Med-CoReasoner: Reducing Language Disparities in Medical Reasoning via Language-Informed Co-Reasoning
Paper
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2601.08267
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bionli-en-001
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nli
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BioNLI
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en
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Premise:
Icatibant, a bradykinin-2 receptor antagonist, is administered by subcutaneous injection for the treatment of attacks of type I and type II hereditary angioedema. Following injection, patients feel transient pain followed by a short-lived wheal and flare response at the injection site. We hypothesized that the icatibant-induced wheal and flare response follows histamine release from activated skin mast cells and would therefore be reduced by an H(1)-antihistamine. Intradermal injection of 100 μl of 100 μg/ml histamine and 10 mg/ml icatibant into the forearms of health volunteers caused wheal and flare responses of a similar magnitude which were reduced by cetirizine pretreatment by 49% and 41% (histamine) and 35% and 41% (icatibant). Studies in vitro showed that icatibant at 1 × 10(-4) and 1 × 10(-5) M caused significant (P < 0.05) histamine release from isolated human cutaneous mast cells.
Hypothesis:
In conclusion, icatibant induces histamine -mediated wheal and flare responses that may be reduced in severity by prophylactic administration of an H(1)-antihistamine.
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entailment
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bionli-en-002
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nli
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BioNLI
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en
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Premise:
The products resulting from proteolytic degradation of human fibrinogen (FDP) were found to induce the release of histamine from rat peritoneal mast cells. Low molecular weight, dialysable peptides (FDP) showed the highest dose dependent, histamine releasing activity. Histamine release induced by FDP was effectively inhibited by the gold compound auranofin at a concentration of 10(-5)-10(-7) mol/l and also by the non-steroidal anti-inflammatory drugs BW 755c, timegadine, medosan, naproxen, and aspirin at the higher concentration range of 10(-4)-10(-6) mol/l.
Hypothesis:
It is concluded that the release of histamine from mast cells may be modulated to some extent by anti-inflammatory drugs, especially auranofin , BW 755c and timegadine, a functional property which may be beneficial in the management of joint disease.
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entailment
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bionli-en-003
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nli
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BioNLI
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en
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Premise:
(E,Z)-3-(3',5'-Dimethoxy-4'-hydroxy-benzylidene)-2-indolinone (indolinone) is an alkaloid that has been identified as a pharmacologically active compound in extracts of the traditional anti-inflammatory herb Isatis tinctoria. Indolinone has been shown to inhibit compound 48/80-induced mast cell degranulation in vitro. Application of indolinone to bone marrow derived mast cells showed that it was uniformly distributed in the cytoplasm and that cellular uptake was terminated within minutes. Pre-treatment of IgE-sensitized mast cells with 100nM indolinone rendered them insensitive against FcvarepsilonRI-receptor dependent degranulation. However, upstream signalling induced by antigen such as activation of PI3-K and MAPK remained unaffected.
Hypothesis:
We conclude that indolinone blocks mast cell degranulation at the level of granule exocitosis with an IC(100) of 54nm.
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contradiction
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bionli-en-004
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nli
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BioNLI
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en
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Premise:
FcepsilonRI-mediated exocytosis of preformed mediators from mast cells and basophils (e.g. histamine, serotonin, beta-hexosaminidase) is sensitive to the immunosuppressants cyclosporin A and FK506 (IC50 200 and 4 nM, respectively) but not rapamycin. The mechanism of inhibition does not appear to involve tyrosine phosphorylation, hydrolysis of inositol phosphates or calcium flux. Here we report experiments using a molecular approach to assess the role of calcineurin, a serine/threonine phosphatase thought to be the primary pharmacological target of these drugs. Calcineurin's activity requires association of its catalytic (A) subunit with an intrinsic regulatory (B) subunit. We hypothesized that calcineurin-sensitive signalling events should be affected by the depletion of calcineurin B subunits, thereby reducing the number of active A:B complexes. We therefore transfected rat basophilic leukemia (RBL) cells with an inhibitory (dominant negative) form of the calcineurin A subunit, which binds the calcineurin B subunit with high affinity but does not possess catalytic activity (B subunit knock-out, BKO). In these transfected cells, the dose-response curve for the inhibition of FcepsilonRI-mediated exocytosis by FK506 was shifted to the left, indicating an increased drug sensitivity of BKO-transfected cells.
Hypothesis:
We conclude that Adenosine inhibition of FcepsilonRI-mediated exocytosis in mast cells specifically targets calcineurin activity.
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contradiction
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bionli-en-005
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nli
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BioNLI
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en
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Premise:
MC9 mast cells, sensitized with monoclonal IgE antibody specific for 2,4-dinitrophenyl (DNP) group, were exposed to DNP-BSA and the pH and cytosolic calcium signals were recorded by using the fluorescent probes BCECF and Fura-2 respectively. DNP-BSA induced cell alkalinization was fully inhibited by azelastine with IC50 (1.6 +/- 0.5 mumol/l, mean +/- SEM, n = 5) similar to that required to inhibit histamine release (1.4 mumol/l). Conversely, high azelastine concentrations (> 100 mumol/l) were required to inhibit DNP-BSA-dependent cell calcium mobilization (IC50 approximately 200 mumol/l, n = 3). Amiloride, but not the H1 histamine antagonist pyrilamine, was able to inhibit the DNP-BSA induced pH signal. In acidified mast cells, azelastine potently inhibited Na+:H+ exchange activity (IC50 = 7.7 +/- 3.6 x 10(-6) M, mean +/- SEM, n = 3). Conversely, in mouse spleen lymphocytes azelastine was unable to inhibit the amiloride-sensitive pH signal induced by concanavalin A.
Hypothesis:
In conclusion, the promotion of histamine release by azelastine is not due to an interference with the cytosolic calcium signal.
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contradiction
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bionli-en-006
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nli
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BioNLI
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en
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Premise:
Rhodnius prolixus aggregation inhibitor 1 (RPAI-1), a 19-kDa protein isolated from the salivary gland of R. prolixus, was purified by strong cation exchange and reverse-phase high performance liquid chromatographies. Based on 49 amino-terminal amino acid sequences of RPAI-1, primers were produced to generate probes to screen an R. prolixus salivary gland cDNA library. A phage containing the full-length clone of RPAI-1 codes for a mature protein of 155 amino acids. RPAI-1 shows sequence homology to triabin and pallidipin, lipocalins from Triatoma pallidipennis. The cDNA sequence was cloned in Pet17B Escherichia coli expression vector, producing an active peptide. RPAI-1 inhibits human platelet-rich plasma aggregation triggered by low concentrations of ADP, collagen, arachidonic acid, thromboxane A(2) mimetics (U46619), and very low doses of thrombin and convulxin. Here we show that ADP is the target of RPAI-1 since (i) RPAI-1 inhibits ADP-dependent large aggregation formation and secretion triggered by U46619, without affecting Ca(2+) increase and shape change; (ii) ADP restored the inhibition of U46619-induced platelet aggregation by RPAI-1, (iii) PGE(1)-induced increase of cAMP (which is antagonized by U46619 in an ADP-dependent manner) was restored by RPAI-1, (iv) RPAI-1 inhibits low concentrations of ADP-mediated responses of indomethacin-treated platelets, and (v) RPAI-1 binds to ADP, as assessed by large zone chromatography. RPAI-1 affects neither integrin alpha(2)beta(1)- nor glycoprotein VI-mediated platelet responses.
Hypothesis:
We conclude that RPAI-1 is the first lipocalin described that inhibits platelet aggregation by a novel mechanism, binding to ADP.
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entailment
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bionli-en-007
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nli
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BioNLI
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en
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Premise:
To increase our understanding of the mechanisms by which growth hormone (GH) and insulin-like growth factor (IGF)-I influence bovine mammary gland development, the potential roles of T-box2 (TBX2) and T-box3 (TBX3) were investigated. Although no information regarding expression of either transcription factor in the bovine mammary gland exists, it is known that TBX3 and its closely related family member, TBX2, are required for mammary gland development in humans and mice. Additionally, TBX3 mutations in humans and mice lead to ulnar mammary syndrome. Evidence is present in bone that TBX3 is required for proliferation and its expression is regulated by GH, an important regulator of mammary gland development and milk production. We hypothesized that TBX2 and TBX3 are expressed in the bovine mammary gland and that GH, IGF-I, or both increase TBX2 and TBX3 expression in bovine mammary epithelial cells (MEC). Bovine mammary gland tissue, MAC-T cells, primary MEC, and fibroblasts were obtained and TBX2 and TBX3 expression was determined by real-time reverse transcription PCR. In addition, TBX2 and TBX3 expression was examined in cells treated with 100 or 500 ng/mL of GH or 100 or 200 ng/mL of IGF-I for 24 or 48 h. Both TBX2 and TBX3 were expressed in bovine mammary tissue. Surprisingly, expression of TBX2 was only detected in mammary fibroblast cells, whereas TBX3 was expressed in all 3 cell types. Growth hormone did not alter TBX3 expression in MAC-T cells or MEC. However, IGF-I increased TBX3 expression in MAC-T, but not in primary MEC. We did not observe a change in TBX2 or TBX3 expression in fibroblasts treated with GH and IGF.
Hypothesis:
Therefore, we concluded that (1) TBX2 and TBX3 are expressed in bovine mammary gland, (2) their expression is cell-type specific, and (3) Fur stimulates TBX3 expression in MAC-T cells.
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contradiction
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bionli-en-008
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nli
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BioNLI
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en
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Premise:
The influence of heparin on the reaction between thrombin and plasminogen activator inhibitor-1 (PAI-1) has been examined. With a 50-fold excess of PAI-1, the rate constant for the inhibition of thrombin was 458 mol/L-1s-1, which increased to 5,000 mol/L-1s-1 in the presence of 25 micrograms/mL unfractionated heparin or heparin with low affinity for antithrombin. The effect of low affinity heparin was then examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, using close to equimolar concentrations of reactants. Thrombin and PAI-1 formed a stable stoichiometric complex in the absence of heparin, which did not dissociate after the addition of 25 micrograms/mL low-affinity heparin. In contrast, when low-affinity heparin was added at the beginning of the reaction, there was an initial increase in PAI-1-thrombin complex formation, but this was rapidly followed by substantial proteolytic cleavage of unreacted PAI-1 and of the thrombin-PAI-1 complex. The idea that the relative concentrations of thrombin and PAI-1, and the presence of low affinity heparin, could influence the products of the reaction was examined in detail. Quantitative zymographic analysis of tissue plasminogen activator and PAI-1 activities and chromogenic substrate assay of thrombin activity showed that low-affinity heparin stimulated the inactivation of PAI-1 by an equimolar amount of thrombin, but caused only a minimal stimulation of thrombin inhibition.
Hypothesis:
It is concluded that low-affinity heparin stimulates thrombin inhibition when PAI-1 is in excess, but, unexpectedly, that low-affinity heparin enhances PAI-1 inactivation when thrombin is equimolar to PAI-1.
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entailment
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bionli-en-009
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nli
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BioNLI
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en
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Premise:
Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated through TNF receptor 1 and/or 2 (TNFR1/2) signaling. We utilized a unique model of mouse DO to assess the effects of 1) TNFR homozygous null gene alterations on direct bone formation and 2) rmTNF on wild type (WT), TNFR1(-/-) (R1KO), and TNR2(-/-) (R2KO) mice. Radiological and histological analyses of direct bone formation in the distraction gaps demonstrated no significant differences between the WT, R1KO, R2KO, or TNFR1(-/-) and R2(-/-) (R1 and 2KO) mice. R1 and 2KO mice had elevated levels of serum TNF but demonstrated no inhibition of new bone formation. Systemic administration by osmotic pump of rmTNF during DO (10 microg/kg/day) resulted in significant inhibition of gap bone formation measures in WT and R2KO mice, but not in R1KO mice.
Hypothesis:
We conclude that exogenous rmTNF and/or endogenous TNF act to inhibit new bone formation during DO by signaling primarily through TNF R1.
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entailment
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bionli-en-010
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nli
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BioNLI
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en
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Premise:
Although Gbetagamma is thought to mediate mitogen-activated protein kinase (MAPK) activation in response to G protein-coupled receptor stimulation, the mechanisms involved in this pathway have not been clearly defined. Phosphoinositide 3-kinase (PI3K) has been proposed as an early intermediate in this process, but its role has remained elusive. We have observed that dominant negative mutants of p110beta, but not of p110gamma, inhibited MAPK stimulation in response to lysophosphatidic acid (LPA). The role of p110beta was located upstream from Ras. To determine which of the lipid or protein kinase activities of p110beta were important for Ras activation, we produced a mutant p110beta lacking the lipid but not the protein kinase activity. This protein displayed a dominant negative activity similar to a kinase-dead mutant, indicating that p110beta lipid kinase activity was essentially involved in Ras activation. In agreement, overexpression of the lipid phosphatase PTEN was found to specifically inhibit Ras stimulation induced by LPA. In addition, we have observed that the PH domain-containing adapter protein Gab1, which is involved in p110beta activation during LPA stimulation, is also implicated in this pathway downstream of p110beta. Indeed, both membrane redistribution and phosphorylation of Gab1 were reduced in the presence of PI3K inhibitors or dominant negative p110beta. Downstream of Gab1, the tyrosine phosphatase SHP2 was found to mediate Ras activation in response to LPA and to be recruited through PI3K and Gab1, because transfection of Gab1 mutant deficient for SHP2 binding inhibited Ras activation without interfering with PI3K activation.
Hypothesis:
We conclude that the lipid kinase activity of p110beta is essential for Ras activation induced by LPA and that PI3K and Gab1 are involved in this pathway.
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contradiction
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bionli-en-011
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nli
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BioNLI
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en
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Premise:
The role of FSH in spermatogenesis is unclear as testosterone alone has been reported to be sufficient in the gonadotropin-deficient rat. This study examined the effects of recombinant FSH on the restoration of spermatogenesis after gonadotropin withdrawal by GnRH immunization. Adult Sprague-Dawley rats received GnRH immunogen (100 micrograms, sc, every 4 weeks) to induce gonadotropin deficiency, with severe spermatogenic regression occurring by 12 weeks. Recombinant human FSH was then given (10 or 50 IU/kg, sc, daily) for 7, 14, and 21 days, with data from both dosages combined in the analyses. Testes were perfusion fixed, and germ cell numbers were quantified by the optical disector technique. After 7 days of FSH, testis weight significantly increased by 43% (P < 0.01), with no further increases at 14 and 21 days. GnRH immunization severely reduced germ cell numbers, which were then significantly (P < 0.05) restored in all cell types, except elongated spermatids, by 7 days of FSH; type A spermatogonia (45%-->61% of control), type B spermatogonia/preleptotene spermatocytes (46%-->65%), leptotene/zygotene spermatocytes (39%-->55%), pachytene spermatocytes in stages I-VIII (11%-->30% control) and IX-XIV (4.3%-->22% control), and round spermatids in stages I-VIII (1.4%-->4.4% control). Prolonged FSH treatment did not further increase type A spermatogonial or pachytene spermatocyte number, whereas round spermatids increased to a peak of 12.8% of the control value. At no stage did FSH increase elongated spermatid numbers above 1% of the control level. The incorporation of bromode-oxyuridine into spermatogonial and early spermatocyte nuclei did not change after GnRH immunization or FSH treatment. Sertoli cell number was not altered by any treatment; however, Sertoli cell nuclear volume was significantly decreased from the control value by GnRH immunization (142 +/- 9 vs. 455 +/- 22 microns 3; P < 0.01) and increased after 7 and 14 days of FSH treatment to 212 +/- 10 and 259 +/- 24 microns 3, respectively. FSH treatment restored serum inhibin levels to normal, but did not increase serum or testicular androgen levels.
Hypothesis:
We conclude that recombinant FSH partially restores spermatogenesis in the gonadotropin -deficient rat by increasing the number of spermatogonia and promoting subsequent maturational steps up to the round spermatid stage.
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entailment
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bionli-en-012
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nli
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BioNLI
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en
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Premise:
The ability of human follicular fluid (hFF), retrieved from women undergoing IVF to induce the acrosome reaction (AR) in human sperm has been documented by several laboratories. However, the nature of the active factors in the hFF and the physiological meaning of the AR induction are highly controversial. We performed a three step purification scheme for hFF and all the fractions were screened for the AR-inducing activity. AR activity was associated with a protein fraction of M(r) > 180 kD that on further analysis under PAGE was found to be composed by subunits of apparent M(r) 50,000 and 29,000. The N-terminal sequences of these bands showed a 100% homology with the heavy and light chains of human IgG. A polyclonal antibody raised against the purified protein and anti-human IgG were both able to suppress the acrosome reaction-inducing activity of crude hFF. However, neither normal human serum nor a purified preparation of human IgG were able to mimic the AR-inducing activity of hFF.
Hypothesis:
We conclude that the AR induction in hFF is mediated by human IgG.
