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Biomedical subjects

H Yu

Publications and source records attributed to H Yu.

At least 217 records · Page 12Linked to original sources
PubMed2000

Neurochemical neutralization of amphetamine-type stimulants in rat brain by the indatraline analog (-)-HY038.

Amphetamine-type stimulants are substrates for the proteins that serve as transporters for the biogenic amines dopamine (DA), serotonin (5HT), and norepinephrine (NE) and release these neurotransmitters from neurons located in the peripheral and central nervous system. Using indatraline as a lead compound, we sought to develop a long-acting depot medication that would neutralize the deleterious effects of amphetamine-type stimulants. Our first efforts produced (+/-)-HY038, and its two stereoisomers, which are hydroxy-substituted analog of indatraline. The K(i) values for [(3)H]DA reuptake inhibition by (-)-HY038 and (+)-HY038 were 3.2 +/- 0.1 and 32 +/- 1 nM. Similar results were obtained for [(3)H]5HT reuptake inhibition. (-)-HY038 and (+)-HY038 were slightly less potent at inhibiting [(3)H]NE reuptake (K(i) values of 20 +/- 2 and 159 +/- 12 nM). Low doses of (-)-HY038 blunted the ability of AMPH to release [(3)H]DA by shifting the AMPH dose-response curve to the right in a dose-dependent manner. (-)-HY038 also inhibited the ability of (+)-methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) to release [(3)H]DA. Low doses of (-)-HY038 blunted the ability of these stimulants to release [(3)H]NE and [(3)H]5HT by shifting their dose-response curves to the right in a manner similar to that seen for inhibition of [(3)H]DA release. These data indicate that (-)-HY038 inhibits the ability of AMPH, (+)-methamphetamine and (+/-)-MDMA to release DA, NE, and 5HT and therefore might have the potential to neutralize the neurotoxic and cardiovascular side-effects of substrate-type stimulants.

Amphetamine-Related Disorders↗
PubMed2000

Regional oral absorption, hepatic first-pass effect, and non-linear disposition of salmon calcitonin in beagle dogs.

The dose-dependent disposition, first pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100-1000 microg) demonstrated higher total plasma clearance (CL) and V(dss) than the low dose groups (1-25 microg). However, the MRT did not change for doses ranging from 10 to 1000 microg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic first-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V(dss) values, and it is hypothesized that increased renal blood flow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.

Administration, Oral↗
PubMed2000

Detection of biological threat agents by immunomagnetic microsphere-based solid phase fluorogenic- and electro-chemiluminescence.

This article reviews the recent development of two solid-phase chemiluminescence-based techniques, fluorogenic-chemiluminescence (FCL) and electro-chemiluminescence (ECL) for detection of biological threat agents. Both techniques entail a labeled sandwich immunoassay. The objectives of this work are to develop advanced techniques for sensitive and effective detection of a target analyte, particularly in cases where the analysis includes complex samples containing multiple contaminating factors. Other important considerations in developing such detection techniques include the ease of use, the rapid determination of the results, and system automation for field applications. In FCL, alkaline phosphatase is used as a label and this technique utilizes the dual features of fluorescence and visual color generated upon the presence of the fluorogenic compound, AttoPhos. The assay reaction is determined by measuring the fluorescence. In ECL, the label is a ruthenium-trisbipyridal, which is excited to a higher energy state by an electric current-driven redox reaction, and the extent of the reaction is assessed via photon emission. Both techniques depend upon the magnetic separation technique as a means to isolate the target immunological agents from the sample for analysis. This magnetic capture system allows for a reaction to occur on the electron effective-transfer zone in the ECL and also provides the reaction site for the labeled sandwich in the FCL. Comparative studies of these two techniques for detection of biological threat agents have been performed and the advantages of using magnetic microspheres versus conventional solid-phase matrices are discussed.

Biological Warfare↗
PubMed2000

Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters.

Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan-1-one (2), (1R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-diethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this study is that the in vivo activity of diethylpropion on biogenic amine transporters is most likely due to metabolite 2 as diethylpropion (1) and the metabolites 3a and 3b showed little or no effect in the assays studied. These studies also revealed that 2 acted as a substrate at the norepinephrine (IC50 = 99 nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibitor at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at the NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine.

Animals↗
PubMed2000

Construction and selection of the novel recombinant Escherichia coli strain for poly(beta-hydroxybutyrate) production.

Heterogeneous cloning of Vitreoscilla hemoglobin gene (vgb), lytic genes of phage lambda with S amber mutation (S(-)RRz) and PHB biosynthetic genes (phbCAB) in the same host strain E. coli JM105 was carried out for production of poly(beta-hydroxybutyrate) (PHB). A superior novel strain, VG1 (pTU14), was constructed and selected, which contained the vgb gene in the chromosomal DNA and the plasmid pTU14 containing S(-)RRz and phbCAB genes. When cultured in 100 ml of LBG medium in a 300-ml flask, all of the exogenous genes in VG1 (pTU14) were expressed. The cell concentration of VG1 (pTU14) grown by batch culture in a flask reached 10.2 gl(-1); PHB concentration, PHB content and PHB yield, which is the ratio of the PHB accumulation to the glucose consumption, were 8.54 gl(-1), 84% and 0.43 gg(-1), respectively. When cultured by batch-feeding of glucose in a 300-ml shaking flask, the cell concentration and PHB content reached 26 gl(-1) and over 96%, respectively.

Journal Article↗
PubMed2000

Inhibitory effects on HIV-1 protease of constituents from the wood of Xanthoceras sorbifolia.

