Biomedical subjects

S Yu

Publications and source records attributed to S Yu.

At least 55 records · Page 3Linked to original sources

PubMed2003

Negatively charged 2- and 10-microm particles activate vanilloid receptors, increase cAMP, and induce cytokine release.

Exposure to airborne pollutants, such as particulate matter (PM), is associated with increased mortality and morbidity. Indirect evidence suggested that PM-induced responses could be initiated by the activation of proton-gated receptors, including vanilloid receptors (VRs) and acid-sensitive ion channels (e.g. ASICS). We tested this hypothesis by characterizing the effects of 10- and 2-microm polystyrene carboxylate-modified particles (PC(10) and PC(2)) on HEK 293 cells expressing VR1 receptors, rat trigeminal ganglion (TG) neurons, and BEAS-2B airway epithelial cells. Zeta potential measurements revealed that these particles are negatively charged, meaning that when they adhere to a membrane they can lower the surface pH and activate proton-gated receptors. Both types of PCs induced currents and/or elevated intracellular Ca(2+) in cells that were capsaicin sensitive (CS). In about 70% of CS neurons, 10 microM capsazepine (CPZ), a VR antagonist, blocked PC-induced responses. In TG neurons in which VRs were blocked or desensitized, PCs induced an amiloride-inhibitable inward current having the characteristics of ASIC-mediated currents. Incubation of TG neurons with either capsaicin or PCs produced a CPZ-sensitive increase in cyclic AMP and cytokine (IL-6) release. In summary, we provide unequivocal evidence demonstrating that negatively charged PCs could activate VR1 and other proton-gated receptors. These data suggest that pharmacological manipulation of such receptors could prevent the physiological actions of PMs.

Air Pollutants↗

PubMed2003

X-linked myotubular myopathy in a family with three adult survivors.

We describe a family with an extremely mild form of X-linked myotubular myopathy. Three affected males survived to adulthood with sufficient muscle strength to enable them to carry out normal daily activities. The mildness of the myopathy in this family is highlighted by the following: no neonatal or infant mortality resulting from the myopathy; one affected male who did not have neonatal asphyxia and had normal early motor milestones - this affected male was able to increase his muscle bulk and strength to normal by weightlifting; and a 55-year-old male who still lives an independent life. DNA sequencing identified a novel missense mutation - G469A (E157K) - in exon 7 of the MTM1 gene in this family. To our knowledge, this is the third X-linked myotubular myopathy family, with multiple adult survivors, to be reported in the literature.

Base Sequence↗

PubMed2003

Magnesium balance in adult cats fed a dry food rich in lactose.

The question addressed was whether lactose consumption would stimulate apparent magnesium absorption in adult cats. In a cross-over study, eight cats were fed dry diets without or with 10% lactose, which was added at the expense of the glucose component. Urine and faeces were quantitatively collected and the balance of magnesium, calcium and phosphorus was determined. Lactose feeding did not affect mineral absorption. The dry matter content of faeces was unchanged after lactose consumption. Urinary excretion of galactose represented 0.2% of the intake. It is concluded that lactose ingestion at a level of 1.2 g/kg body weight has no effect on mineral absorption and on the consistency of faeces in adult cats.

Animal Feed↗

PubMed2003

Determination of the selenium requirement in kittens.

The purpose of this study was to determine the selenium (Se) requirement in kittens. Thirty-six specific-pathogen-free kittens (9.8 weeks old) were utilized in a randomized complete block design to determine the Se requirement in cats with gender and weight used as blocking criteria. Kittens were fed a low Se (0.02 mg/kg Se) torula yeast-based diet for 5 weeks (pre-test) after which an amino acid-based diet (0.027 mg Se/kg diet) was fed for 8 weeks (experimental period). Six levels of Se (0, 0.05, 0.075, 0.10, 0.20 and 0.30 mg Se/kg diet) as Na2SeO3 were added to the diet and were used to construct a response curve. Response variables included Se concentrations and Se-dependent glutathione peroxidase activities (GSHpx) in plasma and red blood cells (RBC) as well as plasma total T3 (TT3) and total T4 (TT4). No significant changes in food intake, weight gain or clinical signs of Se deficiency were noted. Estimates of the kitten's Se requirement (i.e. breakpoints) were determined for RBC and plasma GSHpx (0.12 and 0.15 mg Se/kg diet, respectively), but no definitive breakpoint was determined for plasma Se. Plasma TT3 increased linearly, whereas plasma TT4 and the ratio of TT4 : TT3 decreased in a quadratic fashion to dietary Se concentration. The requirement estimate determined in this study (0.15 mg Se/kg) for kittens is in close agreement with other species. As pet foods for cats contain a high proportion of animal protein with a Se bioavailability of 30%, it is recommended that commercial diets for cats contain 0.5 mg Se/kg DM.

