OHFD). mRNA expression of Lep and Ppar-α was also significantly altered in the liver of these OHFD. In OHFD oocytes, the DNA methylation level of Ppar-α promoter was increased.Conclusions: Our results indicate that DNA methylation patterns of several metabolism-related genes are changed not only in oocytes of obese mice but also in oocytes and liver of their offspring. These data may contribute to the understanding of adverse effects of maternal obesity on reproduction and health of the offspring.Citation: Ge ZJ, Luo SM, Lin F, Liang QX, Huang L, Wei YC, Hou Y, Han ZM, Schatten H, Sun QY. 2014. DNA methylation in oocytes and liver of female mice and their offspring: effects of high-fat-diet–induced obesity. Environ Health Perspect 122:159–164; http://dx.doi.org/10.1289/ehp.1307047
A Simple Method for Estimating and Testing Minimum-Evolution Trees
Authors: Andrey Rzhetsky, Masatoshi Nei
Journal: Molecular Biology and Evolution (1992)

A simple method for estimating and testing phylogenetic trees under the principle of minimum evolution (ME) is presented. The basic procedure of this method is first to obtain the neighbor-joining (NJ) tree by Saitou and Nei’s method and then to search for a tree with the minimum value of the sum (S) of branch lengths by examining all trees that are closely related to the NJ tree. Once the ME tree is identified, a statistical test is conducted for the difference in S between this tree and other closely related trees. The mathematical method required for conducting this test is developed by using the least-squares approach. Computer simulation has shown that this method identifies the correct tree with a high probability, as long as the number of nucleotides examined is sufficiently large. It has also been shown that the topology of the NJ tree is almost always identical with that of the ME tree. A method for obtaining least-squares estimates (and their standard errors) of branch lengths for a given topology is also presented. This method can be used for testing the reliability of the branching pattern of the ME tree. However, the statistical test of S values is more powerful in rejecting incorrect trees than is the branch-length test or bootstrapping. Furthermore, both a mathematical method for computing the number of trees with a given value of topological difference from the NJ tree and a computer algorithm for identifying all the topologies are developed.
Wild-Type p53 Overexpression and Its Correlation With MDM2 and p14ARF Alterations: An Alternative Pathway to Non–Small-Cell Lung Cancer
Authors: Yu-Chien Wang, Ruo-Kai Lin, Yi-Hung Tan, Jung-Ta Chen, Chih-Yi Chen, Yi-Ching Wang
Journal: Journal of Clinical Oncology (2004)

We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization.We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non-small-cell lung cancer (NSCLC) patients.Immunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P < .001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P < .001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P < .05) and was correlated with advanced stages (P < .05) and poor prognosis (P < .05).Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.
Heart Valve Development
Authors: Ehrin J. Armstrong, Joyce Bischoff
Journal: Circulation Research (2004)

During the past decade, single gene disruption in mice and large-scale mutagenesis screens in zebrafish have elucidated many fundamental genetic pathways that govern early heart patterning and differentiation. Specifically, a number of genes have been revealed serendipitously to play important and selective roles in cardiac valve development. These initially surprising results have now converged on a finite number of signaling pathways that regulate endothelial proliferation and differentiation in developing and postnatal heart valves. This review highlights the roles of the most well-established ligands and signaling pathways, including VEGF, NFATc1, Notch, Wnt/β-catenin, BMP/TGF-β, ErbB, and NF1/Ras. Based on the interactions among and relative timing of these pathways, a signaling network model for heart valve development is proposed.
Clinical trial of deglydyrrhizinized liquorice in gastric ulcer.
Authors: A G Turpie, J Runcie, T J Thomson
Journal: Gut (1969)