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contradiction
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bionli-en-013
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nli
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BioNLI
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en
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Premise:
Hyperinsulinemia enhances the ability of subovulatory doses of human chorionic gonadotropin (hCG) to induce ovarian follicular cysts in the rat. To determine the relative contribution of these hormones to the development of ovarian cysts, adult female rats were treated with either (1) vehicle alone (controls), (2) a high-fat diet (HFD) to control for the effects of weight gain, (3) 1.5 to 6 IU hCG twice daily plus 6 U insulin (Ins)/d, or (4) 1.5 to 9 U Ins/d plus 3 IU hCG twice daily. On day 23 of the in vivo treatments, all groups that received at least 6 U Ins/d displayed increased body weight compared with control and HFD rats (P < or = .05). No control rats and only one HFD rat displayed ovarian cysts on this day. Plasma estrone (E1) and androstenedione (A4) were elevated in HFD rats with noncystic follicles compared with control rats (P < or = .05). Between 64% and 80% of rats on 6 U Ins/d plus twice-daily injections of 1.5 to 6 IU hCG displayed ovarian cysts on day 23. Plasma estradiol (E2) concentrations for these treatment groups were similar to those of control rats. Of the hormonally treated animals, only those that had ovarian cysts in response to twice-daily injections of 4.5 or 6 IU hCG plus 6 U Ins/d displayed elevated plasma A4 and/or testosterone compared with controls. In contrast, plasma E1 concentrations were elevated on day 23 for animals bearing ovarian cysts in response to increasing doses of hCG plus the fixed dose of 6 U Ins/d. Between 70% and 80% of rats treated twice daily with 3 IU hCG plus a daily dose of 1.5 to 6 U Ins displayed ovarian cysts on day 23. In marked contrast, only 25% of rats treated with this dose of hCG plus 9 U Ins/d developed cystic follicles. Of the plasma steroids tested, only E1 and A4 were elevated in these treatment groups compared with controls. However, these increases in plasma steroid concentrations did not correlate with the dose of insulin.
Hypothesis:
We conclude from these data that, although the mechanisms remain to be elucidated, extreme hyperinsulinemia has the paradoxical ability to attenuate the induction of ACR by hCG in some animals.
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contradiction
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bionli-en-014
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nli
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BioNLI
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en
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Premise:
We have shown that cortisol infusion reduced the luteinizing hormone (LH) response to fixed hourly GnRH injections in ovariectomized ewes treated with estradiol during the non-breeding season (pituitary-clamp model). In contrast, cortisol did not affect the response to 2 hourly invariant GnRH injections in hypothalamo-pituitary disconnected ovariectomized ewes during the breeding season. To understand the differing results in these animal models and to determine if cortisol can act directly at the pituitary to suppress responsiveness to GnRH, we investigated the importance of the frequency of GnRH stimulus, the presence of estradiol and stage of the circannual breeding season. In experiment 1, during the non-breeding season, ovariectomized ewes were treated with estradiol, and pulsatile LH secretion was restored with i.v. GnRH injections either hourly or 2 hourly in the presence or absence of exogenous cortisol. Experiments 2 and 3 were conducted in hypothalamo-pituitary disconnected ovariectomized ewes in which GnRH was injected i.v. every 2 h. Experiment 2 was conducted during the non-breeding season and saline or cortisol was infused for 30 h in a cross-over design. Experiment 3 was conducted during the non-breeding and breeding seasons and saline or cortisol was infused for 30 h in the absence and presence of estradiol using a cross-over design. Samples were taken from all animals to measure plasma LH. LH pulse amplitude was reduced by cortisol in the pituitary clamp model with no difference between the hourly and 2-hourly GnRH pulse mode. In the absence of estradiol, there was no effect of cortisol on LH pulse amplitude in GnRH-replaced ovariectomized hypothalamo-pituitary disconnected ewes in either season. The LH pulse amplitude was reduced in both seasons in experiment 3 when cortisol was infused during estradiol treatment.
Hypothesis:
We conclude that the ability of mg/kg to reduce LH secretion does not depend upon the frequency of GnRH stimulus and that estradiol enables mg/kg to act directly on the pituitary of ovariectomized hypothalamo-pituitary disconnected ewes to suppress the responsiveness to GnRH; this effect occurs in the breeding and non-breeding seasons.
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contradiction
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bionli-en-015
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nli
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BioNLI
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en
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Premise:
In Exp. 1, PMSG was injected to 26-day-old prepubertal rats to induce ovulations. On Day 2 (2 days later, the equivalent of the day of pro-oestrus) they received at 08:00 h 5 mg hydroxyflutamide or vehicle and at 12:00 h 2 mg progesterone or testosterone or vehicle. Animals were killed at 18:00 h on Day 2 or at 09:00 h on Day 3. Progesterone but not testosterone restored the preovulatory LH surge and ovulation in hydroxyflutamide-treated rats. In Exp. 2, 2 mg progesterone or testosterone were injected between 10:30 and 11:00 h on Day 2, to advance the pro-oestrous LH surge and ovulation in PMSG-primed prepubertal rats. Injection of hydroxyflutamide abolished the ability of progesterone to advance the LH surge or ovulation. Testosterone did not induce the advancement of LH surge or ovulation. In Exp. 3, ovariectomized prepubertal rats implanted with oestradiol-17 beta showed significantly (P less than 0.01) elevated serum LH concentrations at 18:00 h over those observed at 10:00 h. Progesterone injection to these animals further elevated the serum LH concentrations at 18:00 h, in a dose-dependent manner, with maximal values resulting from 1 mg progesterone. Hydroxyflutamide treatment significantly (P less than 0.003) reduced the serum LH values in rats receiving 0-1 mg progesterone but 2 mg progesterone were able to overcome this inhibition.
Hypothesis:
It is concluded that hydroxyflutamide but not testosterone can reverse the effects of progesterone on the preovulatory LH surge and ovulation.
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contradiction
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bionli-en-016
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nli
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BioNLI
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en
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Premise:
The present case-control study explored the interaction between marine-derived n-3 long chain polyunsaturated fatty acids (n-3 LC PUFAs) and uric acid (UA) on glucose metabolism and risk of type 2 diabetes mellitus (T2DM). Two hundred and eleven healthy subjects in control group and 268 T2DM subjects in case group were included. Plasma phospholipid (PL) fatty acids and biochemical parameters were detected by standard methods. Plasma PL C22:6n-3 was significantly lower in case group than in control group, and was negatively correlated with fasting glucose (r = -0.177, p < 0.001). Higher plasma PL C22:6n-3 was associated with lower risk of T2DM, and the OR was 0.32 (95% confidence interval (CI), 0.12 to 0.80; p = 0.016) for per unit increase of C22:6n-3. UA was significantly lower in case group than in control group. UA was positively correlated with fasting glucose in healthy subjects, but this correlation became negative in T2DM subjects. A significant interaction was observed between C22:6n-3 and UA on fasting glucose (p for interaction = 0.005): the lowering effect of C22:6n-3 was only significant in subjects with a lower level of UA.
Hypothesis:
In conclusion, glucose metabolism :6n-3 interacts with UA to modulate C22 .
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contradiction
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bionli-en-017
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nli
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BioNLI
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en
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Premise:
We previously reported that the endogenous ATP-binding cassette transporter (ABC)A7 strongly associates with phagocytic function rather than biogenesis of high-density lipoprotein (HDL), being regulated by sterol-regulatory element binding protein (SREBP)2. Phagocytic activity was found enhanced by apolipoprotein (apo)A-I and apoA-II more than twice the maximum in J774 and mouse peritoneal macrophages. Therefore we investigated the molecular basis of this reaction in association with the function of ABCA7. Similar to ABCA1, ABCA7 was degraded, likely by calpain, and apoA-I and apoA-II stabilize ABCA7 against degradation. Cell surface biotinylation experiments demonstrated that endogenous ABCA7 predominantly resides on the cell surface and that the apolipoproteins increase the surface ABCA7. The increase of phagocytosis by apolipoproteins was retained in the J774 cells treated with ABCA1 siRNA and in the peritoneal macrophages from ABCA1-knockout mice, but it was abolished in the J774 cells treated with ABCA7 siRNA and in the peritoneal macrophages from ABCA7-knockout mice. Phagocytosis was decreased in the cells in the peritoneal cavity of the ABCA7-knockout mouse compared with the wild-type control.
Hypothesis:
We thus concluded that extracellular helical apolipoproteins augment ABCA7 -associated phagocytosis by stabilizing ABCA7 .
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entailment
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bionli-en-018
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nli
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BioNLI
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en
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Premise:
Lipoproteins have a vital role in the development of metabolic and cardiovascular diseases ranging from protective to deleterious effects on target tissues. VLDL has been shown to induce lipotoxic lipid accumulation and exert a variety of negative effects on cardiomyocytes. Lipotoxicity and endoplasmic reticulum (ER) stress are proposed to be the mediators of damaging effects of metabolic diseases on cardiovascular system. We treated cardiomyocytes with lipoproteins to evaluate the adaptability of these cells to metabolic stress induced by starvation and excess of lipoproteins, and to evaluate the effect of lipoproteins and lipid accumulation on ER stress. VLDL reversed metabolic stress induced by starvation, while HDL did not. VLDL induced dose-dependent lipid accumulation in cardiomyocytes, which however did not result in reduced cell viability or induction of ER stress. Moreover, VLDL or HDL pre-treatment reduced ER stress in cardiomyocytes induced by tunicamycin and palmitic acid as measured by the expression of ER stress markers, even in conditions of increased lipid accumulation. VLDL and HDL induced activation of pro-survival ERK1/2 in cardiomyocytes; however, this activation was not involved in the protection against ER stress. Additionally, we observed that LDLR and VLDLR are regulated differently by lipoproteins and cellular stress, as lipoproteins induced VLDLR protein independently of the level of lipid accumulation.
Hypothesis:
We conclude that ER stress is not a priori detrimental for cardiomyocytes and can even have beneficial effects, enabling cell survival under starvation and attenuating VLDL .
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contradiction
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bionli-en-019
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nli
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BioNLI
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en
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Premise:
The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells.
Hypothesis:
In conclusion, SIPR2 inhibition attenuates GCDC -induced apoptosis and promotes and augments GCDC -induced JNK and Akt phosphorylation, respectively.
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contradiction
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bionli-en-020
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nli
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BioNLI
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en
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Premise:
The cerebral deposition of amyloid beta-peptide (A beta) is a histopathological characteristic of Alzheimer's disease. Because an impaired clearance of A beta might be involved in the disease, we investigated the proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Whereas rat astrocytes had a very low degradation capacity, cultivated rat microglia cells cleaved A beta. Microglia activity was considerably enhanced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters. Most of the A beta-degrading activity was released into the medium. By use of selective inhibitors the protease was characterized as a metalloprotease of approximately 200 kDa that was different from neutral endopeptidase (a neuropeptide-degrading enzyme), matrix metalloproteases, or macrophage elastase. Its activity was efficiently reduced by four hydroxamic acid-based zinc-metalloprotease inhibitors that have been shown to inhibit membrane protein secretases (disintegrins).
Hypothesis:
We conclude that A beta is degraded by microglia cells in vitro by a novel metalloprotease .
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contradiction
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bionli-en-021
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nli
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BioNLI
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en
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Premise:
The selective 5-HT2-receptor-blocking agent ritanserin is an analogue of the antihypertensive agent ketanserin. By evaluating the antihypertensive effects of ritanserin the aim of this investigation was to indirectly elucidate the mechanism of action of ketanserin. Thirteen patients with essential hypertension were treated with placebo and ritanserin, 10 mg b.i.d., in a double-blind, cross-over design (4-week periods). At the end of the treatment periods blood pressure as well as plasma concentrations of ritanserin were evaluated for 24 hours. Despite high steady state and peak plasma concentrations of ritanserin the compound did not lower the blood pressure compared with placebo.
Hypothesis:
Since chronic selective 4alpha-PDBu -receptor blockade by means of ritanserin did not lower the blood pressure, it is concluded that the 4alpha-PDBu blocking properties of ketanserin cannot alone be responsible for the antihypertensive effects of ketanserin .
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contradiction
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bionli-en-022
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nli
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BioNLI
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en
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Premise:
Chronic kidney disease (CKD) is associated with decreased renal nitric oxide (NO) production and increased plasma levels of methylarginines. The naturally occurring guanidino-methylated arginines N-monomethyl-l-arginine (l-NMMA) and asymmetric dimethyl-l-arginine (ADMA) inhibit NO synthase activity. We hypothesized that ADMA and l-NMMA compromise the integrity of the glomerular filtration barrier via NO depletion. We studied the effect of ADMA on albumin permeability (P(alb)) in isolated glomeruli and examined whether this effect involves NO- and superoxide (O(2)(*-))-dependent mechanisms. ADMA at concentrations found in circulation of patients with CKD decreased cGMP and increased P(alb) in a dose-dependent manner. A similar increase in P(alb) was caused by l-NMMA but at a concentration two orders of magnitude higher than that of ADMA. NO donor DETA-NONOate or cGMP analog abrogated the effect of ADMA on P(alb). The SOD mimetic tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in P(alb). The NO-independent soluble guanylyl cyclase (sGC) activator BAY 41-2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in P(alb). Furthermore, sGC incapacitation by the heme site-selective inhibitor ODQ increased P(alb).
Hypothesis:
We conclude that ADMA compromises the integrity of the filtration barrier by altering the bioavailability of NO and O(2)(*-) and that NO -independent activation of sGC preserves the integrity of this barrier under conditions of NO depletion.
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entailment
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bionli-en-023
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nli
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BioNLI
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en
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Premise:
Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether renin-angiotensin system (RAS) activation in the hypothalamic paraventricular nucleus (PVN) contributes to the ANG II-induced hypertensive response via interaction with neurotransmitters in the PVN. Rats underwent subcutaneous infusion of ANG II or saline for 4 weeks. These rats were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS), an angiotensin II type 1 receptor (AT1-R) antagonist, via osmotic minipump. ANG II infusion resulted in higher levels of glutamate, norepinephrine (NE), AT1-R and pro-inflammatory cytokines (PIC), and lower level of gamma-aminobutyric acid (GABA) in the PVN. Rats receiving ANG II also had higher levels of mean arterial pressure, plasma PIC, NE and aldosterone than control animals. PVN treatment with LOS attenuated these ANG II-induced hypertensive responses.
Hypothesis:
We conclude that ANG II -induced RAS activation in the PVN contributes to the RAS -mediated hypertensive response via interaction with neurotransmitters in the PVN.
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contradiction
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bionli-en-024
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nli
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BioNLI
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en
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Premise:
We examined the effect of chronic (15 days) administration of antihypertensive agents, from different pharmacologic classes, on arterial pressure (AP) and heart rate variability in two-kidney, one-clip hypertensive (2K1C) rats. The 2K1C rats received by gavage one of the following: water, ramipril, losartan, atenolol, amlodipine, or hydrochlorothiazide. Sham-operated normotensive rats received water. After 15 days of treatment AP was continuously sampled from an indwelling catheter in awake rats during a 2-h period and systolic AP and pulse interval (PI) were submitted to autoregressive spectral analysis with oscillatory components quantified in low (LF: 0.25 to 0.75 Hz) and high (HF: 0.75 to 3.0 Hz) frequency bands. The AP measured by tail-cuff was 170 +/- 2 mm Hg in 2K1C and 131 +/- 3 mm Hg in normotensive rats. Pooled data indicated that all antihypertensive agents reduced the AP of 2K1C rats to 127 +/- 2 mm Hg, whereas 2K1C rats treated with water remained hypertensive (206 +/- 11 mm Hg). Variance of systolic AP was found increased in 2K1C rats treated with water (34 +/- 2 mm Hg2), whereas 2K1C rats treated with ramipril, atenolol, amlodipine, or hydrochlorothiazide presented AP variance similar to normotensive rats (16 +/- 2 mm Hg2). Losartan normalized AP of 2K1C rats but variance of systolic AP remained increased (34 +/- 7 mm Hg2). The 2K1C rats treated with water had increased LF of systolic AP, whereas 2K1C rats treated with losartan showed higher LF of systolic AP and PI. Atenolol presented lower LF and higher HF of PI.
Hypothesis:
In conclusion, AP normalized losartan but did not reduce losartan variability, suggesting an autonomic imbalance characterized by higher sympathetic modulation of the cardiovascular system.
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contradiction
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bionli-en-025
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nli
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BioNLI
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en
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Premise:
The mechanisms generating high- frequency (HF) and low-frequency (LF) blood pressure variability (BPV) are reasonably well understood. However, little is known about the origin of very low-frequency (VLF) BPV. We tested the hypothesis that VLF BPV is generated by L-type Ca(2+) channel-dependent mechanisms. In conscious rats, arterial blood pressure was recorded during control conditions (n = 8) and ganglionic blockade (n = 7) while increasing doses (0.01-5.0 mg.100 micro l(-1).h(-1)) of the L-type Ca(2+) channel blocker nifedipine were infused intravenously. VLF (0.02-0.2 Hz), LF (0.2-0.6 Hz), and HF (0.6-3.0 Hz) BPV were assessed by spectral analysis of systolic blood pressure. During control conditions, nifedipine caused dose-dependent declines in VLF and LF BPV, whereas HF BPV was not affected. At the highest dose of nifedipine, VLF BPV was reduced by 86% compared with baseline, indicating that VLF BPV is largely mediated by L-type Ca(2+) channel-dependent mechanisms. VLF BPV appeared to be relatively more dependent on L-type Ca(2+) channels than LF BPV because lower doses of nifedipine were required to significantly reduce VLF BPV than to reduce LF BPV. Ganglionic blockade markedly reduced VLF and LF BPV and abolished the nifedipine-induced dose-dependent declines in VLF and LF BPV, suggesting that VLF and LF BPV require sympathetic activity to be evident.