Animals↗

PubMed2003

Decision tree SAR models for developmental toxicity based on an FDA/TERIS database.

Humans are exposed to thousands of environmental chemicals for which no developmental toxicity information is available. Structure-activity relationships (SARs) are models that could be used to efficiently predict the biological activity of potential developmental toxicants. However, at this time, no adequate SAR models of developmental toxicity are available for risk assessment. In the present study, a new developmental database was compiled by combining toxicity information from the Teratogen Information System (TERIS) and the Food and Drug Administration (FDA) guidelines. We implemented a decision tree modeling procedure, using Classification and Regression Tree software and a model ensemble approach termed bagging. We then assessed the empirical distributions of the prediction accuracy measures of the single and ensemble-based models, achieved by repeating our modeling experiment many times by repeated random partitioning of the working database. The decision tree developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the accuracy of prediction. Also, the model ensemble approach reduced the variability of prediction measures compared to the single model approach. Further research with data derived from animal species- and endpoint-specific components of an extended and refined FDA/TERIS database has the potential to derive SAR models that would be useful in the developmental risk assessment of the thousands of untested chemicals.

Abnormalities, Drug-Induced↗

PubMed2003

What level of physical activity protects against premature cardiovascular death? The Caerphilly study.

OBJECTIVE: To examine the optimal intensity of leisure time physical activity (LTPA) to decrease the risk of all cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in a population sample of middle aged British men. DESIGN: Prospective study of middle aged men with an 11 year follow up. SETTING: A whole population sample of men from Caerphilly, South Wales, UK. SUBJECTS: 1975 men aged 49-64 years without historical or clinical evidence of CHD at baseline examination. MAIN OUTCOME MEASURES: All cause, CVD, and CHD mortality. RESULTS: Total (cumulative) LTPA had a graded, significant relation with all cause, CVD, and CHD mortality but no trend with cancer deaths. When different intensities of activity were considered, light and moderate intensity LTPA had inconsistent and non-significant relations with all cause, CVD, or CHD mortality whether adjusted only for age or for other cardiovascular risk factors. In contrast a significant dose-response relation was found for heavy intensity LTPA for all cause, CVD, and CHD mortality fully adjusted for other risk factors. CONCLUSIONS: These data suggest that, in a population of men without evidence of CHD at baseline, only leisure exercise classified as heavy or vigorous was independently associated with reduced risk of premature death from CVD.

Cardiovascular Diseases↗

PubMed2003

Effect of vaccination with selective bacterins on conventional pigs infected with type 2 porcine circovirus.

The objective of this study was to determine whether vaccination with bacterins commonly used in the USA, when administered at a time typical of US protocol, enhances porcine circovirus type 2 (PCV2) replication and the incidence and severity of clinical signs and lesions characteristic of postweaning multisystemic wasting syndrome (PMWS) in conventional pigs. Sixty-one pigs free of PCV2 were randomly assigned to four groups. Groups 1 (n = 15) and 2 (n = 15) pigs served as sham-inoculated negative controls. Groups 3 (n = 14) and 4 (n = 17) pigs were inoculated intralymphoid with PCV2 field isolate ISU-40895. Pigs in groups 2 and 4 were vaccinated with Actinobacillus pleuropneumoniae (APP) and Mycoplasma hyopneumoniae (M. hyopneumoniae) bacterins 21 days before and again 1 day before inoculation with PCV2. Mild transient respiratory disease and diarrhea were observed from 13 to 34 days postinoculation (DPI) in pigs in groups 3 and 4. Half the pigs from each group were necropsied at 22 and 34 DPI, respectively. Moderately enlarged, tan-colored lymph nodes were observed in the majority of pigs in groups 3 and 4. There was a significantly (P < 0.05) longer length of viremia (2.14 +/- 0.26 versus 4.44 +/- 0.23 weeks), a higher copy number of the PCV2 genome in serum, a wider range of tissue distribution of PCV2 antigen, and an increased severity of lymphoid depletion in pigs vaccinated with commercial APP and M. hyopneumoniae vaccines and inoculated with PCV2 compared with PCV2-inoculated unvaccinated pigs. Swine producers and veterinarians may need to consider changes in vaccination protocols in herds with recurrent PCV2-associated PMWS.

Actinobacillus pleuropneumoniae↗

PubMed2002

LC-MS/MS determination of a farnesyl transferase inhibitor in human plasma and urine.