Inthepasttwenty years evidence hasaccumulated that liquorice andrelated compounds accelerate the rateofhealing ofgastric ulcers. Powdered succus liquiritiae (Revers, 1948) and glycyrrhiza extract (Schulze, Franke, andKeller, 1954; Ferenbach, 1954; Ohrt, 1955) wereshownto bebeneficial inpatients withgastric ulcer but adequately controlled clinical trials ofliquorice extracts werenotavailable until 1962withthe result thatlittle attention waspaidtothis formof treatment. Interest inliquorice asatherapeutic agent was revived withthesynthesis ofcarbenoxolone sodium fromglycyrrhizinic acid, aglycoside extracted from liquorice. Carbenoxolone sodium hasbeenshown inanumberofcontrolled clinical trials (Doll, Hill, Hutton, andUnderwood, 1962; Doll, 1964; Doll, Hill, andHutton, 1965;Doll, Langman, and Shawdon, 1968;HorwichandGalloway, 1965; Bank, Marks, Palmer, Groll, andVanEldick, 1967) topromote thehealing ofgastric ulcers. However, treatment witheither carbenoxolone sodiumor succus liquiritiae wasoften complicated byretention ofwaterandelectrolyte imbalance. Thefrequency andseverity ofsideeffects occurring inpatients receiving carbenoxolone sodium havebeenemphasized bymanyauthors (Doll etal,1962; Turpie and Thomson, 1965; Mohamed, Chapman, andCrooks, 1966). Themainsideeffects notedhaveincluded frank oedema, elevation ofdiastolic blood pressure, hypokalaemia, andparesis ofmuscles. Langman(1968) stated that avariant ofcarbenoxolone whichisdevoid ofside effects onfluid and electrolyte balance isclearly needed. Borst, Blomhert, Molhuysen, Gerbrandy, Turner, anddeVries (1950) found that theglycyrrhizinic acid moiety ofliquorice wasresponsible forthefluid retention andelectrolyte imbalance. This view wasconfirmed byRevers (1952). Thereisnowavailable apreparation ofliquorice whichdoesnotcontain glycyrrhizinic acid; itis foundintheproprietary preparation, Caved-(S) Eachtablet ofCaved-(S) contains:
Relation of the perception of airway obstruction to the severity of asthma
Authors: I D Bijl-Hofland, S G M Cloosterman, H T. M Folgering, R P Akkermans, C P van Schayck
Journal: Thorax (1999)

Patients with a poor perception of their symptoms of asthma seem to have an increased risk of an asthma attack. The influence of factors such as airway calibre, bronchial hyperresponsiveness, age and sex on the "perceptiveness" of a patient are poorly understood. It is of clinical importance to identify patients who are likely to have a poor perception of their symptoms. We have studied the perception of bronchoconstriction by asthmatic patients during a histamine provocation test and analysed the influence of bronchial obstruction, hyperresponsiveness, sex, and age. We were particularly interested to establish whether there was any difference in perception between subjects with a greater or lesser severity of asthma (expressed as bronchial obstruction, hyperresponsiveness).One hundred and thirty four patients with allergic asthma underwent a histamine provocation test. The FEV1 was measured after each inhalation of histamine. Subjects were asked to rate subjective quantification of the sensation of breathlessness on a visual analogue scale (VAS). The relationship between changes in VAS values and the reduction in FEV1 as a percentage of the baseline value was analysed by determining the linear regression slope (alpha) between the two parameters and indicates the perception of airway obstruction. Multiple regression analysis was performed to investigate the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the "perceptiveness" for bronchoconstriction.The median value of the slope alpha (indicating the perception of airway obstruction) was 0.91 (25-75th percentile: 0.48-1.45). Age and sex had no influence on the perception of bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial hyperresponsiveness (PC20) showed a significant correlation with the perception of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the multiple regression model were 0.20 and 0.10. Patients who had a low baseline FEV1 and/or a high bronchial responsiveness to histamine were more likely to show a low perceptiveness for bronchoconstriction during the challenge test.Low baseline FEV1 and high bronchial responsiveness are associated with a low degree of "perceptiveness" for bronchoconstriction. This suggests that patients with a more severe degree of asthma either show adaptation of "perceptiveness" for airway obstruction or that low perceptiveness leads to more severe asthma.
GC-Biased Gene Conversion Impacts Ribosomal DNA Evolution in Vertebrates, Angiosperms, and Other Eukaryotes
Authors: Juan S. Escobar, Sylvain Glémin, Nicolas Galtier
Journal: Molecular Biology and Evolution (2011)

Ribosomal DNA (rDNA) is one of the most conserved genes in eukaryotes. The multiples copies of rDNA in the genome evolve in a concerted manner, through unequal crossing over and/or gene conversion, two mechanisms related to homologous recombination. Recombination increases local GC content in several organisms through a process known as GC-biased gene conversion (gBGC). gBGC has been well characterized in mammals, birds, and grasses, but its phylogenetic distribution across the tree of life is poorly understood. Here, we test the hypothesis that recombination affects the evolution of base composition in 18S rDNA and examine the reliability of this thoroughly studied molecule as a marker of gBGC in eukaryotes. Phylogenetic analyses of 18S rDNA in vertebrates and angiosperms reveal significant heterogeneity in the evolution of base composition across both groups. Mammals, birds, and grasses experience increases in the GC content of the 18S rDNA, consistent with previous genome-wide analyses. In addition, we observe increased GC contents in Ostariophysi ray-finned fishes and commelinid monocots (i.e., the clade including grasses), suggesting that the genomes of these two groups have been affected by gBGC. Polymorphism analyses in rDNA confirm that gBGC, not mutation bias, is the most plausible explanation for these patterns. We also find that helix and loop sites of the secondary structure of ribosomal RNA do not evolve at the same pace: loops evolve faster than helices, whereas helices are GC richer than loops. We extend analyses to major lineages of eukaryotes and suggest that gBGC might have also affected base composition in Giardia (Diplomonadina), nudibranch gastropods (Mollusca), and Asterozoa (Echinodermata).
A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children
Authors: Janne C. de Ruyter, Margreet R. Olthof, Jacob C. Seidell, Martijn B. Katan
Journal: New England Journal of Medicine (2012)