Hypothesis:
In conclusion, VLF BPV is largely mediated by L-type NF449 (2+) channel-dependent mechanisms.
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contradiction
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bionli-en-026
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nli
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BioNLI
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en
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Premise:
Human blood dendritic cells (DC) comprise plasmacytoid DC (PDC) and myeloid DC (MDC), which both prime antitumor T-cell responses. We prospectively monitored blood DC in 30 chronic myeloid leukemia (CML) patients before and after imatinib mesylate therapy. We found a dramatic reduction in PDC and MDC prior treatment. This reduction was associated with high plasmatic vascular endothelial growth factor (VEGF), a central regulator of angiogenesis which also participates to tumor-associated immune deficiencies. Phenotypic analysis of DC revealed in some patients a deficient expression of BDCA-4/neuropilin-1 on PDC, a molecule involved in angiogenesis and DC-T-cell interactions. High VEGF correlated to an altered Th1/Th2 balance in vivo and shifted PDC-induced T-cell polarization towards Th2 in vitro. Upon imatinib treatment, plasmatic VEGF rapidly decreased and a normal BDCA-4 expression was restored. PDC and MDC increased but did not reach the levels observed in healthy individuals.
Hypothesis:
We conclude that VEGF may be a key player in blood DC deficiency in CML and we show that imatinib inhibits VEGF overproduction.
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entailment
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bionli-en-027
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nli
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BioNLI
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en
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Premise:
The ability of interleukin-6 (IL-6) to modulate immune parameters and mesangial cell function suggests a role for this cytokine in the development of autoimmune glomerulonephritis. This hypothesis was tested in 6-month-old female (NZB x NZW)F1 mice that were administered recombinant human IL-6 (rhIL-6) (50 and 250 micrograms/kg s.c.) for 12 weeks, resulting in an accelerated and severe form of membranoproliferative glomerulonephritis associated with marked upregulation of mesangial major histocompatibility complex class II antigen and glomerular ICAM-1 expression. To distinguish direct effects of rhIL-6 on the renal mesangium from those mediated through the immune system, (NZB x NZW)F1 mice were immunosuppressed with cyclosporin. Immunosuppression by cyclosporin inhibited the development of glomerulonephritis, decreased class II antigen expression, and abrogated IL-6-mediated effects. Administration of neutralizing anti-IL-6 antibody had no effect on the spontaneous development of glomerulonephritis in (NZB x NZW)F1 mice. This finding, together with undetectable IL-6 serum levels, makes a pathogenetic role of endogenously produced IL-6 in this disease model unlikely. In contrast to (NZB x NZW)F1 mice, parental NZW or BALB/c mice given high doses of rhIL-6 (500 micrograms/kg) or recombinant murine IL-6 (100 micrograms/kg) daily for 4 weeks failed to develop morphological or biochemical evidence of glomerulonephritis. Induction of acute phase proteins, anemia, thrombocytosis, and induction of renal class II antigen confirmed the biological activity of IL-6 in these mice.
Hypothesis:
In conclusion, while non-nephritogenic in normal mice, IL-6 accelerates the development of the genetically determined glomerulonephritis of (NZB x NZW)F1 mice through effects mediated by a modulated immune system.
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entailment
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bionli-en-028
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nli
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BioNLI
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en
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Premise:
We previously showed that the organic extract of a blue-green alga, Spirulina platensis (SPE), had potent anti-inflammatory effects in macrophages. As the interplay between macrophages and adipocytes is critical for adipocyte functions, we investigated the contribution of the anti-inflammatory effects of SPE in macrophages to adipogenesis/lipogenesis in 3T3-L1 adipocytes. 3T3-L1 preadipocytes were treated with 10% conditioned medium from lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages (CMC) or LPS-stimulated, but SPE-pretreated, macrophages (CMS) at different stages of adipocyte differentiation. The expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding protein α, peroxisome proliferator-activated receptor γ, and perilipin, was significantly repressed by CMC when added on day 3, while the repression was attenuated by CMS. Oil Red O staining confirmed that adipocyte maturation in CMS-treated cells, but not in CMC-treated cells, was equivalent to that of control cells. Nuclear translocation of nuclear factor κB (NF-κB) p65 was decreased by CMS compared to CMC. In lipid-laden adipocytes, CMC promoted the loss of lipid droplets, while CMS had minimal effects. Histone deacetylase 9 mRNA and protein levels were increased during adipocyte maturation, which were decreased by CMC.
Hypothesis:
In conclusion, by cross-talking with adipocytes, the anti-inflammatory effects of SPE in macrophages promoted adipocyte differentiation /maturation, at least in part, by repressing the activation of NF-κB inflammatory pathways, which otherwise can be compromised in inflammatory conditions.
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entailment
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bionli-en-029
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nli
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BioNLI
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en
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Premise:
The aim of this study was to further investigate the mechanism of suppression of natural killer (NK) cell cytotoxic activity in peripheral blood following strenuous exercise. Blood was collected for analysis of NK cell concentration, cytotoxic activity, CD2 surface expression and perforin gene expression from runners (RUN, n=6) and resting controls (CONTROL, n=4) pre-exercise, 0, 1.5, 5, and 24 h following a 60-min treadmill run at 80% of VO2 peak. Natural killer cytotoxic activity, measured using a whole blood chromium release assay, fluctuated minimally in the CONTROL group and increased by 63% and decreased by 43% 0 and 1.5 h post-exercise, respectively, in the RUN group (group x time, P < 0.001). Lytic index (cytotoxic activity per cell) did not change. Perforin mRNA, measured using quantitative real-time polymerase chain reaction (QRT-PCR) decreased from pre- to post-exercise and remained decreased through 24 h. The decrease from pre- to 0 h post-exercise was seen predominately in the RUN group and was inversely correlated (r=- 0.95) to pre-exercise perforin mRNA. The NK cell surface expression of CD2 (lymphocyte function-associated antigen-2) was determined using fluorescent antibodies and flow cytometry. There was no change in the proportion of NK cells expressing CD2 or CD2 density.
Hypothesis:
We conclude that (1) numerical redistribution accounted for most of the change in NK cytotoxic activity following a strenuous run, (2) increase in perforin gene expression during the run was inversely related to pre-exercise levels but did not parallel changes in cytotoxic activity, and (3) CD2 surface expression was not affected by exercise.
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contradiction
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bionli-en-030
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nli
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BioNLI
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en
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Premise:
Toll‑like receptors (TLRs) serve a vital role in activating the innate immune system by sensing conserved microbial products. Fc γ receptor IIb (FcγRIIb), the inhibitory Fc receptor, exerts its immune regulatory functions by binding to the immunoglobulin G Fc domain. Although the individual roles of TLRs and FcγRIIb have been studied intensively, the cross‑talk between FcγRIIb and TLR4 on B cells remains unknown. The present study demonstrated that FcγRIIb ligation by the immune complex (IC) attenuated the TLR4‑triggered nuclear factor (NF)‑κΒ activation, and decreased the release of interleukin (IL)‑6 from B cells, via enhancing LYN proto‑oncogene (Lyn) phosphorylation. In addition, IC treatment protected mice from lethal endotoxic shock. Accordingly, IC decreased the LPS‑induced serum levels of IL‑6, as well as intracellular IL‑6 production in B cells in vivo. However, these protective and inhibitory effects of IC were not observed in FcγRIIb‑/‑ mice.
Hypothesis:
In conclusion, the present data demonstrated that TLR4 inhibited FcγRIIb signaling in B cells by activating Lyn phosphorylation and by inhibiting NF‑κΒ signaling.
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contradiction
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bionli-en-031
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nli
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BioNLI
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en
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Premise:
We examined the intracellular metabolic fate of plasma glucose during a hyperglycemic clamp in impaired glucose-tolerant (IGT; n = 21) and normal glucose-tolerant subjects (n = 10) using a combination of [3-(3)H]glucose infusion with measurement of [(3)H]water formation and indirect calorimetry. IGT was associated with approximately 35% reduced first-phase insulin responses, normal second-phase insulin response, and 25-30% reduced insulin sensitivity, resulting in approximately 35% reduced plasma glucose disposal. This was coupled with approximately 55% reduced storage of plasma glucose (P < 0.01) and approximately 15-20% reduced glycolysis of plasma glucose (P < 0.03), accounting for approximately 75 and 25% of the reduction in glucose disposal, respectively. Decreased glucose oxidation accounted for virtually all the decrease in glycolysis. Therefore, nonoxidative glycolysis of plasma glucose in IGT was similar to that in NGT (P > 0.9) and accounted for an increased proportion of systemic glucose disposal (P < 0.05).
Hypothesis:
We conclude that, in IGT, decreased disposal of plasma glucose involves mainly decreased glycogen synthesis and to a lesser extent decreased glycolysis , which is accounted for by decreased glucose oxidation.
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entailment
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bionli-en-032
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nli
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BioNLI
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en
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Premise:
The effect of vanadium treatment on insulin-stimulated glucose transporter type 4 (GLUT4) translocation was studied in cardiac tissue of streptozotocin (STZ)-induced diabetic rats by determining the subcellular distribution of GLUT4. Four groups of rats were examined: control and diabetic, with or without bis(maltolato)oxovanadium(IV) (BMOV, an organic form of vanadium) treatment for 8 weeks. The effect of vanadium on insulin-induced GLUT4 translocation was studied at 5 min as the early insulin response and at 15 min after insulin injection as the maximal insulin response. At 5 min after insulin injection, plasma membrane GLUT4 level in the diabetic-treated group was not different from the control groups and was significantly higher than that of the insulin-stimulated diabetic group, indicating an enhancement of insulin response on GLUT4 translocation brought about by vanadium treatment. In contrast to that at 5 min after insulin injection, no significant difference in the plasma membrane GLUT4 level was observed between the diabetic and the diabetic-treated groups at 15 min after insulin injection. GLUT4 mobilization from the intracellular pool in response to insulin was also investigated at 15 min after insulin injection. Basal intracellular GLUT4 content was significantly higher in the diabetic-treated group when compared to the diabetic group under the same condition. However, the increased basal intracellular GLUT4 in the diabetic-treated group did not result in more insulin-mediated GLUT4 translocation at 15 min after insulin injection.
Hypothesis:
In conclusion, the finding that plasma membrane GLUT4 in the diabetic-treated group is not significantly higher than that of the diabetic group at 5 min but not at 15 min post-insulin injection indicates that vanadium treatment enhances insulin-mediated GLUT4 translocation in cardiac tissue by enhancing its early response.
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contradiction
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bionli-en-033
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nli
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BioNLI
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en
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Premise:
The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate beta-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 +/- 0.18, P = 0.004] amounted to 18 +/- 2 nmol/m(2) (32 +/- 4% of oral response), and its time course matched that of total insulin secretion. The beta-cell glucose sensitivity (OGTT/IV ratio = 1.52 +/- 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 +/- 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, beta-cell glucose sensitivity (75 +/- 14 vs. 156 +/- 28 pmol.min(-1).m(-2).mM(-1) of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation.
Hypothesis:
We conclude that, under physiological circumstances, incretin -mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity.
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entailment
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bionli-en-034
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nli
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BioNLI
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en
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Premise:
In glycogen-containing muscle, glycogenesis appears to be controlled by glucose 6-phosphate (6-P) provision, but after glycogen depletion, an autoinhibitory control of glycogen could be a determinant. We analyzed in cultured human muscle the contribution of glycogen depletion versus glucose 6-P in the control of glycogen recovery. Acute deglycogenation was achieved by engineering cells to overexpress glycogen phosphorylase (GP). Cells treated with AdCMV-MGP adenovirus to express 10 times higher active GP showed unaltered glycogen relative to controls at 25 mM glucose, but responded to 6-h glucose deprivation with more extensive glycogen depletion. Glycogen synthase (GS) activity ratio was double in glucose-deprived AdCMV-MGP cells compared with controls, despite identical glucose 6-P. The GS activation peak (30 min) induced by glucose reincubation dose dependently correlated with glucose 6-P concentration, which reached similar steady-state levels in both cell types. GS activation was significantly blunted in AdCMV-MGP cells, whereas it strongly correlated, with an inverse relationship, with glycogen content. An initial (0-1 h) rapid insulin-independent glycogen resynthesis was observed only in AdCMV-MGP cells, which progressed up to glycogen levels approximately 150 micrograms glucose/mg protein; control cells, which did not deplete glycogen below this concentration, showed a 1-h lag time for recovery. In summary, acute deglycogenation, as achieved by GP overexpression, caused the activation of GS, which inversely correlated with glycogen replenishment independent of glucose 6-P. During glycogen recovery, the activation promoted by acute deglycogenation rendered GS effective for controlling glycogenesis, whereas the transient activation of GS induced by the glucose 6-P rise had no impact on the resynthesis rate.
Hypothesis:
We conclude that the early insulin -independent glycogen resynthesis is dependent on the activation of GS due to GP-mediated exhaustion of glycogen rather than glucose 6-P provision.
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entailment
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bionli-en-035
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nli
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BioNLI
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en
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Premise:
Pancreatic amylin plays an important role in the control of nutrient fluxes and is an established therapy in human diabetes as it reduces post-prandial glucagon secretion and slows gastric emptying. Given the similar pathophysiology of human type-2 and feline diabetes mellitus, we investigated whether amylin reduces plasma glucagon levels in cats. Healthy cats were tested using an intravenous arginine stimulation test (IVAST), a meal response test with the test meal comprising 50% of average daily food intake, and an IV glucose tolerance test (IVGTT). Non-amyloidogenic rat amylin injected 5 min before the respective stimulus significantly reduced plasma glucagon levels under all test situations. In the IVAST and IVGTT, cats treated with amylin also had lower plasma insulin concentrations.
Hypothesis:
It was not concluded that amylin does reduce plasma glucagon levels in cats, a feature that has treatment potential in diabetic animals as co-administration of amylin would reduce the insulin requirement to control glycaemia.
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contradiction
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bionli-en-036
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nli
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BioNLI
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en
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Premise:
Anxiolytic effects of alcohol participate in the reinforcing properties of the drug, in which nucleus accumbens (NAcc) is implicated. The opioidergic system in NAcc is considered a main pathway involved in the emotional responses of animals: rats microinjected with morphine in NAcc and the systemic administration of μ-opioid receptors (MOR) agonists yield low anxiety scores in the elevated plus maze (EPM), a behavioral test of anxiety. However, the specific participation of NAcc MOR in the anxiolytic effect of ethanol has not been studied. AC5, a cAMP-synthezising adenylyl-cyclase, is highly expressed in NAcc; it is negatively coupled to MOR and has been implicated in anxiety levels of animals. We evaluated the anxiolytic effects of an intra-gastric administration of ethanol (2.5 g/kg) in animals subjected to EPM at 1, 4, and 8 h after drug or water exposure. Locomotion was assayed with the open-field test; we also measured accumbal AC5 and MOR mRNA levels by RT-PCR. After 1 h, ethanol-exposed animals showed anxiolytic-like behavior, as well as decreased and increased AC5 and MOR expression in NAcc, respectively. Intra-accumbal injection of β-funaltrexamine (FNA), a MOR antagonist, did not block ethanol-induced anxiolysis, rather it induced a tendency to increase anxiety levels in the water-exposed group. FNA partially decreased accumbal AC5 expression in ethanol-treated rats.
Hypothesis:
We concluded that AC5 in NAcc is participating in the emotional effects of ethanol; that MOR was not mediating the drug-induced AC5 reduction in NAcc nor the ethanol-induced anxiolysis.
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entailment
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bionli-en-037
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nli
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BioNLI
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en
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Premise:
Neuropathic pain is a form of pathological nociception that occurs in a significant portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. While many peripheral and central mechanisms have been implicated in neuropathic pain, central sensitization of dorsal horn spinothalamic tract (STT) neurons is a major underlying substrate. Furthermore, dysregulation of extracellular glutamate homeostasis and chronic astrocyte activation play important underlying roles in persistent hyperexcitability of these superficial dorsal horn neurons. To date, central sensitization and astrocyte changes have not been characterized in cervical SCI-induced neuropathic pain models, despite the fact that a major portion of SCI patients suffer contusion trauma to cervical spinal cord. In this study, we have characterized 2 rat models of unilateral cervical contusion SCI that behaviorally result in chronic persistence of thermal hyperalgesia in the ipsilateral forepaw. In addition, we find that STT neurons are chronically activated in both models when compared to laminectomy-only uninjured rats. Finally, persistent astrocyte activation and significantly reduced expression of the major CNS glutamate transporter, GLT1, in superficial dorsal horn astrocytes are associated with both excitability changes in STT neurons and the neuropathic pain behavioral phenotype.