To support clinical pharmacokinetic studies in cancer patients, sensitive and specific methods for measuring 4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(3-chlorophenyl) piperazinone (I), a farnesyl transferase inhibitor (FTI), in human plasma and urine were developed and validated. The methods are based on high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization (APCI) and tandem mass spectrometric (MS/MS) detection in the positive ion mode using a heated nebulizer interface. Drug and internal standard were isolated from plasma or basified urine using automated solid-phase extraction on cyano cartridges. The organic extracts were dried, reconstituted in aqueous acetonitrile and injected into the system. Chromatographic separation of I and internal standard (IS) was achieved using a BDS Hypersil C8 analytical column, with a mobile phase consisting of acetonitrile:methanol:water (50:4:46) and trifluoroacetic acid (0.05%) at a flow rate of 0.6 ml/min. MS/MS detection was performed on a PE-Sciex API 300 tandem mass spectrometer operated in selected reaction monitoring mode. The parent-->product ions monitored were m/z 406-->195 for analyte I and m/z 448-->195 for the internal standard. Unusual in this method is that quantitation is accomplished using a secondary product ion, m/z 195, of drug I and IS. The assays were validated over the concentration range of 0.5-1000 ng/ml (1.2 nM to 2.5 microM, respectively) in plasma, and 2.5-500 ng/ml (6.2 nM to 1.23 microM) in urine. Accuracy was within +/-10% of nominal concentration at all levels in urine, and all but the lowest standard in plasma (+/-14% at 0.5 ng/ml). Intraday precision (expressed as coefficients of variation, CVs) for standard replicates and interday precision for quality control (QC) samples were less than 8% at all concentrations in both matrices. Detailed descriptions of the extraction procedure and analytical methodology used in the assay of I in plasma and urine are presented. This procedure may have utility in the quantitation of other imidazole-based FTIs with cyanobenzyl substructures.

Alkyl and Aryl Transferases↗

PubMed2002

Ascopyrone P, a novel antibacterial derived from fungi.

AIMS: To assess the antimicrobial efficacy of ascopyrone P (APP), a secondary metabolite formed by the fungi Anthracobia melaloma, Plicaria anthracina, Plic. leiocarpa and Peziza petersi belonging to the order Pezizales. METHODS AND RESULTS: In vitro testing using a well diffusion procedure showed that APP at a high concentration (approximately 5%) inhibited the growth of Gram-positive and Gram-negative bacteria. Using an automated microbiology reader, growth curve analysis showed that 2000-4000 mg l(-1) APP caused total or significant bacterial inhibition after incubation for 24 h at 30 degrees C. Against certain yeast strains, 1000- 2000 mg l(-1) APP enhanced growth, although at higher concentrations inhibition of some yeasts was observed. Clostridium and fungal strains were not sensitive to 2000 mg l(-1) APP. No significant cidal effect was observed after 2 h against Listeria monocytogenes or Escherichia coli. Results were identical whether the APP samples tested had been produced enzymatically or chemically. CONCLUSIONS: At a level of 2000 mg l(-1), APP demonstrated growth inhibitory activity against a broad range of bacteria, but not yeasts or moulds. SIGNIFICANCE AND IMPACT OF THE STUDY: A possible application for this novel natural antimicrobial is in food preservation, to control the growth of Gram-negative and Gram-positive bacteria in raw and cooked foods. Effective dosage levels would be 500-4000 mg kg(-1), depending on food type. The efficacy, organoleptic and safety aspects of this compound in food still need to be assessed.

Anti-Bacterial Agents↗

PubMed2002

A low-selenium diet increases thyroxine and decreases 3,5,3'triiodothyronine in the plasma of kittens.

The effect of a low-selenium diet on thyroid hormone metabolism was investigated in growing kittens. Twelve specific-pathogen-free kittens with ages ranging from 16 to 18 weeks were divided into two groups of equal number with equal sex distribution in each group. One group was fed a yeast-based low-selenium diet (0.02 mg Se/kg diet) while the other group was fed the same diet supplemented with Na2SeO3 at 0.4 mg Se/kg diet for 8 weeks. Food intake, body weight and body weight gain were not affected by the low-Se diet during the study period. However, kittens given the low-Se diet had significantly reduced plasma selenium concentration and glutathione peroxidase activity. Plasma total thyroxine (T4) increased and total 3,5,3'triiodothyronine (T3) decreased significantly in kittens fed the low-Se diet at the end of the study. These results suggest that type I deiodinase in cats is a selenoprotein- or a selenium-dependent enzyme.