The consumption of beverages that contain sugar is associated with overweight, possibly because liquid sugars do not lead to a sense of satiety, so the consumption of other foods is not reduced. However, data are lacking to show that the replacement of sugar-containing beverages with noncaloric beverages diminishes weight gain.
Divergent Biophysical Defects Caused by Mutant Sodium Channels in Dilated Cardiomyopathy With Arrhythmia
Authors: Thao P. Nguyen, Dao W. Wang, Thomas H. Rhodes, Alfred L. George
Journal: Circulation Research (2007)

Mutations in SCN5A encoding the principal Na + channel α-subunit expressed in human heart (Na V 1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel Na V 1.5 mutations associated with this syndrome (D2/S4 – R814W; D4/S3 – D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased “window current.” This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na + and Ca 2+ homeostasis leading to myocardial dysfunction.
The medical manpower debate
Authors: D G. Wardle
Journal: BMJ (1977)

We describe a patient with chronic hypernatraemia (plasma sodium 148-155 mmol/l) and partial nephrogenic diabetes insipidus who had received prolonged lithium treatment. Despite stopping the drug for one year the abnormalities remained. Infusion of hypertonic saline (NaCl 855 mmol/l) allowed the characterization of osmoregulation of thirst and vasopressin secretion. Linear regression analysis of plasma vasopressin and osmolality defined the function, pAVP = 0.27 (pOsm - 301), and analysis of thirst measured by a visual analogue scale and plasma osmolality, the function, thirst = 0.16 (pOsm - 302) where pAVP and pOsm represent plasma arginine vasopressin and osmolality respectively. The slopes of the regression lines which describe the sensitivity of the osmoreceptors were within the normal range, but both abscissal intercepts, which define the thresholds for vasopressin release and thirst, were markedly elevated in comparison to normal (upper limit less than 290 mOsm/kg). Other investigations of electrolytes, anterior pituitary function and high definition computed tomographic scanning of hypothalamo-pituitary region were all normal. We conclude that this patient9s chronic hypernatraemia was due to resetting of the osmostats for both vasopressin release and thirst, a rarely described mechanism to account for hypernatraemia. Although it is probable that the partial nephrogenic diabetes insipidus was related to prolonged lithium therapy, the cause of the reset osmostats remains unclear.
CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF
Authors: Nobuyasu Baba, Vu Quang Van, Keiko Wakahara, Manuel Rubio, Geneviève Fortin, Benoît Panzini, Geneviève Soucy, Ramses Wassef, Carole Richard, Raja Tamaz, Raymond Lahaie, Edmond-Jean Bernard, Yves Caussignac, Raymond Leduc, Rasmy Lougnarath, Carole Bergeron, Marc-André Racicot, Fanny Bergeron, Marie-Andrée Panzini, Pieter Demetter, Denis Franchimont, Knut Schäkel, Gisbert Weckbecker, Frank Kolbinger, Christoph Heusser, Thomas Huber, Karl Welzenbach, Marika Sarfati
Journal: The Journal of Experimental Medicine (2013)

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.
Tumor necrosis factor alpha stimulates the growth of the clonogenic cells of acute myeloblastic leukemia in synergy with granulocyte/macrophage colony-stimulating factor.
Authors: T Hoang, B Levy, N Onetto, A Haman, J C Rodriguez-Cimadevilla
Journal: The Journal of Experimental Medicine (1989)

TNF-alpha has been shown to antagonize the proliferative effects of growth factors present in crude conditioned media from PHA-stimulated leukocytes or cell lines on the clonogenic cells of acute myeloblastic leukemia (AML) (19,21). In the present study, we investigated the responses of AML blasts to TNF-alpha in the presence of defined growth factors (recombinant granulocyte/macrophage-CSF [rGM-CSF], recombinant granulocyte-CSF [rG-CSF], rIL-3, and rIL-1) and under conditions described for autocrine stimulation (32). While TNF-alpha antagonized the stimulatory effects of G-CSF and IL-3 on blast progenitors, TNF-alpha did not affect blast colony formation in the presence of IL-1. Unexpectedly, TNF-alpha significantly enhanced blast proliferation in the presence of GM-CSF. Further, TNF-alpha also acted synergistically with an endogenous source of growth stimulatory signal to promote proliferation of blast clonogenic cells. Thus, on human leukemic cells, TNF-alpha appears to be a molecule that is at least bifunctional, having the ability to either support or inhibit cell proliferation, depending on the other growth factors present. It is postulated that the proliferative response of blast progenitors to TNF-alpha under conditions that favor autocrine stimulation may represent one property that allows the cells to escape from negative regulation and proliferate in AML.