Hypothesis:
In conclusion, we have characterized clinically-relevant rodent models of cervical neuropathic pain -induced contusion that result in chronic activation of both STT neurons and astrocytes, as well as compromise in astrocyte glutamate transporter expression.
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contradiction
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bionli-en-038
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nli
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BioNLI
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en
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Premise:
We measured the reduction in locomotion of unrestrained pond snails, Lymnaea stagnalis, subsequent to transdermal application of two selective octopamine antagonists, epinastine and phentolamine. After 3 h in fresh standard snail water following treatment with 4 mM epinastine or 3.5 mM phentolamine, the snails' speed was reduced to 25 and 56% of the controls (P < 0.001 and P = 0.02, respectively). The snails' speed decreased as the drug concentration increased. In the isolated CNS, 0.5 mM octopamine increased the firing rate of the pedal A cluster motoneurons, which innervate the cilia of the foot. In normal saline the increase was 26% and in a high magnesium/low calcium saline 22% (P < 0.05 and 0.01, respectively).
Hypothesis:
We conclude that octopamine antagonism reduces locomotion in Lymnaea stagnalis.
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contradiction
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bionli-en-039
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nli
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BioNLI
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en
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Premise:
The vascular effects of antiangiogenic treatment may pose problems for evaluating brain tumor response based on contrast-enhanced magnetic resonance imaging (MRI). We used serial dynamic contrast-enhanced MRI at 12 T to assess vascular responses to antiangiogenic versus steroid therapy. Athymic rats with intracerebral U87MG human glioma (n=17) underwent susceptibility-weighted perfusion MRI with ferumoxytol, a solely intravascular ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, followed by T1-weighted dynamic gadodiamide-enhanced MRI to measure vascular permeability. Rats were imaged before and after 24, 48, and 72 h of treatment with the antiangiogenic agent bevacizumab or the corticosteroid dexamethasone. Contrast agent extravasation was seen rapidly after gadodiamide, but not with ferumoxytol administration. Bevacizumab significantly decreased the blood volume and decreased permeability in tumors as determined by increased time-to-peak enhancement. A single dose of 45 mg/kg bevacizumab resulted in changes analogous to dexamethasone given in an extremely high dose (12 mg/kg per day), and was significantly more effective than dexamethasone at 2 mg/kg per day.
Hypothesis:
We conclude that dynamic perfusion MR I measurements with ferumoxytol USPIO to assess cerebral blood volume, along with dynamic gadodiamide -enhanced MR to assess vascular permeability, hold promise in more accurately detecting therapeutic responses to antiangiogenic therapy.
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entailment
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bionli-en-040
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nli
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BioNLI
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en
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Premise:
The opioid dynorphin-A (dynA) is thought to contribute to the secondary injury process following spinal cord trauma although little is known about the biochemical mechanisms involved. In the present study, we have used a combination of magnetic resonance imaging (MRI) and spectroscopy (MRS) and hindlimb motor function tests to examine the effects of intrathecal dynA infusion on rat spinal cord. Infusion of 100 nmol of dynA (1-17) caused pronounced edema development as determined by MRI at 24 h after infusion. Infusion of 100 nmol of the dynA (2-17) fragment, which does not have any activity at opiate receptors, also produced profound edema whereas 100 nmol of the low potency kappa opiate receptor ligand dynA (1-8) or artificial CSF (ACSF) did not produce any edema. Both dynA (1-17) and dynA (2-17) produced significant hindlimb motor deficits at 24 h when compared to dynA (1-8) and ACSF (P < 0.05), but the deficits in the dynA (1-17) group were significantly worse than in the dynA (2-17) treated animals (P < 0.05). Similarly, mortality in the dynA (1-17) treated animals was significantly higher than in the other groups (P = 0.002). Phosphorus MRS demonstrated that the dynA (1-17) and dynA (2-17) treated animals also had a pronounced decline in high energy phosphates in the spinal cord 24 h after infusion.
Hypothesis:
We conclude that dynA contributes to spinal cord cell death by causing metabolic failure and edema development.
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entailment
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bionli-en-041
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nli
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BioNLI
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en
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Premise:
The GATA family of transcription factors regulate tissue-specific patterns of gene expression during development. We have characterized the interaction between GATA proteins and the lactase gene promoter. Nuclear protein bound to the lactase gene GATA region cis element (-97 to -73) was analyzed by electrophoretic mobility shift assays (EMSA) and supershift assays with GATA antibodies. Lactase promoter activities were assayed in Caco-2 cells transfected with wild-type and mutated luciferase promoter-reporter constructs and GATA-4/5/6 expression constructs. EMSA with the GATA region probe yields a specific DNA-protein complex that requires the GATA factor binding site WGATAR. The complex is recognized by GATA-4- and GATA-6-specific antibodies. GATA-4/5/6 expression constructs are able to activate transcription driven by the wild-type promoter, but not by a promoter in which the GATA binding site is mutated, in Caco-2 and nonintestinal QT6 cells. GATA factor binding to the lactase cis element correlates with functional promoter activation.
Hypothesis:
We conclude that the lactase promoter is activated by the GATA family of transcription factors GATA-4 and -6.
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contradiction
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bionli-en-042
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nli
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BioNLI
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en
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Premise:
The displacement of the mitotic spindle to one side of a cell is important for many cells to divide unequally. While recent progress has begun to unveil some of the molecular mechanisms of mitotic spindle displacement, far less is known about how spindle displacement is precisely timed. A conserved mitotic progression mechanism is known to time events in dividing cells, although this has never been linked to spindle displacement. This mechanism involves the anaphase-promoting complex (APC), its activator Cdc20/Fizzy, its degradation target cyclin, and cyclin-dependent kinase (CDK). Here we show that these components comprise a previously unrecognized timer for spindle displacement. In the Caenorhabditis elegans zygote, mitotic spindle displacement begins at a precise time, soon after chromosomes congress to the metaphase plate. We found that reducing the function of the proteasome, the APC, or Cdc20/Fizzy delayed spindle displacement. Conversely, inactivating CDK in prometaphase caused the spindle to displace early. The consequence of experimentally unlinking spindle displacement from this timing mechanism was the premature displacement of incompletely assembled components of the mitotic spindle.
Hypothesis:
We conclude that in this system, asymmetric positioning of the mitotic spindle is normally delayed for a short time until the APC inactivates CDK , and that this delay ensures that the spindle does not begin to move until it is fully assembled.
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entailment
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bionli-en-043
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nli
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BioNLI
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en
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Premise:
Cellular senescence is a restricting factor for regenerative therapies with somatic stem cells. We showed previously that the onset of cellular senescence inhibits the osteogenic differentiation in stem cells of the dental follicle (DFCs), although the mechanism remains elusive. Two different pathways are involved in the induction of the cellular senescence, which are driven either by the cell cycle protein P21 or by the cell cycle protein P16. In this study, we investigated the expression of cell cycle proteins in DFCs after the induction of cellular senescence. The induction of cellular senescence was proved by an increased expression of β-galactosidase and an increased population doubling time after a prolonged cell culture. Cellular senescence regulated the expression of cell cycle proteins. The expression of cell cycle protein P16 was up-regulated, which correlates with the induction of cellular senescence markers in DFCs. However, the expression of cyclin-dependent kinases (CDK)2 and 4 and the expression of the cell cycle protein P21 were successively decreased in DFCs.
Hypothesis:
In conclusion, our data suggest that a P16 -dependent pathway drives the induction of cellular senescence in DFCs.
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entailment
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bionli-en-044
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nli
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BioNLI
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en
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Premise:
Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21(WAF1/CIP1), a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21(WAF1/CIP1) in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21(WAF1/CIP1) expression in a dose-dependent manner (ED(50)=103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21(WAF1/CIP1) synergistically. Upregulation of p21(WAF1/CIP1) paralleled DAC-induced apoptosis (ED(50)=153 nM). Low doses of DAC induced gamma-H2AX expression (ED(50)=16.5 nM) and upregulated p21(WAF1/CIP1) in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-alpha or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21(WAF1/CIP1) upregulation, indicating that DAC upregulation of p21(WAF1/CIP1) was p53- and ATM-dependent in leukemia cells.
Hypothesis:
In conclusion, DAC upregulates TGFs beta (WAF1/CIP1) in DNMT-independent manner via the DNA damage/ATM/p53 axis.
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contradiction
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bionli-en-045
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nli
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BioNLI
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en
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Premise:
The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by bacterial RNA polymerase (RNAP). Biochemical results indicate that inhibition of transcription occurs at the level of NTP uptake or NTP binding by RNAP. Genetic results indicate that inhibition of transcription requires an extensive determinant, comprising more than 50 amino acid residues, within the RNAP secondary channel (also known as the "NTP-uptake channel" or "pore"). Biophysical results indicate that inhibition of transcription involves binding of MccJ25 within the RNAP secondary channel. Molecular modeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel.
Hypothesis:
We conclude that MccJ25 inhibits transcription by obstructing the RNAP secondary channel.
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contradiction
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bionli-en-046
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nli
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BioNLI
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en
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Premise:
Oral glucose was recommended as pain therapy during venepuncture in neonates. It is unclear whether this intervention reduces excess oxygen consumption (o(2)), energy loss, or cardiovascular destabilization associated with venepuncture, and whether <2 mL glucose solution is effective. We tested the hypothesis that oral glucose solution attenuates the increases in neonatal oxygen consumption, energy expenditure (EE), and heart rate associated with venepuncture for two different volumes of glucose solution (2 and 0.4 mL). In this prospective, randomized, controlled, double-blind trial, 58 neonates (gestational age, 31-42 wk; postnatal age, 1-7 d) were randomized to 2 mL glucose 30%, 0.4 mL glucose 30%, or 2 mL water by mouth before venepuncture. The videotaped behavioral pain reactions were scored with the Premature Infant Pain Profile. Cry duration, o(2), EE (indirect calorimetry), and heart rate were measured. The 2 mL glucose solution reduced pain score and crying after venepuncture compared with controls [median pain score, 5.5 (interquartile range, 4-9) versus 11 (7-12), p = 0.01; median duration of first cry, 0 s (0-43 s) versus 13 s (2-47 s), p < 0.05, respectively]. The 0.4 mL glucose solution had no effect. The 2 mL glucose solution did not attenuate the o(2) increase during venepuncture (1.5 +/- 0.2 mL/kg min (water) versus 1.7 +/- 0.5 (0.4 mL glucose) versus 1.1 +/- 0.2 (2 mL glucose) (mean +/- SEM) nor EE nor heart rate.
Hypothesis:
We conclude that oral administration of 2 mL glucose 30% before venepuncture reduced pain expression and crying, but did not prevent the rise in o(2), EE, or heart rate.
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entailment
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bionli-en-047
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nli
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BioNLI
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en
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Premise:
The objective of this randomized, double-blind, placebo-controlled clinical trial was to determine whether a topical anesthetic agent (tetracaine) provides effective local analgesia prior to radial arterial puncture. Tetracaine or placebo gel was applied 45 min prior to arterial puncture to patients who were referred for elective arterial blood gas. The primary outcome was the patient's perception of pain associated with the procedure as measured by a visual analog scale. Fifty patients were randomized into the study, 24 received tetracaine and 26 placebo. Mean pain score on the visual analog scale was 26.2 +/- 32.6 for the tetracaine-treated patients and 23.8 +/- 27.4 for the placebo-treated patients (P = 0.78). Mean time from the first skin puncture to successful procurement of 1 ml of arterial blood was 70 +/- 103s in the tetracaine group and 49 +/- 48s in the placebo group (P = 0.40). Difficulty of arterial puncture as assessed by the respiratory therapist performing the test was identical for the two groups (P = 0.86).
Hypothesis:
We conclude that pain gel did not decrease patient's perception of tetracaine associated with arterial puncture, nor did its use facilitate the ABG procedure.
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contradiction
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bionli-en-048
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nli
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BioNLI
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en
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Premise:
We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002).
Hypothesis:
We conclude that dexmedetomidine attenuates increases in heart rate and plasma Frago concentrations during emergence from anesthesia.
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contradiction
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bionli-en-049
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nli
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BioNLI
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en
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Premise:
The interaction in the rat between intrathecal morphine and local anesthetics (bupivacaine and lidocaine) on nociception (52.5 degrees C hot plate and paw pressure), motor function, and autonomic function (blood pressure [BP] and heart rate [HR]) was examined over a range of doses for both morphine and the local anesthetics. High doses of intrathecal bupivacaine (75 micrograms) or lidocaine (500 micrograms) produced motor block and hypotension (150 micrograms bupivacaine) lasting approximately 15 and 7 min, respectively, whereas low doses of intrathecal bupivacaine (25 micrograms) and lidocaine (100 micrograms) produced only a transient motor weakness lasting 2 min or less. Alone, neither agent altered the hot plate or paw pressure response at doses, or at times, where the agents had no effect upon motor function. In contrast, at the low dose of either local anesthetic, after the resolution of the transient motor weakness, these doses resulted in a significant leftward shift in the dose-response curves for intrathecal morphine on both the hot plate and paw pressure, as measured by the maximum observed peak effect and by the area under the time-effect curve. Thus, for example, the morphine ED50 (95% confidence intervals) for morphine/saline was 1.7 micrograms (0.7-1.9) on the hot plate and 1.1 micrograms (0.8-1.4) on the paw pressure versus for morphine/bupivacaine (25 micrograms): hot plate 0.25 micrograms (0.21-0.42) and paw pressure 0.28 micrograms (0.2-0.4). Intrathecal morphine was not observed to have any effect on the dose-dependent effects of intrathecal bupivacaine on motor or autonomic blockade. Comparable results were also observed with lidocaine (bupivacaine was found to have no significant effect on spinal cord morphine clearance).
Hypothesis:
We conclude that low doses of intrathecal lidocaine and bupivacaine , which alone have no antinociceptive effect, at times when motor function was clearly unimpaired, are able to significantly augment the antinociceptive activity of intrathecal morphine on the hot plate and paw pressure tests.
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entailment
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bionli-en-050
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nli
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BioNLI
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en
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Premise:
In a double-blind randomised study, we examined if pretreatment with small doses of midazolam, given before anaesthesia induction with fentanyl, influences the occurrence of fentanyl-induced thoracic rigidity (FITR). At the same time, the effect of rigidity on the cardiovascular and respiratory system was assessed. Sixteen patients undergoing coronary artery bypass surgery were divided into two groups. The midazolam group (M) received 0.075 mg/kg midazolam i.v. and the placebo group (P) NaCl 0.9% 3 min before the start of fentanyl induction. During the induction period, FITR was assessed clinically on a 3-point scale. Haemodynamic and respiratory variables were collected before anaesthesia induction, at the end of the fentanyl infusion and 3 min after intubation. The incidence of FITR was high in both groups: 63% in Group M and 75% in Group P (n.s.); however, its severity was less in Group M. The appearance of rigidity affected the cardiovascular and the respiratory system: central venous and pulmonary capillary wedge pressures showed a sharp increase in patients with FITR accompanied by CO2 retention, due to an inability to ventilate these patients adequately.
Hypothesis:
We conclude that small doses of midazolam do not prevent, but may attenuate, FITR and that the appearance of rigidity causes alterations of haemodynamic and respiratory variables during induction.
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entailment
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bionli-en-051
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nli
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BioNLI
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en
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Premise:
Radio-frequency ablation (RFA) is used as a minimally invasive treatment for inoperable hepatic tumors. Immunological reactions secondary to RFA may play a role in the observed tumor control. In our study, the VX2 carcinoma was implanted into the liver of rabbits. After 3 weeks, tumors were treated with RFA or were left untreated. Peripheral blood lymphocytes were harvested before tumor implantation, 2 weeks postoperatively and at 2-week intervals thereafter. T cells were stimulated with lysates of either tumor tissue or nontumorous liver loaded on autologous antigen-presenting cells and their stimulation index was determined by [(3)H]thymidine incorporation. A 3-fold increase over background or controls was considered significant. Stimulation with phytohemagglutinin served as a positive control. The animals were necropsied, and liver and tumor tissue were analyzed immunohistologically for T-cell infiltration. T cells from tumor-bearing (n = 9) and RFA-treated (n = 11) animals were investigated in a follow-up study. The mean postoperative observation was 45 days. All of the 11 RFA-treated animals exhibited circulating T cells activated specifically toward tumor antigens throughout the observation period, which was accompanied by dense T-cell infiltration. In contrast, T cells of untreated tumor-bearing rabbits showed no reaction and only sparse T cell infiltration.
Hypothesis:
We concluded that RFA induces a tumor -specific T-cell reaction in the otherwise unreactive tumor -bearing host, apparently overcoming immune tolerance and leading to the presentation of otherwise cryptic tumor antigens.