Animals↗

PubMed2002

Excessive hepatic copper accumulation in jaundiced rats fed a high-copper diet.

The response of copper metabolism to dietary copper challenge was investigated in jaundiced rats with elevated plasma concentrations of conjugated bilirubin as a result of impaired canicular transport of bilirubin glucuronides. Control and jaundiced rats were fed purified diets with either normal (64 micromol Cu/kg) or high (640 micromol Cu/kg) concentration of added copper. Copper loading produced a greater increase in hepatic copper concentrations in the jaundiced than in control rats. The greater dietary-copper-induced increase in hepatic copper in the jaundiced rats can be explained by the observed smaller rise in biliary copper excretion and a greater efficiency of dietary copper absorption. In individual rats, there was a positive relationship between hepatic copper concentrations and biliary copper concentrations. It is suggested that not the transport of copper from liver cells to bile but that from plasma to bile is diminished in the jaundiced rats. The elevated plasma copper concentrations in the jaundiced rats may support this suggestion.

Animal Feed↗

PubMed2002

Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy.

The glycaemic and lipid effects of treatment with pioglitazone in combination with a stable insulin regimen were evaluated in patients with type 2 diabetes. Patients (n=566) receiving stable insulin regimens for > or = 30 days yet who had HbA1c > or = 8.0% and C-peptide > 0.7 microg/l were randomised to receive once-daily 15 mg pioglitazone, 30 mg pioglitazone, or placebo in a 16-week multicentre, double-blind, placebo-controlled trial. Per study protocol, the insulin dose was to remain unchanged, but could be decreased in response to hypoglycaemia. At the end of double-blind treatment, patients receiving pioglitazone (15 mg or 30 mg) showed statistically significant mean decreases relative to baseline HbA1c (-1.0 and -1.3, respectively; p<0.0001) and fasting plasma glucose (FPG) (-34.5 mg/dl [-1.92 mmol/l] and -48.0 mg/dl [-2.67 mmol/l], respectively; p<0.0001); these differences compared with placebo were also significant (p<0.0001). Pioglitazone (15 or 30 mg) yielded significant increases in HDL-C levels (mean increases ranging from +7.1% to + 9.3%) compared with baseline or placebo (p<0.01). The 30 mg dose also significantly reduced mean triglyceride levels (-23.7%) compared with placebo (p=0.0218). No consistent changes in TC or LDL-C levels were observed. The incidence of adverse events was similar in all treatment groups, although the incidences of weight increase, hypoglycaemia and oedema were higher among patients receiving insulin plus pioglitazone. There was no evidence of hepatotoxicity or drug-induced elevations of serum ALT > or = 3 x ULN. Pioglitazone, when added to stable insulin regimens, significantly improved HbA1c and FPG in type 2 diabetes. Pioglitazone treatment also provided significant benefit with respect to plasma HDL-C and triglyceride levels. Whether these lipid changes have an impact on overall diabetic complications remains to be determined.

Adult↗

PubMed2002

Inferior vena caval filters following deep vein thrombosis in patients with ruptured intracranial aneurysm.

Anticoagulant therapy is highly effective and prevents death in more than 95% of patients who have suffered pulmonary embolism following deep vein thrombosis. Inferior vena caval filters provide an alternative to full anticoagulation in those patients at highest risk of catastrophic haemorrhagic complications. We report on two patients who developed deep vein thrombosis following ruptured unsecured intracranial aneurysms. Inferior vena caval filters were inserted prior to aneurysm clipping, as a prophylactic measure to prevent pulmonary embolism while awaiting surgery. The patients did not receive anticoagulant therapy following successful clipping of the aneurysm. Both patients had clinical resolution of the lower limb swelling and no radiological evidence of propagation of the thrombus. During 18 months of follow-up there were no complications and no evidence of post-thrombotic syndrome.

Aneurysm, Ruptured↗

PubMed2001

Role of TGFbeta in development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice.