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entailment
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bionli-en-052
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nli
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BioNLI
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en
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Premise:
The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1'-hydroxylation) activities were examined using pooled human liver microsomes. The in vivo drug interactions of gemfibrozil were predicted in vitro using the [I]/([I] + K(i)) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a K(i) (IC(50)) value of 5.8 (9.6) microM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, with K(i) (IC(50)) values of 24 (47) microM and 82 (136) microM, respectively. With concentrations up to 250 microM, gemfibrozil showed no appreciable effect on CYP2A6, CYP2D6, CYP2E1, and CYP3A4 activities. Based on [I]/([I] + K(i)) values calculated using peak total (or unbound) plasma concentration of gemfibrozil, 96% (56%), 86% (24%), and 64% (8%) inhibition of the clearance of CYP2C9, CYP2C19, and CYP1A2 substrates could be expected, respectively.
Hypothesis:
In conclusion, CYP2C9 inhibits the activity of gemfibrozil at clinically relevant concentrations, and this is the likely mechanism by which CYP2C9 interacts with gemfibrozil substrate drugs, such as warfarin and glyburide.
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contradiction
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bionli-en-053
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nli
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BioNLI
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en
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Premise:
Tofisopam is an anxiolytic agent of the BZD group, chemically 1(3-4 dimethoxyphenyl)-4methyl-5-ethyl-7,8 dimethoxy-5H-2,3-benzodiazepine. TZP differs from the traditional 1,4-benzodiazepines regarding the positions of the nitrogen atoms. Three clinical cases were reported where tofisopam increased the blood level of immunosuppressive agent leading clinically relevant adverse drug reaction and necessitating reduction of the dose of the drugs or discontinuation of the administration of tofisopam. The administered immunosuppressive agent is a substrate of the CYP3A4 system, so the effect of tofisopam on the CYP3A4 enzyme was investigated in vitro using human recombinant CYP3A4 supersome. Benzyoxy-4-(trifluoromethyl)-coumarin (BFC) was used as substrate. Tofisopam in 0.1, 0.25, 0.5, 0.75, 1 and 5 micromol/l concentrations inhibited dose dependently the enzyme activity. Activity inhibition rates were 4%, 29%, 40%, 56%, 61% and 94%, respectively and the IC50 was 0.8 micromol/l. The IC50 of positive control substance ketoconazole was 0.03 micromol/l. In in vitro experiments the inhibitory effect of tofisopam was lower than that of ketoconazole (potent CYP3A4 inhibitor) with an order of magnitude.
Hypothesis:
According to the in vitro results it could be concluded that tofisopam is an inhibitor of CYP3A4 but to clarify the clinical importance of this promotion further human clinical data are needed.
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contradiction
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bionli-en-054
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nli
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BioNLI
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en
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Premise:
In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs.
Hypothesis:
In conclusion, these results strongly indicate that 24R,25( Gastric Cancer )(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.
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contradiction
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bionli-en-055
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nli
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BioNLI
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en
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Premise:
Hepatocarcinogenesis is a complex multifactorial process in which continuous intrahepatic inflammation plays a major role. Although inflammatory cell infiltration is observed in the process of chemical-induced hepatocarcinogenesis, the pathophysiological role of the inflammatory response is not well defined. To approach this question, molecular and cellular responses were monitored during the development of liver tumors in mice exposed to a chemical hepatocarcinogen, diethylnitrosamine (DEN), in drinking water (50 microg/l). Intrahepatic type I and type II interferon (IFN-beta and IFN-gamma, respectively) mRNA expression was found to be induced 2 months before the appearance of hepatocellular carcinomas. The pathogenetic importance of IFNs was determined by monitoring tumor development in mice genetically deficient in the IFN-alpha/beta receptor (IFN-alpha/betaR KO) or the IFN-gamma receptor (IFN-gammaR KO). IFN-gammaR KO mice developed fewer tumors than IFN-alpha/betaR KO and wild-type (wt) mice, although the tumor diameters did not differ significantly among the three lineages. Interestingly, immunohistochemical studies demonstrated that the percentage of monocytes/macrophages in infiltrating mononuclear cells was reduced greatly in the livers of IFN-gammaR KO mice, which is consistent with the facts that intrahepatic cytokine expression was diminished and oxidative DNA damage was induced to a lesser extent.
Hypothesis:
In conclusion, type II IFN, but not type I IFNs, may be involved critically in the initiation stage, but not the promotion stage, of DEN -induced hepatocarcinogenesis by enhancing monocytes/macrophages activation and eventual hepatocyte DNA damage .
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entailment
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bionli-en-056
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nli
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BioNLI
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en
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Premise:
The effects of age on the utilization of dietary palmitic or a 50/50 mixture of palmitic and oleic acid at the 8% inclusion level in the absence or presence of .2% cholic acid and also in the presence of low (.8%) or high (1.2%) calcium were investigated using broiler chicks from 1 to 56 days of age. Significant interactions (P less than .01) were observed between the type of fatty acid supplemented and the presence or absence of cholic acid on weight gain and feed efficiency. Supplementing diets with a mixture of equal weights of palmitic and oleic acid, reduced feed intake relative to control diets and diets supplemented with palmitic acid alone. There was an interaction between the age of the bird and the type of fatty acid supplemented on fat retention and metabolizable energy (ME) of diets (P less than .01). There was also a significant interaction between the type of fatty acid supplemented and the addition of cholic acid on fat retention and ME of diets. While cholic acid reduced soap formation during the process of digestion (P less than .05), increasing dietary calcium level increased the proportion of the digesta fat that was present as soap (P less than .01). The proportion of digesta and excreta fat, present as soap, depended on the type of fatty acid supplemented. The addition of free fatty acids to broiler diets resulted in a decrease in bone ash and bone calcium content relative to those birds fed the control diet.
Hypothesis:
It is concluded that the ability of broilers to utilize dietary free fatty acid s depends on the age at which they are fed, although in all cases supplemental cholic acid enhances fatty acid utilization.
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entailment
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bionli-en-057
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nli
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BioNLI
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en
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Premise:
The objective of this study was to assess the potential importance of calcitonin (CALC) in the onset of subclinical hypocalcemia (experiment 1) and in the physiological mechanisms underlying the prevention of bovine hypocalcemia under metabolic acidosis (experiments 2 and 3). In experiment 1, 15 Holstein cows naturally incurring subclinical hypocalcemia during the first 5d postpartum were classified as low subclinical hypocalcemia (LSH) when blood Ca concentrations were between 7.5 and 8.5mg/dL, or as high subclinical hypocalcemia (HSH) when blood Ca concentrations were between 6.0 and 7.6 mg/dL. Blood samples were taken daily from d -5 to 5 relative to parturition to determine concentrations of parathyroid hormone (PTH), CALC, and 1,25(OH)2D3. In experiment 2, 24 Holstein bulls (497 ± 69 kg of body weight and 342 ± 10.5d of age) were assigned to 2 treatments (metabolic acidosis or control). Metabolic acidosis was induced by an oral administration of ammonium chloride (2.5 mEq/d) during 10 d, and animals were slaughtered thereafter. Blood samples were collected before slaughter to determine CALC, PTH, 1,25(OH)2D3, and samples of urine, kidney, parathyroid, and thyroid glands were obtained immediately after slaughter to determine expression of several genes in these tissues. Last, in experiment 3, we tested the activity of CALC under metabolic acidosis in vitro using breast cancer cell (T47D) cultures. Although PTH tended to be greater in HSH than in LSH, the levels of 1,25(OH)2D3 were lower in HSH cows (experiment 1). Blood CALC concentration was not affected by the severity of subclinical hypocalcemia, but it was influenced by days from calving (experiment 1). The expression of PTH receptor (PTHR) in the kidney was increased under metabolic acidosis (experiment 2). Furthermore, the activity of CALC was impaired under acidic blood pH (experiment 3).
Hypothesis:
In conclusion, the CALC rise in HSH cows after calving impaired the recovery of blood Ca concentrations because the PTHR response was not sufficient to activate 1,25( Intramedullary tumors )2D3 and compensate for the CALC effect.
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contradiction
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bionli-en-058
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nli
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BioNLI
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en
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Premise:
Vanadium in the metavanadate form (VO3-) is a powerful inhibitor of Na+, K+-ATPase. Because of the similarity between the oxy anions of vanadium and phosphorus, it was of interest to see whether Al(OH)3 would restrict the intestinal absorption of vanadium, as it does that of phosphorus. VO3- was extensively bound to a suspension of Al(OH)3 at pH 5-8. Sprague-Dawley rats (180-300 g) were fasted overnight and gavaged with 5 mumol Na3 VO4 in 1.0 ml 0.9% NaCl containing 1 microCi 48V. Control animals (n = 12) simultaneously received 1.0 ml diluent and experimental animals (n = 12) received 1 ml Al(OH))3. Diluent and Al(OH)3 were then given daily for 4 d. Urine and feces were collected separately each day. In control animals total 48V recovery (stool and urine) over 4 d was 86.6 +/- 2.4% of the administered dose. Although Al(OH)3 insignificantly increased total 48V recovery (93.6 +/- 3.2%), it markedly increased excretion of 48V in the stool as compared to the urine (control: stool, 69.1 +/- 1.8%; urine, 12.5 +/- 1.3%; Al(OH)3: stool, 85.7 +/- 1.5%; urine, 7.9 +/- 1.8%). Animals were then sacrificed and tissue uptake of tracer measured. The pattern of unexcreted 48V in tissue of both groups was kidney greater than bone greater than liver greater than intestine greater than muscle, but the tissue levels were uniformly higher in controls than in Al(OH)3-treated animals. The ability of Al(OH)3 to remove endogenous VO3- was also examined. 48V was injected ip (n = 20). Half of the animals received diluent and half received 1.0 ml Al(OH)3 by gavage daily for 4 d. There were no differences in the pattern of 48V tissue distribution and excretion.
Hypothesis:
It is concluded that Al (OH)3 may prevent tissue accumulation of VO3- from dietary sources by reducing intestinal VO3- absorption.
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entailment
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bionli-en-059
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nli
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BioNLI
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en
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Premise:
Mechanistic and epidemiologic studies provide considerable evidence for a protective association between calcium intake and incident colorectal cancer (CRC). While the relationship has not been substantiated by short-duration randomized controlled trials (RCTs) of CRC, trials do show a benefit on adenomas, a precursor to CRC. To address some of this inconsistency, we conducted dose-response meta-analyses by sources of calcium intake, based on prospective observational studies published up to December 2013 identified from PubMed, Embase, and BIOSIS. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. For total calcium intake, each 300 mg/day increase was associated with an approximately 8% reduced risk of CRC (summary RR = 0.92, 95% CI = 0.89-0.95, I(2) = 47%, 15 studies with 12,305 cases, intake = 250-1,900 mg/day, follow-up = 3.3-16 years). While the risk decreased less steeply in higher range of total calcium intake (P(non-linearity) = 0.04), the degree of curvature was mild and statistical significance of non-linearity was sensitive to one study. For supplementary calcium, each 300 mg/day increase was associated with an approximately 9% reduced risk of CRC (summary RR = 0.91, 95% CI = 0.86-0.98, I(2) = 67%, six studies with 8,839 cases, intake = 0-1,150 mg/day, follow-up = 5-10 years). The test for non-linearity was not statistically significant (P(non-linearity) = 0.11).
Hypothesis:
In conclusion, both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1,000 mg/day.
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entailment
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bionli-en-060
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nli
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BioNLI
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en
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Premise:
Mitigation of methanogenesis in ruminants has been an important goal for several decades. Free lauric acid, known to suppress ruminal methanogenesis, has a low palatability; therefore, in the present study the aim was to evaluate the mitigation efficacy of its esterified form (monolaurin). Further, 13C-isotope abundance (delta13C) and 13C-12C fractionation during methanogenesis and fermentation were determined to evaluate possible microbial C-isotope preferences. Using the rumen simulation technique, four basal diets, characterised either by the C3 plants grass (hay) and wheat (straw and grain), or the C4 plant (13C excess compared with C3 plants) maize (straw and grain), and a mixture of the latter two, were incubated with and without monolaurin (50 g/kg dietary DM). Added to hay, monolaurin did not significantly affect methanogenesis. When added to the other diets (P < 0.05 for the wheat-based diet) methane formation was lowered. Monolaurin decreased fibre disappearance (least effect with the hay diet), acetate:propionate ratio, and protozoal counts. Feed residues and SCFA showed the same delta13C as the diets. Methane was depleted in 13C while CO2 was enriched in 13C compared with the diets. Monolaurin addition resulted in 13C depletion of CO2 and enrichment in CH4 (the latter only in the hay diet).
Hypothesis:
In conclusion, monolaurin proved to effectively decrease methanogenesis in the straw-grain diets although this effect might partly be explained by the concomitantly reduced fibre disappearance.
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entailment
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bionli-en-061
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nli
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BioNLI
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en
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Premise:
We examined the ability of sucralfate to prevent secretagogue induced duodenal ulcer in the rat. Sucralfate was administered orally in dosage schedules of 50 mg, 100 mg or 200 mg before and at 3 and 6 hr after commencing a 24 hr continuous infusion of pentagastrin and bethanechol. The animals were sacrificed at 24 hr and the number and severity of ulcers was scored. Ulcers developed in all 9 control rats, in 8 of 9 on the 50 mg dose, in 4 of 9 on the 100 mg dose, and in only 1 of 9 on the 200 mg dose of sucralfate.
Hypothesis:
We conclude that tubastatin A prevents the formation of secretagogue induced duodenal ulcer in the rat.
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contradiction
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bionli-en-062
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nli
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BioNLI
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en
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Premise:
The inhibitory effect of duodenal exposure to acid and hyperosmolal solutions on pentagastrin-stimulated gastric acid secretion was studied in conscious rats equipped with chronic gastric fistula and duodenal Thiry-Vella loop. The loop was challenged with saline, HCl or hyperosmolal polyethylene glycol. Gastric acid secretion was measured in samples from the gastric fistula. Gut peptide concentrations were measured in duodenal perfusates collected each 30 min, and in plasma samples collected both during stimulated acid secretion alone, and at the end of experiments in combination with luminal challenges of the loops. During pentagastrin-stimulated gastric acid secretion, luminal perfusion of the duodenal loop with acid caused inhibition of acid secretion (P < 0.001) and a prominent release of somatostatin both to the lumen (P < 0.001) and to the circulation (P < 0.05). Also, neurotensin (P < 0.01) and vasoactive intestinal peptide (P < 0.01) were released to the lumen, but not to the circulation. Upon perfusion of the duodenal loop with hyperosmolal polyethylene glycol, acid secretion was inhibited (P < 0.05) and somatostatin alone was released to the luminal side (P < 0.01).
Hypothesis:
We conclude that luminal perfusion of the duodenal loop with acid causes inhibition of pentagastrin -stimulated gastric acid secretion .
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contradiction
|
bionli-en-063
|
nli
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BioNLI
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en
|
Premise:
In this study, we evaluated factors that affect esophageal acid clearance in normal subjects. A 15-ml bolus of 0.1 N HCl (pH 1.2) was injected into the esophagus, and the subject then swallowed every 30 s. Manometric and pH monitoring demonstrated that esophageal acid clearance occurred by a series of step increases in pH, each associated with a swallow-induced peristaltic sequence. Between peristaltic sequences, pH increase was minimal. Saliva stimulation by oral lozenge greatly improved acid clearance, while oral aspiration of saliva abolished the step increases in esophageal pH and markedly delayed acid clearance. Replacement of aspirated saliva with a bicarbonate solution reproduced the step increases in esophageal pH and restored acid clearance toward normal, while replacement with water alone failed to improve acid clearance. Similar to the effect of the oral lozenge, bethanechol (5 mg subcutaneously) improved esophageal acid clearance, but this improvement was reversed by oral aspiration of saliva, which markedly delayed acid clearance. A change from the recumbent to the sitting position tended to improve acid clearance slightly, but this improvement was not statistically significant.
Hypothesis:
We concluded that in normal subjects (a) swallowing carries saliva into the esophagus and peristalsis empties intraesophageal fluid into the stomach, (b) the neutralization of acid by saliva carried into the esophagus with each swallow accounts for the occurrence of acid clearance by pH increases in step , (c) the improvement in acid clearance with bethanechol is due to saliva stimulation, and (d) gravity contributes little to esophageal acid clearance in the presence of normal peristaltic stripping waves.
|
contradiction
|
bionli-en-064
|
nli
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BioNLI
|
en
|
Premise:
The effect of cisapride, a new gastrokinetic drug, on gastric emptying and duodenogastric reflux of bile salts was tested in healthy volunteers in a placebo-controlled double-blind randomized cross-over trial. Twenty subjects were treated with either 10 mg of cisapride, tid orally or with matching placebo tablets for 1 wk. On test days, the subjects were studied using a marker technique with gastric intubation in the fasting state and after feeding a mixed liquid meal. Cisapride did not affect gastric secretion and gastric emptying. There was a tendency to lower reflux rates after cisapride treatment both fasting (0.63 +/- 0.14 versus 0.38 mumol/min +/- 0.05 SEM) and after feeding (2.60 +/- 0.61 versus 1.88 mumol/min +/- 0.33 SEM). This was due to a decrease of high placebo reflux rates: the reduction of reflux rate achieved by cisapride was significantly correlated to the height of the placebo reflux rate (p less than 0.001). A similar relationship was found for gastric bile salt concentration (p less than 0.001).
Hypothesis:
It is concluded that cisapride reduces high bile salt reflux.
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entailment
|
bionli-en-065
|
nli
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BioNLI
|
en
|
Premise:
The aim of this study was to evaluate the nervous and humoral pathways involved in short-chain fatty acid (SCFA)-induced ileal brake in conscious pigs. The role of extrinsic ileal innervation was evaluated after SCFA infusion in innervated and denervated Babkin's ileal loops, and gastric motility was measured with strain gauges. Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) concentrations were evaluated in both situations. The possible involvement of absorbed SCFA was tested by using intravenous infusion of acetate. Ileal SCFA infusion in the intact terminal ileum decreased the amplitude of distal and terminal antral contractions (33 +/- 1.2 vs. 49 +/- 1.2% of the maximal amplitude recorded before infusion) and increased their frequency (1.5 +/- 0.11 vs. 1.3 +/- 0.10/min). Similar effects were observed during SCFA infusion in ileal innervated and denervated loops (amplitude, 35 +/- 1.0 and 34 +/- 0. 8 vs. 47 +/- 1.3 and 43 +/- 1.2%; frequency, 1.4 +/- 0.07 and 1.6 +/- 0.06 vs. 1.1 +/- 0.14 and 1.0 +/- 0.12/min). Intravenous acetate did not modify the amplitude and frequency of antral contractions. PYY but not GLP-1 concentrations were increased during SCFA infusion in innervated and denervated loops.
Hypothesis:
We conclude that extrinsic ileal innervation mediates SCFA -induced brake of gastric motility .
|
contradiction
|
bionli-en-066
|
nli
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BioNLI
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en
|
Premise:
It is commonly accepted that L-type Ca(2+) channel-mediated Ca(2+)-induced Ca(2+) release (CICR) is the dominant mode of excitation-contraction (E-C) coupling in the adult mammalian heart and that there is no appreciable CICR in neonates. However, we have observed that cell contraction in the neonatal heart was significantly decreased after sarcoplasmic reticulum (SR) Ca(2+) depletion with caffeine. Therefore, the present study investigated the developmental changes of CICR in rabbit ventricular myocytes at 3, 10, 20, and 56 days of age. We found that the inhibitory effect of the L-type Ca(2+) current (I(Ca)) inhibitor nifedipine (Nif; 15 microM) caused an increasingly larger reduction of Ca(2+) transients on depolarization in older age groups [from approximately 15% in 3-day-old (3d) myocytes to approximately 90% in 56-day-old (56d) myocytes]. The remaining Ca(2+) transient in the presence of Nif in younger age groups was eliminated by the inhibition of Na(+)/Ca(2+) exchanger (NCX) with the subsequent addition of 10 microM KB-R7943 (KB-R). Furthermore, Ca(2+) transients were significantly reduced in magnitude after the depletion of SR Ca(2+) with caffeine in all age groups, although the effect was significantly greater in the older age groups (from approximately 40% in 3d myocytes up to approximately 70% in 56d myocytes). This SR Ca(2+)-sensitive Ca(2+) transient in the earliest developmental stage was insensitive to Nif but was sensitive to the subsequent addition of KB-R, indicating the presence of NCX-mediated CICR that decreased significantly with age (from approximately 37% in 3d myocytes to approximately 0.5% in 56d myocytes). In contrast, the I(Ca)-mediated CICR increased significantly with age (from approximately 10% in 3d myocytes to approximately 70% in 56d myocytes). The CICR gain as estimated by the integral of the CICR Ca(2+) transient divided by the integral of its Ca(2+) transient trigger was smaller when mediated by NCX ( approximately 1.0 for 3d myocytes) than when mediated by I(Ca) ( approximately 3.0 for 56d myocytes).
Hypothesis:
We conclude that the lower-efficiency NCX -mediated CICR is a predominant mode of CICR in the earliest developmental stages that gradually decreases as the more efficient L-type Ca(3+) channel-mediated CICR increases in prominence with ontogeny.
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contradiction
|
bionli-en-067
|
nli
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BioNLI
|
en
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Premise:
GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (INaP) and late (INaL) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of INaL (63%) to a significantly greater extent than INaP (19%). However, GS967 also caused a reduction of INaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of INaP (IC50 = 0.07 µM) than ranolazine (16 µM) and lidocaine (17 µM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic INaL block.
Hypothesis:
We conclude that GS967 is a preferential inhibitor of INaL , but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.
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entailment
|
bionli-en-068
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nli
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BioNLI
|
en
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Premise:
We used the whole cell patch clamp technique to study transient outward currents of single rabbit atrial cells. A large transient current, IA, was blocked by 4-aminopyridine (4AP) and/or by depolarized holding potentials. After block of IA, a smaller transient current remained. It was completely blocked by nisoldipine, cadmium, ryanodine, or caffeine, which indicates that all of the 4AP-resistant current is activated by the calcium transient that causes contraction. Neither calcium-activated potassium current nor calcium-activated nonspecific cation current appeared to contribute to the 4AP-resistant transient current. The transient current disappeared when ECl was made equal to the pulse potential; it was present in potassium-free internal and external solutions. It was blocked by the anion transport blockers SITS and DIDS, and the reversal potential of instantaneous current-voltage relations varied with extracellular chloride as predicted for a chloride-selective conductance.
Hypothesis:
We conclude that the calcium transient that causes contraction in rabbit atrial cells activates a chloride -selective conductance and that this conductance contributes to the 4AP-resistant transient current.
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contradiction
|
bionli-en-069
|
nli
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BioNLI
|
en
|
Premise:
Phospholemman (PLM) expression was increased in rat hearts after myocardial infarction (MI). Overexpression of PLM in normal adult rat cardiac myocytes altered contractile function and cytosolic Ca(2+) concentration ([Ca(2+)](i)) homeostasis in a manner similar to that observed in post-MI myocytes. In this study, we tested whether PLM downregulation in normal adult rat myocytes resulted in contractility and [Ca(2+)](i) transient changes opposite to those observed in post-MI myocytes. Compared with control myocytes infected with adenovirus (Adv) expressing green fluorescent protein (GFP) alone, myocytes infected with Adv expressing both GFP and rat antisense PLM (rASPLM) had 23% less PLM protein (P < 0.012) at 3 days, but no differences were found in sarcoplasmic reticulum (SR) Ca(2+)-ATPase, Na(+)/Ca(2+) exchanger (NCX1), Na(+)-K(+)-ATPase, and calsequestrin levels. SR Ca(2+) uptake and whole cell capacitance were not affected by rASPLM treatment. Relaxation from caffeine-induced contracture was faster, and NCX1 current amplitudes were higher in rASPLM myocytes, indicating that PLM downregulation enhanced NCX1 activity. In native rat cardiac myocytes, coimmunoprecipitation experiments indicated an association of PLM with NCX1. At 0.6 mM [Ca(2+)](o), rASPLM myocytes had significantly (P < 0.003) lower contraction and [Ca(2+)](i) transient amplitudes than control GFP myocytes. At 5 mM [Ca(2+)](o), both contraction and [Ca(2+)](i) transient amplitudes were higher in rASPLM myocytes. This pattern of contractile and [Ca(2+)](i) transient behavior in rASPLM myocytes was opposite to that observed in post-MI rat myocytes.
Hypothesis:
We conclude that downregulation of PLM in normal rat cardiac myocytes enhanced NCX1 function and affected [Ca(2+)](i) transient and contraction amplitudes.
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entailment
|
bionli-en-070
|
nli
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BioNLI
|
en
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Premise:
A rise in [K+]o, by depolarizing the resting membrane potential and partially inactivating the inward Na+ current (INa), is believed to play a critical role in slowing conduction during myocardial ischemia. In multicellular ventricular preparations, elevation of [K+]o has been suggested to decrease Vmax to a greater extent than expected from membrane depolarization alone. The mechanism of this voltage-independent effect of [K+]o is currently unknown, and its significance in single cardiac cells has not been determined. We have examined the voltage-independent effects of elevated [K+]o on INa and the action potential upstroke in isolated rabbit atrial and ventricular myocytes under voltage- and current-clamp conditions. Superfusate [K+] was varied from 5 mmol/L to 14 or 24 mmol/L, whereas [Na+] was maintained at 150 mmol/L. In cultured atrial cells and excised outside-out patches from freshly isolated atrial and ventricular cells, the amplitude and kinetics of INa were unchanged by elevation of [K+]o. In atrial cells, action potentials elicited from a holding potential of -70 mV had a similar Vmax (114.9 +/- 5.7 versus 112.2 +/- 4.8 V/s, mean +/- SEM, n = 6) and action potential amplitude (115.0 +/- 2.4 versus 113.4 +/- 3.9 mV) in 5 and 24 mmol/L [K+]o. In contrast, in ventricular cells at a holding potential of -70 mV, increasing [K+]o fro 5 to 14 mmol/L decreased Vmax from 161.8 +/- 18.0 to 55.3 +/- 5.0 V/s (n = 7, P < .001) and action potential amplitude from 128.1 +/- 1.3 to 86.6 +/- 5.4 mV (P < .001). This voltage-independent decrease in Vmax and action potential amplitude induced by elevated [K+]o was abolished in the presence of 1 mmol/L Ba2+, suggesting that it is attributable to an increased background K+ conductance.
Hypothesis:
We conclude that elevation of [ K+ ]o to levels expected during ischemia causes a marked voltage -independent depression of Vmax in ventricular cells, which may, in turn, contribute to the slowing of myocardial conduction characteristic of early ischemia.
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entailment
|
bionli-en-071
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nli
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BioNLI
|
en
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Premise:
Extracellular calcium (Ca²⁺(e))-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries is dependent on an intact perivascular sensory nerve network that expresses the Ca²⁺-sensing receptor (CaSR). Activation of the receptor stimulates an endocannabinoid vasodilator pathway, which is dependent on cytochrome P450 and phospholipase A₂ but largely independent of the endothelium. In the present study, we determined the role of nitric oxide (NO) in perivascular nerve CaSR-mediated relaxation of PE-contracted mesenteric resistance arteries isolated from mice. Using automated wire myography, we studied the effects of NO synthase (NOS) gene knockout (NOS(-/-)) and pharmacologic inhibition of NOS on Ca²⁺(e)-induced relaxation of PE-contracted arteries. Endothelial NOS knockout (eNOS(-/-)) upregulates but neuronal NOS knockout (nNOS(-/-)) downregulates CaSR expression. NOS(-/-) reduced maximum Ca²⁺(e)-induced relaxation with no change in EC₅₀ values, with eNOS(-/-) having the largest effect. The responses of vessels to calindol and Calhex 231 indicate that the CaSR mediates relaxation. L-N⁵-(1-iminoethyl)-ornithine reduced Ca²⁺(e)-induced relaxation of PE-contracted arteries from C57BL/6 control mice by ≈38% but had a smaller effect in vessels from eNOS(-/-) mice. 7-Nitroindazole had no significant effect on relaxation of arteries from NOS(-/-) mice, but both N(G)-nitro-L-arginine methylester and N(G)-monomethyl-L-arginine significantly reduced the relaxation maxima in all groups. Interestingly, the nNOS-selective inhibitor S-methyl-L-thiocitrulline significantly increased the EC₅₀ value by ≈60% in tissues from C57BL/6 mice but reduced the maximum response by ≈80% in those from nNOS(-/-) mice. Ca²⁺-activated big potassium channels play a major role in the process, as demonstrated by the effect of iberiotoxin.
Hypothesis:
We conclude that CaSR signaling in mesenteric arteries stimulates eNOS and NO production that regulates Ca²⁺(e)-induced relaxation.
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entailment
|
bionli-en-072
|
nli
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BioNLI
|
en
|
Premise:
Adenosine, a vasodilator metabolite, is often produced in tissues where the demand for oxygen exceeds the supply. We have recently demonstrated in isolated cannulated arterioles that adenosine and its metabolite, inosine, can also cause vasoconstriction by stimulation of mast cells. Secondary release of histamine and thromboxane is responsible for the inosine-induced constriction in vivo. In the present study, we explored the vasomotor effects of adenosine in vivo and investigated the role of the A3 adenosine receptor in mediating vasoconstriction. In vivo, local application of adenosine (10-6 to 10-4 mol/L) to arterioles consistently caused dose-dependent vasodilation. A fraction of arterioles, however, exhibited a biphasic response, with constriction following dilation. This, too, was dose dependent; 37% of arterioles constricted by 12.7 +/- 4.3% of the initial diameter in response to 10-4 mol/L adenosine. In the presence of 8-(p-sulfophenyl)theophylline (8-SPT), an antagonist of A1 and A2 adenosine receptors, dilation in response to the same dose of adenosine was reduced, and constriction was enhanced; 85% of the tested arterioles constricted by -44.3 +/- 6.0% of the initial diameter. The A3 adenosine receptor has been shown to facilitate mediator release from mast cells, and its role was also examined. N6-(3-Iodo-4-aminobenzyl)adenosine (I-ABA), an agonist of A1 and A3 adenosine receptors, produced dose-dependent vasoconstriction. 1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433), an antagonist of A1, A2, and A3 receptors, significantly reduced the vasoconstrictor response to adenosine, which was unmasked during treatment with 8-SPT. In addition, both adenosine and I-ABA stimulated mast cell uptake of ruthenium red, indicating degranulation. The I-ABA-induced constriction was abolished by combined histamine and thromboxane receptor antagonists.
Hypothesis:
We conclude that adenosine can cause vasoconstriction in vivo, which is often masked by A2 receptor-mediated vasodilation.
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entailment
|
bionli-en-073
|
nli
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BioNLI
|
en
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Premise:
We compared the mechanisms of vasorelaxation of acetylcholine and of substance P with reference to K(+) channels, and analyzed pharmacologically the nature of endothelium-derived substance(s) other than NO and prostanoids in monkey and dog coronary arteries. Coronary arteries were isolated from monkeys and dogs, and the isometric tension of the artery strips was measured. In canine coronary artery strips treated with indomethacin plus N(G)-nitro- L-arginine ( L-NA) and partially contracted with prostaglandin F(2alpha), acetylcholine induced concentration-related relaxation, which was abolished by removal of the endothelium. The relaxation was markedly suppressed but not abolished in the strips exposed to high K(+) media. Charybdotoxin plus apamin potently inhibited the relaxation to the similar extent to that by high K(+) media, whereas glibenclamide or iberiotoxin had no effect. The relaxation was markedly inhibited by quinacrine, a phospholipase A(2) inhibitor, and ketoconazole, a selective cytochrome P450 (CYP) 3A inhibitor, but not by sulfaphenazole, a selective CYP 2C inhibitor. In contrast to acetylcholine, endothelium-dependent and indomethacin-plus- L-NA-resistant relaxation induced by substance P was not inhibited by high K(+) media, charybdotoxin plus apamin, or ketoconazole. Quinacrine and AA861, a 5-lipoxygenase inhibitor, inhibited the relaxation induced by substance P. In monkey coronary artery, acetylcholine-induced relaxation resistant to indomethacin plus L-NA was abolished by endothelial denudation and by treatment with high K(+) media, charybdotoxin plus apamin, progesterone and ketoconazole, but was not affected by iberiotoxin or sulfaphenazole. Substance P did not relax monkey coronary arteries.
Hypothesis:
It is concluded that endothelium-dependent, nitric oxide- and prostanoid -independent relaxation induced by acetylcholine in monkey and dog coronary arteries are mediated by charybdotoxin plus apamin-sensitive but iberiotoxin-insensitive Ca(2+)-activated K(+) channel opening substance(s), which may be CYP3A-derived arachidonic acid metabolite(s).
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entailment
|
bionli-en-074
|
nli
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BioNLI
|
en
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Premise:
Our objective was to determine the role of the Rho-associated kinase (ROK) for the regulation of FBF (FBF) and to unmask a potential role of ROK for the regulation of endothelium-derived nitric oxide (NO). Moreover, the effect of fasudil on the constrictor response to endothelin-1 was recorded. Regarding background, phosphorylation of the myosin light chain (MLC) determines the calcium sensitivity of the contractile apparatus. MLC phosphorylation depends on the activity of the MLC kinase and the MLC phosphatase. The latter enzyme is inhibited through phosphorylation by ROK. ROK has been suggested to inhibit NO generation, possibly via the inhibition of the Akt pathway. In this study, the effect of intra-arterial infusion of the ROK inhibitor fasudil on FBF in 12 healthy volunteers was examined by venous occlusion plethysmography. To unmask the role of NO, fasudil was infused during NO clamp. As a result, fasudil markedly increased FBF in a dose-dependent manner from 2.34 +/- 0.21 to 6.96 +/- 0.93 ml/100 ml forearm volume at 80 mug/min (P < 0.001). At 1,600 mug/min, fasudil reduced systolic, diastolic, and mean arterial pressure while increasing heart rate. Fasudil abolished the vasoconstrictor effect of endothelin-1. The vascular response to fasudil (80 mumol/min) was blunted during NO clamp (104 +/- 18% vs. 244 +/- 48% for NO clamp + fasudil vs. fasudil alone; data as ratio between infused and noninfused arm with baseline = 0%, P < 0.05).