Nearly 100% of NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and produce anti-mouse thyroglobulin autoantibodies when they receive 0.05% NaI in their drinking water beginning at 8 wk of age. Our previous studies showed that TGFbeta1 mRNA was constitutively expressed in thyroids and spleens of normal NOD.H-2h4 mice but not other strains of mice. To determine whether TGFbeta might have a role in SAT, mice were given anti-TGFbeta mAb at various times during development of SAT. Anti-TGFbeta markedly inhibited development of SAT and production of anti-mouse thyroglobulin IgG1 autoantibodies. Anti-TGFbeta was most effective in inhibiting SAT when given during the time thyroid lesions were developing, i.e., starting 4 wk after administration of NaI water. The active form of the TGFbeta1 protein was present in thyroids of mice with SAT but not in normal NOD.H-2h4 thyroids. However, thyrocytes of normal NOD.H-2h4 thyroids did express latent TGFbeta1. TGFbeta1 protein expression in the thyroid correlated with SAT severity scores, and administration of anti-TGFbeta inhibited TGFbeta1 protein expression in both the thyroid and spleen. TGFbeta1 was produced primarily by inflammatory cells and was primarily localized in areas of the thyroid containing clusters of CD4(+) T and B cells. Depletion of CD8(+) T cells had no effect on TGFbeta1 protein expression. Activation of splenic T cells was apparently not inhibited by anti-TGFbeta, because up-regulation of mRNA for cytokines and other T cell activation markers was similar for control and anti-TGFbeta-treated mice. TGFbeta1 may function by promoting migration to, or retention of, inflammatory cells in the thyroid.

Animals↗

PubMed2001

Sequence and structure of the mouse gene for RPE65.

PURPOSE: To determine the genomic organization of the mouse gene for the retinal pigment epithelium (RPE) specific protein RPE65. METHODS: A genomic clone containing the entire Rpe65 gene was isolated from a mouse genomic P1 library. Fragments of this clone were subcloned and sequenced by automated fluorescent dideoxy DNA sequencing and analyzed. Direct sequencing of PCR amplification products was used to complete the structure. Primer extension analysis was used to determine the transcription start site. RESULTS: Southern hybridization of restriction digests of mouse genomic DNA reveals a likely single autosomal gene for Rpe65 with no evidence of pseudogenes. Sequence analysis of the mouse P1 clone for Rpe65 and fragments thereof reveals 14 exons distributed over 27 kbp. The transcription start site is located 57 bp upstream of the initiation codon. The protein encoded by the mouse Rpe65 gene is highly conserved when compared with RPE65s from other species. CONCLUSIONS: RPE65 is a highly conserved protein and it appears that the genes for the mouse and human RPE65s, at least, are also conserved in overall structure.

Amino Acid Sequence↗

PubMed2001

Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling.

In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor-stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems.

Adaptor Proteins, Signal Transducing↗

PubMed2001

A soluble dominant negative fibroblast growth factor receptor 4 isoform in human MCF-7 breast cancer cells.

Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases encoded by four closely related genes. FGFR 1, 2, and 3 have a number of isoforms derived by alternative splicing, alternative initiation and exon switching; however, FGFR4 has been reported to encode a single intact receptor with three extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and a split intracellular kinase. Here we describe a novel C-terminally truncated soluble isoform of FGFR4 expressed by human epithelial breast cancer MCF-7 cells. This isoform results from failure of splicing of intron 4 resulting in an mRNA species that encodes an in-frame premature stop codon. Cells transfected with the corresponding cDNA containing intron 4 express a truncated releasable protein that is identified in conditioned media. This soluble FGFR4 isoform (sFGFR4) abrogates the effect of FGF-1-induced MAPK phosphorylation and PRL gene activation. These findings represent the first description of an endogenous soluble C-terminally truncated FGFR4 isoform with FGF modulatory properties.

3T3 Cells↗

PubMed2001

Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver.

Peroxisome proliferators, which function as peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, induce peroxisomal, microsomal, and mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisome proliferation, in liver cells. Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. The assertion that synthetic PPARalpha ligands pose negligible carcinogenic risk to humans is attributable, in part, to the failure to observe peroxisome proliferation in human hepatocytes. To explore the mechanism(s) of species-specific differences in response to PPARalpha ligands, we determined the functional competency of human PPARalpha in vivo and compared its potency with that of mouse PPARalpha. Recombinant adenovirus that expresses human or mouse PPARalpha was produced and administered intravenously to PPARalpha-deficient mice. Human as well as mouse PPARalpha fully restored the development of peroxisome proliferator-induced immediate pleiotropic responses, including peroxisome proliferation and enhanced expression of genes involved in lipid metabolism as well as nonperoxisomal genes, such as CD36, Ly-6D, Rbp7, monoglyceride lipase, pyruvate dehydrogenase kinase-4, and C3f, that have been identified recently to be up-regulated in livers with peroxisome proliferation. These studies establish that human PPARalpha is functionally competent and is equally as dose-sensitive as mouse PPARalpha in inducing peroxisome proliferation within the context of mouse liver environment and that it can heterodimerize with mouse retinoid X receptor, and this human PPARalpha-mouse retinoid X receptor chimeric heterodimer transcriptionally activates mouse PPARalpha target genes in a manner qualitatively similar to that of mouse PPARalpha.

Animals↗