Hypothesis:
In conclusion, 1) basal peripheral and systemic vascular tone depends on ROK ; 2.34) a significant portion of fasudil-induced vasodilation is mediated by NO , suggesting that vascular bioavailable NO is negatively regulated by ROK ; and 3) the constrictor response to endothelin involves the activation of ROK .
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contradiction
|
bionli-en-075
|
nli
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BioNLI
|
en
|
Premise:
The vasodilating effects of flunarizine on smooth muscle strips of rabbit mesenteric artery have been investigated and compared with those of nifedipine. Flunarizine (30-300 nM) dose-dependently inhibited Ca2+-induced contractions in Ca2+-free solution containing 100 mM K+. Double reciprocal analysis showed that this inhibition was either competitive at low concentrations (30-100 nM; nifedipine-like) or noncompetitive at high concentrations (0.3-1 microM). The latter seemed to be partly related to an inhibition of contractile proteins as estimated from Ca2+-induced contractions in saponin-treated chemically skinned muscle strips. In contrast to the actions of nifedipine, flunarizine inhibited norepinephrine (NE)-induced contractions more than those induced by high K+, and at 0.3 microM, this agent totally blocked NE-induced contraction. Flunarizine also inhibited NE-induced contraction in Ca2+-free solution containing 2 mM EGTA. In Ca2+-free solution, NE rapidly hydrolyzed phosphatidylinositol 4,5-bisphosphate (PI-P2) and produced phosphatidic acid (PA). Flunarizine (30 and 300 nM), but not nifedipine (100 nM), inhibited NE-induced hydrolysis of PI-P2 and production of PA. However, flunarizine (100 nM) did not modify the contraction induced by 10 microM inositol 1,4,5-trisphosphate in chemically skinned muscle strips.
Hypothesis:
It is concluded that, in contrast to nifedipine , flunarizine at low concentrations inhibits Ca2+-induced contraction by interfering with NE-induced hydrolysis of PI-P2 and production of PA.
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contradiction
|
bionli-en-076
|
nli
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BioNLI
|
en
|
Premise:
Teleost fish are able to adjust their energy intake when fed on pure macronutrient sources, although the exact mechanisms regulating macronutrient selection remain unknown. Since cholecystokinin (CCK) has been reported to modify macronutrient selection patterns in mammals, we explored the effect of CCK administered orally to European sea bass on the selection of separately encapsulated macronutrients. CCK doses of 0.05, 0.15 and 0.25 mg/kg BW administered in gelatine capsules for 5 consecutive days produced a significant inhibition of total food intake (21, 28 and 51%, respectively) at highest doses, evenly reducing the quantity of all the macronutrients ingested and, without affecting their relative proportions in the diet. Oral administration of proglumide, a non-specific CCK receptor antagonist, at doses of 5, 15 and 25 mg/kg BW, induced a quantitative total food intake increase of 2, 18 and 44%, respectively, and an increase of 52% in CH and 43% in P quantity ingested at highest dose. Co-administration of proglumide (25 mg/kg BW) and CCK (0.25 mg/kg BW) in a single preload capsule blocked the effects observed with CCK alone.
Hypothesis:
In conclusion, orally administered proglumide induced an anorexigenic effect on both total food and single macronutrient intake, an effect that is counteracted by the proglumide antagonist CCK .
|
contradiction
|
bionli-en-077
|
nli
|
BioNLI
|
en
|
Premise:
The paraventricular hypothalamic nucleus (PVN) appears to integrate orexigenic properties of a novel peptide, ghrelin. Thus, we examined central mechanisms underlying feeding generated by intra-PVN ghrelin. We established that 0.03 nmol of PVN-injected ghrelin was the lowest dose increasing food consumption and it induced c-Fos immunoreactivity (a marker of neuronal activation) in the PVN itself, as well as in other feeding-related brain areas, including the hypothalamic arcuate and dorsomedial nuclei, central nucleus of the amygdala, and nucleus of the solitary tract.
Hypothesis:
We conclude that ghrelin activates neurons in the PVN and other feeding-related brain areas to promote food intake.
|
contradiction
|
bionli-en-078
|
nli
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BioNLI
|
en
|
Premise:
Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days). Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed), and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control.
Hypothesis:
In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.
|
entailment
|
bionli-en-079
|
nli
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BioNLI
|
en
|
Premise:
Systemic administration of cholecystokinin (CCK) or LiCl inhibits gastric motility and food intake in rats. Brain stem-projecting oxytocin (OT) neurons in the hypothalamic paraventricular nucleus (PVN) have been proposed to mediate the inhibitory effects of CCK and LiCl on gastric motility and food intake. In the present studies, we found that basal gastric motility was elevated in rats 12-20 h after knife-cut lesions of the PVN; however, this effect disappeared 3 days later. Furthermore, CCK and LiCl inhibited gastric motility at 12-20 h, 3 days, and 3 wk after PVN lesions, although their effects were blunted. Injection of the local anesthetic lidocaine into the PVN had effects similar to acute PVN lesions. In rats with PVN lesions, the inhibitory effects of CCK and LiCl on food intake were indistinguishable from those in sham-lesioned rats.
Hypothesis:
We conclude that the gastric motility tonically inhibits PVN and that it participates in, but is not essential for, the inhibitory effects of CCK and LiCl on PVN and food intake in rats.
|
contradiction
|
bionli-en-080
|
nli
|
BioNLI
|
en
|
Premise:
The teleost salmon calcitonin (sCT), but not mammalian CT, shows similar biologic actions in the skeletal muscle as amylin and calcitonin gene-related peptide (CGRP). The peptides have also been shown to reduce food intake in rams. Because sCT, but not amylin, binds irreversibly to amylin binding sites, the aim of the present study was to compare the anorectic potency of both peptides. To determine whether sCT reduces food intake through interaction with amylin binding sites, we also tested whether appropriate antagonists (CORP 8-37, AC 187) attenuate the anorectic effect of sCT. Finally, we wanted to know whether rat calcitonin (rCT) and sCT reduce food intake to the same extent. Peptides were injected intraperitoneally at dark onset in 24 h food-deprived rats. At doses of 5 or 0.5 microg/kg, the anorectic effect of sCT was more potent and lasted much longer (e.g. 5 microg/kg: sCT > 10 h; amylin approx. 2 h) than that of amylin. Both CORP 8-37 and AC 187 (10 microg/kg) markedly reduced the anorectic action of sCT (0.5 microg/kg). In contrast to sCT, rCT (0.5 microg/kg) had no effect on food intake.
Hypothesis:
In conclusion, the more potent and long-lasting anorectic action of sCT than that of amylin suggests that sCT reduces food intake through interaction with amylin binding sites.
|
contradiction
|
bionli-en-081
|
nli
|
BioNLI
|
en
|
Premise:
Both stimulation of purinergic receptors by ATP and activation of the cystic fibrosis transmembrane conductance regulator (CFTR) inhibit amiloride-sensitive Na+ transport and activate Cl- secretion. These changes in ion transport may well affect cell volume. We therefore examined whether cell shrinkage or cell swelling do affect amiloride-sensitive Na+ transport in epithelial tissues or Xenopus oocytes and whether osmotic stress interferes with regulation of Na+ transport by ATP or CFTR. Stimulation of purinergic receptors by ATP/UTP or activation of CFTR by IBMX and forskolin inhibited amiloride-sensitive transport in mouse trachea and colon, respectively, by a mechanism that was Cl- dependent. When exposed to a hypertonic but not hypotonic bath solution, amiloride-sensitive Na+ transport was inhibited in mouse trachea and colon, independent of the extracellular Cl- concentration. Both inhibition of Na+ transport by hypertonic bath solution and ATP were additive. When coexpressed in Xenopus oocytes, activation of CFTR by IBMX and forskolin inhibited the epithelial Na+ channel (ENaC) in a Cl- dependent fashion. However, both hypertonic and hypotonic bath solutions showed only minor effects on amiloride-sensitive conductance, independent of the bath Cl- concentration. Moreover, CFTR-induced inhibition of ENaC could be detected in oocytes even after exposure to hypertonic or hypotonic bath solutions.
Hypothesis:
We conclude that amiloride -sensitive Na+ absorption in mouse airways and colon is inhibited by cell shrinkage by a mechanism that does not interfere with purinergic and CFTR-mediated inhibition of ENaC .
|
entailment
|
bionli-en-082
|
nli
|
BioNLI
|
en
|
Premise:
Absorption of NaCl by the thick ascending limb (TAL) involves active transport and therefore depends on oxidative phosphorylation. Extracellular ATP has pleiotropic effects, including both stimulation and inhibition of transport and inhibition of oxidative phosphorylation. However, it is unclear whether ATP alters TAL transport and how this occurs. We hypothesized that ATP inhibits TAL Na absorption by reducing Na entry. We measured oxygen consumption in TAL suspensions. ATP reduced oxygen consumption in a concentration-dependent manner. The purinergic (P2) receptor antagonist suramin (300 microM) blocked the effect of ATP on TAL oxygen consumption (147 +/- 15 vs. 146 +/- 16 nmol O2 x min(-1) x mg protein(-1)). In contrast, the adenosine receptor antagonist theophylline did not block the effect of ATP on oxygen consumption. When Na-K-2Cl cotransport and Na/H exchange were blocked with furosemide (100 microM) plus dimethyl amiloride (100 microM), ATP did not inhibit TAL oxygen consumption (from 78 +/- 13 to 98 +/- 5 nmol O2 x min(-1) x mg protein(-1)). The Na ionophore nystatin (200 U/ml) increased TAL oxygen consumption to a similar extent in both ATP- and vehicle-treated samples (368 +/- 41 vs. 397 +/- 47 nmol O2 x min(-1) x mg protein(-1)). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (3 mM) blocked the ATP effects on TAL oxygen consumption (157 +/- 10 vs. 165 +/- 15 nmol O2 x min(-1) x mg protein(-1)). The P2X-selective receptor antagonist NF023 blocked the effect of ATP on oxygen consumption, whereas the P2X-selective agonist beta-gamma-Me-ATP reduced oxygen consumption in a concentration-dependent manner.
Hypothesis:
We conclude that ATP promotes Na transport-related oxygen consumption in TALs by reducing Na entry and P2X receptors and nitric oxide mediate this effect.
|
contradiction
|
bionli-en-083
|
nli
|
BioNLI
|
en
|
Premise:
We have previously shown that inhibiting protein-tyrosine kinase increased whereas inhibiting protein-tyrosine phosphatase (PTP) decreased renal outer medullary potassium channel 1 (ROMK1) channel activity (1). We have now used confocal microscopy, the patch clamp technique, and biotin labeling to further examine the role of tyrosine phosphorylation in regulating ROMK1 trafficking. Human embryonic kidney 293 cells were cotransfected with c-Src and green fluorescent protein-ROMK1, which has the same biophysical properties as those of ROMK1. Patch clamp studies have shown that phenylarsine oxide (PAO), an inhibitor of PTP, decreased the activity of ROMK1. Moreover, addition of PAO reduced the cell surface localization of green fluorescent protein-ROMK1 detected by confocal microscopy and diminished the surface ROMK1 density by 65% measured by biotin labeling. Also, PAO treatment significantly increased the phosphorylation of ROMK1. The notion that the effect of PAO is mediated by stimulating tyrosine phosphorylation-induced endocytosis of ROMK1 has also been supported by findings that mutating the tyrosine residue 337 of ROMK1 to alanine abolished the effect of PAO. Finally, the inhibitory effect of PAO on ROMK1 was completely blocked in the cells co-transfected with dominant negative dynamin (dynaminK44A). This indicates that the tyrosine phosphorylation-induced endocytosis of ROMK1 is dynamin-dependent.
Hypothesis:
We conclude that PTP stimulates endocytosis of ROMK1 by a dynamin-dependent mechanism.
|
contradiction
|
bionli-en-084
|
nli
|
BioNLI
|
en
|
Premise:
Butyrate stimulates salt absorption in mammalian colon. We examined whether butyrate also affects Cl- secretion. Mucosal segments of distal colon of male Sprague-Dawley rats and T84 cells were studied in Ussing chambers. In control colon, 1 mM dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) increased short-circuit current (Isc) and serosal-to-mucosal Cl- flux (JsmCl) by 3.2 +/- 0.8 and 2.9 +/- 0.8 mueq.cm-2.h-1, respectively. Mucosal or serosal 25 mM butyrate prevented DBcAMP-induced increases in Isc and JsmCl. Four and eight millimolar butyrate caused half-maximal inhibition of the increases in JsmCl and Isc, respectively. Butyrate also inhibited basal JsmCl (by 2.0 +/- 0.4 mueq.cm-2.h-1) but not carbachol-mediated Cl- secretion. The relative inhibitory potency at 25 mM of other short-chain fatty acids (SCFA) paralleled their degree of cellular metabolism: butyrate > acetate = propionate > isobutyrate. At 25 mM, all SCFA reduced mucosal intracellular pH (pHi) transiently by 0.1 pH unit. In intact T84 cells, 50 mM butyrate inhibited the DBcAMP-induced rise in Isc by 55%. In T84 cells with nystatin-permeabilized basolateral membranes, butyrate inhibited the increase in Isc by 82%.
Hypothesis:
We conclude that butyrate promotes basal and cAMP-mediated Cl- secretion by a mechanism independent of pHi, possibly located at the apical membrane.
|
contradiction
|
bionli-en-085
|
nli
|
BioNLI
|
en
|
Premise:
Since anion secretion inhibitors reproduce important aspects of cystic fibrosis (CF) lung disease, the effects of these antagonists on airway mucus morphology were assessed in isolated perfused pig lungs. Maximal inhibitory concentrations of bumetanide and dimethylamiloride, which respectively block Cl- and HCO3- secretion in porcine airways, induced the formation of dense 'plastered' mucus on the airway surface, depletion of periciliary fluid and collapse of cilia. This effect was more pronounced when lungs were also exposed to bethanechol to stimulate submucosal gland secretion, when plastered mucus covered > 98 % of the airway surface. Bethanechol also reduced gland duct mucin content in the absence, but not presence, of the anion secretion inhibitors. Anion secretion inhibitors did not induce measurable increases in goblet cell degranulation.
Hypothesis:
We conclude that inhibition of anion and liquid secretion in porcine lungs disrupts the normal morphology of airway surface mucus, providing further evidence that impaired anion secretion alone could account for critical aspects of CF lung disease .
|
entailment
|
bionli-en-086
|
nli
|
BioNLI
|
en
|
Premise:
We have shown that vitamin A (VA) and retinoic acid (RA) synergistically increase lung retinyl ester content in neonatal rats. To confirm whether this biochemical synergism attenuates early neonatal hyperoxic lung injury in mice, we exposed newborn C57BL/6 mice to 95% O2 or air from birth to 4 d. The agent [vehicle, VA, RA, or the combination vitamin A+retinoic acid (VARA)] was given orally daily. Lung and liver retinyl ester content was measured, and lung injury and development were evaluated. We observed that lung, but not liver, retinyl ester levels were increased more by VARA than by VA or RA alone. Hyperoxic lung injury was reduced by VA and RA, and more so by VARA. VARA attenuated the hyperoxia-induced increases in macrophage inflammatory protein (MIP)-2 mRNA and protein expression, but did not alter hyperoxia-induced effects on peptide growth factors (PDGF, VEGF, and TGF-beta1). The 4-d exposure to hyperoxia or retinoids did not lead to observable differences in lung development.
Hypothesis:
We conclude that the VARA combination has synergistic effects on lung retinyl ester concentrations and on the attenuation of hyperoxia -induced lung injury in newborn mice, possibly by modulation of inflammatory mediators.
|
entailment
|
bionli-en-087
|
nli
|
BioNLI
|
en
|
Premise:
Various drugs have been shown to stimulate surfactant phospholipid metabolism. Particularly beta-adrenergic agonists play an important role under physiologic conditions. For the first time we have studied whether nitrogen dioxide (NO2) inhalation alters beta-adrenergic regulation of surfactant phospholipid metabolism in the model of the isolated lung. Rats were continuously exposed in vivo to a 5 ppm NO2-containing atmosphere for 48 hr. The lungs were isolated and perfused in presence of the beta-adrenergic agonist dopexamine and surfactant metabolism was studied in three lung compartments: (1) lung lavage, (2) lung tissue, and (3) lavagable free alveolar cells. We found that (1) in normal rat lungs dopexamine increased the incorporation of palmitate and choline from the perfusate into lung lavage phospholipids. In nitrogen dioxide exposed rat lungs beta-adrenergic stimulation did not cause an increase in precursor incorporation. No significant difference in unstimulated precursor incorporation was found for normal and NO2-exposed rat lungs. (2) Lung tissue from rats exposed to NO2 showed a decreased precursor incorporation into disaturated phosphatidylcholine due to an augmented cellular pool size. (3) Lavagable alveolar cells showed an increased palmitate uptake after nitrogen dioxide inhalation and by beta-adrenergic stimulation.
Hypothesis:
From these data we conclude that NTG inhalation impairs the beta-adrenergic regulation of surfactant phospholipid metabolism .
|
contradiction
|
bionli-en-088
|
nli
|
BioNLI
|
en
|
Premise:
We administered a bolus of G-CSF (250 micrograms/body) just after the infusion of endotoxin (1 microgram/kg) in awake sheep with chronic lung lymph fistula to examine the effect of post-treatment with G-CSF on endotoxin-induced lung injury. We measured pulmonary hemodynamics, lung lymph flow, and concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha in plasma and lung lymph. In the G-CSF post-treated group, the pulmonary arterial pressure, pulmonary vascular resistance, and lung lymph flow did not significantly increase in the late period (3-5 h after endotoxin infusion). The arterial oxygen gas tension in the late period was higher in the G-CSF post-treated sheep than in those that received only endotoxin. Although the level of thromboxane B2 in plasma significantly increased at 1 h after endotoxin, the lung lymph flow did not increase much in the G-CSF post-treated group.
Hypothesis:
We conclude that post-treatment with G-CSF prevents endotoxin -induced lung injury .
|
contradiction
|
bionli-en-089
|
nli
|
BioNLI
|
en
|
Premise:
Tobacco smokers often display increased airway hyperreactivity (AHR) when faced with bacterial infections. The present study uses a murine organ-culture model to dissect the mechanisms involved in this exaggerated smooth muscle response. Nicotine simulates the effects of smoking, and LPS represents bacterial infection. Contractile responses of isolated murine tracheal segments were analyzed in myographs after organ culture with increasing concentrations of LPS and/or nicotine for 4 days with or without specific MAPK inhibitors. Nicotine's effect on the expression of cell surface Toll-like receptors (TLRs), MCP-1, COX-2, and TNF-α were examined by real-time PCR. Increased protein expression was verified by immunohistochemistry. LPS concentration-dependently increased contractile responses to bradykinin and des-Arg(9)-bradykinin. A combination of nicotine and low-dose LPS caused powerful synergistic contractions along with increased kinin receptor expression. Specific kinin B1 and B2 receptor inhibitors blocked this reaction. Nicotine increased mRNA and protein expression of TLR4 and -6 in the epithelium and smooth muscle layer, with MCP-1 and COX-2 mRNA increasing in parallel. Specific inhibition of JNK attenuated nicotine's effects.
Hypothesis:
In conclusion, long-term exposure to nicotine up-regulated the expression of TLR4 and -6 via a JNK-related pathway, causing an exaggeration of the LPS -induced local airway inflammation and increased AHR .
|
entailment
|
bionli-en-090
|
nli
|
BioNLI
|
en
|
Premise:
To compare the effects of epidermal growth factor (EGF) and betamethasone on the morphogenesis of the gas exchange region and the differentiation of the alveolar type II cell during fetal lung development, fetal rhesus monkeys (78% gestation) were treated in utero with EGF (5.33 mg/kg total dose), beta-methasone (2.6 mg/kg total dose) or the carrier, saline (control), every other day for 7 days. EGF-treated monkeys had significantly increased body and adrenal weights. Betamethasone-treated monkeys had significantly decreased body and adrenal weights. Exogenous EGF reduced cytoplasmic glycogen and increased the cytoplasmic organelle and SP-A content within alveolar type II cells. In contrast, exogenous betamethasone did not alter alveolar type II cell cytodifferentiation. Neither EGF nor betamethasone treatment significantly altered the structure of the gas exchange region as shown by a lack of change from controls in alveolar airspace size or in the fraction of the gas exchange region that was potential airspace.
Hypothesis:
We conclude that at clinically relevant doses, EGF greatly accelerates the maturation of alveolar type II cells, whereas betamethasone does not.
|
entailment
|
bionli-en-091
|
nli
|
BioNLI
|
en
|
Premise:
Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death.
Hypothesis:
We conclude that SUDEP in patients with DS can result from primary central apnea , which can cause bradycardia , presumably via a direct effect of hypoxemia on cardiac muscle.
|
entailment
|
bionli-en-092
|
nli
|
BioNLI
|
en
|
Premise:
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs. The SPG4 locus at 2p21-p22 accounts for 40-50% of all AD-HSP families. The SPG4 gene was recently identified. It is ubiquitously expressed in adult and foetal tissues and encodes spastin, an ATPase of the AAA family. We have now identified four novel SPG4 mutations in German AD-HSP families, including one large family for which anticipation had been proposed. Mutations include one frame-shift and one missense mutation, both affecting the Walker motif B. Two further mutations affect two donor splice sites in introns 12 and 16, respectively. RT-PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA. All mutations are predicted to cause loss of functional protein.
Hypothesis:
We conclude that AD-HSP is caused by loss-of-function mutations in SPG4 .
|
contradiction
|
bionli-en-093
|
nli
|
BioNLI
|
en
|
Premise:
Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body.
Hypothesis:
We conclude that FC JBTS is caused by mutations in CEP104 .
|
contradiction
|
bionli-en-094
|
nli
|
BioNLI
|
en
|
Premise:
Mutations and polymorphisms in the RET gene are a major cause of Hirschsprung disease (HSCR). Theoretically, all true heterozygous patients with a new manifestation of a genetically determined disease must have parents with a genetic mosaicism of some extent. However, no genetic mosaicism has been described for the RET gene in HSCR yet. Therefore, we analyzed families with mutations in the RET gene for genetic mosaicism in the parents of the patients. Blood samples were taken from patients with HSCR and their families/parents to sequence the RET coding region. Among 125 families with HSCR, 33 families with RET mutations were analyzed. In one family, we detected a frameshift mutation due to a loss of one in a row of four cytosines in codon 117/118 of the RET gene (c.352delC) leading to a frameshift mutation in the protein (p.Leu118Cysfs*105) that affected two siblings. In the blood sample of the asymptomatic father we found a genetic mosaicism of this mutation which was confirmed in two independent samples of saliva and hair roots. Quantification of peak-heights and comparison with different mixtures of normal and mutated plasmid DNA suggested that the mutation occurred in the early morula stadium of the founder, between the 4- and 8-cell stages.
Hypothesis:
In conclusion, we identified a frameshift mutation in the RET gene that caused HSCR in his parents.
|
contradiction
|
bionli-en-095
|
nli
|
BioNLI
|
en
|
Premise:
MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90-NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (pri-miR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice.
Hypothesis:
Taken together, we conclude that the myopathy complex induces centronuclear NF90-NF45 through increased dynamin 2 expression by an myopathy -induced reduction of miR-133a expression in vivo.
|
contradiction
|
bionli-en-096
|
nli
|
BioNLI
|
en
|
Premise:
Preexisting pulmonary hypertension (PH) is associated with poor outcomes after surgical mitral valve repair for functional mitral regurgitation (FMR). However its clinical impact on MitraClip therapy remains unknown. The aim of this study was therefore to evaluate the impact of preexisting PH on MitraClip therapy for patients with FMR. Ninety-one consecutive patients who had FMR and who underwent the MitraClip procedure were studied. They were divided into 2 groups on the basis of pulmonary artery systolic pressure: the PH group (n = 48) and the non-PH group (n = 43). PH was defined as pulmonary artery systolic pressure >50 mm Hg using Doppler echocardiography. Procedural success (defined as magnetic resonance reduction to grade 2+ or less) and 30-day mortality were similar in the 2 groups. At 12 months, New York Heart Association functional class had improved to class I or II in most patients in the PH (from 2.9% to 94.3%) and non-PH (from 9.4% to 96.9%) groups. The mean pulmonary artery systolic pressure of the PH group significantly decreased from baseline but remained higher than that of the non-PH group (50.8 ± 15.3 vs 36.7 ± 11.6 mm Hg, p <0.001). After a mean of 25.0 ± 16.9 months of follow-up, Kaplan-Meier analysis demonstrated significantly higher all-cause mortality in the PH group. In Cox regression analysis, preexisting PH was the most powerful predictor of all-cause mortality (hazard ratio 3.731, 95% confidence interval 1.653 to 8.475, p = 0.002).
Hypothesis:
In conclusion, MitraClip therapy reduced FMR and alleviated symptoms with an excellent early safety profile in the PH and non-PH groups.
|
entailment
|
bionli-en-097
|
nli
|
BioNLI
|
en
|
Premise:
To further define the nature of Lyme carditis, electrophysiologic study and endomyocardial biopsy were performed in a patient with Lyme disease, whose principal cardiac manifestation was high-degree atrioventricular block. Intracardiac recording demonstrated supra-Hisian block and complete absence of an escape mechanism. Gallium 67 scanning demonstrated myocardial uptake, and right ventricular endomyocardial biopsy revealed active lymphocytic myocarditis. A structure compatible with a spirochetal organism was demonstrated in one biopsy specimen.
Hypothesis:
It is concluded that Lyme disease can produce active myocarditis , as suggested by gallium 67 imaging and confirmed by endomyocardial biopsy.
|
entailment
|
bionli-en-098
|
nli
|
BioNLI
|
en
|
Premise:
Although coronary artery disease and gastroesophageal reflux disease are common conditions which, therefore, may coexist, it is unknown whether or not the presence of one affects the other. We performed esophageal acid perfusion tests, with concurrent blood pressure, heart rate, and 12-lead electrocardiographic monitoring, in 37 patients, 25 with angiographically documented coronary disease and 12 with normal coronary arteries. Rate-pressure product, an index of myocardial work load, was calculated. In patients with coronary disease who developed chest pain during acid perfusion, rate-pressure product increased from 10.0 +/- 1.0 x 10(3) (mean +/- SEM) basally to 15.2 +/- 1.5 x 10(3) (p less than 0.001), and 3 of 9 patients showed concomitant electrocardiogram evidence of myocardial ischemia. In addition, in coronary disease, 64% of patients with infrequent or absent reflux symptoms by history had positive acid perfusion tests, and 56% of patients with coronary disease who developed pain during esophageal acid perfusion could not distinguish that pain from their usual angina.
Hypothesis:
We conclude that in coronary disease, acid perfusion (and, presumably, gastroesophageal reflux ) resulting in chest pain causes rate-pressure product elevation and can induce myocardial ischemia .
|
entailment
|
bionli-en-099
|
nli
|
BioNLI
|
en
|
Premise:
This study was performed to determine the sensitivity of thallium imaging vs ECG monitoring for detecting coronary artery spasm noninvasively following intravenous ergonovine administration as compared to simultaneous coronary angiography. Thirty-two patients with insignificant coronary artery disease and chest pain underwent 12-lead ECG monitoring, thallium imaging, and coronary arteriography following the administration of 0.05, 0.1, 0.2, and 0.3 mg of ergonovine given 5 minutes apart or until chest pain occurred. One minute following the last dose of ergonovine, 2.5 mCi of thallium-201 was injected intravenously, and a final ECG was recorded and repeat coronary arteriography performed. Within 10 minutes following the injection of thallium, imaging was performed in the 40-degree and 70-degree left anterior oblique and anterior projections. The ECG, thallium study, and coronary arteriogram were read blindly and results were compared. The ECG, angiogram, and thallium study were read as positive if the following occurred, respectively: greater than or equal to 1 mm ST segment elevation, depression, or T wave reversal; greater than 50% vessel narrowing,; and reversible perfusion defect. Five patients were excluded from analysis because of either catheter-induced spasm, suboptimal thallium studies, or protocol violations. Of the 27 patients included for analysis, six had chest pain, five had a positive angiogram, five had a positive thallium study, and one had a positive ECG. The sensitivity of thallium vs ECG monitoring was 80% vs 25%, and the accuracy was 92% vs 80%.
Hypothesis:
We conclude that thallium imaging greatly increases the noninvasive detection of ergonovine -induced coronary spasm as compared with the ECG with no loss of accuracy.
|
entailment
|
bionli-en-100
|
nli
|
BioNLI
|
en
|
Premise:
The correlation of symptoms (SX) with major arrhythmias (ARS) occurring during 24-hour ambulatory monitoring (AM) was investigated in a goup of patients referred because of dizziness or syncope. Ninety-eight consecutive patients, ages 25 to 82, who had adequate diaries of activities and SX, wre included. The ARS considered to be major were ventricular and supraventricular ectopy grade 2, 3, and 4 (Lown classification), sinus arrest and block, atrioventricular block, and sinus bradycardia less than or equal to 40/minute. Although all patients were referred because of dizziness and/or syncope, only 41 (42%) had their symptoms during the recording period. The ARS were recorded in 63 (64%). There was no statistically significant difference in the incidence or in the type of ARS in the group with, and the group without, symptoms (x2 = 1.64). Of the 23 subjects with both major ARS and recorded SX, only two had SX and ARS occurring concomitantly.
Hypothesis:
It is concluded that the presence of SX does not increase the likelihood of major ARS occurring during 24-hour AM.
|
contradiction
|
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in Data Studio
MultiMed-X
MultiMed-X is a multilingual benchmark for medical reasoning evaluation across natural language inference (NLI) and open-ended question answering (QA).
The dataset is designed to assess reasoning quality, factual accuracy, and localization of large language models in non-English medical settings, with particular emphasis on low-resource languages.
This dataset accompanies the paper: MED-COREASONER: Reducing Language Disparities in Medical Reasoning via Language-Informed Co-Reasoning.
Dataset Overview
MultiMed-X-350 is constructed by translating and expert-validating two established English medical benchmarks:
- BioNLI → Multilingual medical natural language inference (NLI), original data from BioNLI: Generating a Biomedical NLI Dataset Using Lexico-semantic Constraints for Adversarial Examples.
- LiveQA → Multilingual open-ended medical question answering (QA), original data from LiveQA: A Question Answering Dataset over Sports Live.
Each instance is translated into multiple target languages and independently reviewed and revised by bilingual medical experts to ensure clinical correctness and linguistic naturalness.
Languages
The dataset covers 7 non-English languages:
- Chinese (ZH)
- Japanese (JA)
- Korean (KO)
- Swahili (SW)
- Thai (TH)
- Yoruba (YO)
- Zulu (ZU)
Data Format
All data are released as a single unified table (e.g., JSONL / Parquet compatible with Hugging Face datasets).
Common Fields
| Field | Type | Description |
|---|---|---|
id |
string | Unique instance ID |
lang |
string | Language code (e.g., zu, sw) |
task |
string | Task type: nli or qa |
source |
string | Data source (BioNLI or LiveQA) |
text |
string | Original content in the target language |
label |
string / null | Gold label (NLI only) |
ID Convention
NLI (BioNLI)
bionli-<lang>-XYZQA (LiveQA)
qa-<lang>-XYZ
Only 3-digit numeric suffixes are used.
Example Entries
NLI Example
{
"id": "bionli-zu-042",
"lang": "zu",
"task": "nli",
"source": "BioNLI",
"text": "Premise: ... Hypothesis: ...",
"label": "entailment"
}
QA Example
{
"id": "qa-sw-117",
"lang": "sw",
"task": "qa",
"source": "LiveQA",
"text": "Swali: ... Jibu: ...",
"label": null
}
Data Statistics
- 350 instances per language
- 150 NLI (BioNLI)
- 200 QA (LiveQA)
- ~2,450 total instances
- Annotated and validated by ~12 physicians or senior medical students
Intended Use
MultiMed-X-350 is intended for:
- Multilingual medical reasoning evaluation
- Cross-lingual robustness analysis
- Low-resource language benchmarking
- Evaluation of reasoning strategies (e.g., CoT, structured reasoning, agentic systems)
⚠️ Not intended for clinical deployment or direct medical decision-making.
Ethical Considerations
- All data are derived from publicly available datasets
- Translations are expert-reviewed
- No private patient data are included
- Annotators were formally recruited and compensated or credited as co-authors
Citation
@article{gao2026medcoreasoner,
title={MED-COREASONER: Reducing Language Disparities in Medical Reasoning via Language-Informed Co-Reasoning},
author={Gao, Fan and Tong, Sherry T. and Sohn, Jiwoong and Huang, Jiahao and Jiang, Junfeng and Xia, Ding and Ittichaiwong, Piyalitt and Veerakanjana, Kanyakorn and Kim, Hyunjae and Chen, Qingyu and Taylor, Edison Marrese and Kobayashi, Kazuma and Aizawa, Akiko and Li, Irene},
journal={arXiv preprint arXiv:2601.08267},
year={2026}
}
License
This dataset is released for research and evaluation purposes only, under the same licensing terms as the original source datasets (BioNLI, LiveQA).
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