From a methanolic extract of the wood of Xanthoceras sorbifolia, two new compounds, 29-hydroxy-3-oxotirucalla-7,24-dien-21-oic acid (3, xanthocerasic acid) and epigallocatechin-(4beta-->8, 2beta-->O-7)-epicatechin (6), were isolated, together with 11 known compounds. Of the isolated compounds, 3-oxotirucalla-7, 24-dien-21-oic acid (2), oleanolic acid (4), and 6 were found to be inhibitory substances against human immunodeficiency virus (HIV-1) protease, with their 50% inhibitory concentrations (IC(50)) being 20, 10, and 70 microg/mL, respectively. Condensed tannins of high molecular weights with epicatechin and epiafzelechin as the main extender units were found to be the most active principles of this plant (IC(50) values ca. 6.0 microg/mL).

Anthocyanins↗
PubMed2000

UVA-Induced DNA single-strand cleavage by 1-hydroxypyrene and formation of covalent adducts between DNA and 1-hydroxypyrene.

1-Hydroxypyrene (HOP), a metabolite found in the urine of humans and laboratory animals exposed to polycyclic aromatic hydrocarbons (PAHs), is known to be both acutely toxic and genotoxic. It has been widely used as a biomarker for studying PAH exposure. In this research, we have found that, upon UVA irradiation, HOP causes DNA single-strand cleavages and forms HOP-DNA covalent adducts. The UVA-induced cleavage of supercoiled plasmid PhiX174 DNA is dependent upon both HOP concentration and UVA dosage. A longer irradiation time or higher HOP concentration induces more DNA cleavage. Results of the photocleavage experiments carried out in the presence of reactive oxygen species scavengers, histidine, sodium azide, mannitol, SOD, and desferal indicate that both the superoxide free radical and singlet oxygen are likely involved in causing DNA single-strand cleavage. The photocleavage is inhibited by the presence of an excited singlet-state quencher, KI, indicating that it is an excited-state reaction. Along with light-induced DNA cleavage, HOP also forms DNA covalent adducts while being degraded upon light irradiation. Light-induced degradation of 20 microM HOP follows first-order reaction kinetics in a 10% methanolic buffer (10 mM phosphate) solution in the absence or presence of 40 microM calf thymus DNA, with degradation half-lives of 20 or 15 min, respectively. The shorter degradation half-life in the presence of DNA is due to the formation of the HOP-DNA covalent adduct. The formation of the HOP-DNA covalent adduct is evidenced by comparing the UV-vis absorption and fluorescence emission spectra of the pure HOP with those of the HOP-DNA adduct. The covalent HOP-DNA adduct produced due to irradiation was purified by either extensive dialysis (3 x 500 mL buffer solutions), phenol and chloroform extraction followed by ethanol precipitation, or chloroform extraction alone. The isolated HOP-DNA adduct has an absorption peak at 353 nm, which is 8 nm red-shifted compared to that of free HOP. The fluorescence emission for HOP-DNA is at least 70 times weaker than that for free HOP in solution. In summary, the findings with HOP reveal that, in addition to metabolic activation that eventually leads to the formation of alkylated DNA adducts or other forms of DNA damage, HOP may be activated by light to produce DNA single-strand cleavage and covalent DNA adducts. These DNA lesions can be sources of toxicity.

Animals↗
PubMed2000

Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer.

The androgen receptor (AR) is a transcription factor mediating the action of androgens. The AR gene is localized on chromosome X and it contains a series of CAG trinucleotide repeats. The length of the CAG repeats varies among individuals and this polymorphism is believed to be related to AR transcriptional activity. Studies have shown that fewer CAG repeats are associated with an increased risk as well as more aggressive forms of prostate cancer. Although AR is expressed in breast cancer and the impact of androgen and AR on breast cancer has been recognized, the role of the CAG repeats in breast cancer remains unknown. In this study, we measured the CAG repeats in breast cancer tissue using a PCR-based method. Of the 133 patients with primary breast cancer, 102 were heterozygous and 31 were homozygous. The mean CAG repeat number for homozygous women was 21; for heterozygous women the repeat number mean was 20 for the short allele and 24 for the long allele. The length of CAG repeats either in one allele or in both alleles was inversely correlated with the histological grade of breast cancer (r = -0.23 or -0.26, respectively, p < 0.05). An association between positive lymph nodes and fewer CAG repeats in both alleles was also suggested (p = 0.06). Furthermore, survival analysis indicated that the total number of CAG repeats in both alleles was associated with patient overall survival. With every CAG repeat increase, there was a 6% reduction in the risk of death (RR = 0.94, p = 0.03). The association remained significant after controlling for the homozygous and heterozygous status (RR = 0.92, p = 0.01). The association became no longer significant when clinical and pathological variables were adjusted in the analysis but this could be due to the reduction of sample size in the multivariate analysis. CAG heterozygosity and difference in number of CAG repeats between the two alleles were not associated with either disease features or patient survival. Our results suggest that longer CAG repeats may occur more frequently in less aggressive cancer and that the CAG repeats may play a role in breast cancer progression.

Adult↗
PubMed2000

Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.

We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

Animals↗
PubMed2000

Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20.

The checkpoint protein Mad2 inhibits the activity of the anaphase promoting complex by sequestering Cdc20 until all chromosomes are aligned at the metaphase plate. We report the solution structure of human Mad2 and its interaction with Cdc20. Mad2 possesses a novel three-layered alpha/beta fold with three alpha-helices packed between two beta-sheets. Using deletion mutants we identified the minimal Mad2-binding region of human Cdc20 as a 40-residue segment immediately N-terminal to the WD40 repeats. Mutagenesis and NMR titration experiments show that a C-terminal flexible region of Mad2 is required for binding to Cdc20. Mad2 and Cdc20 form a tight 1:1 heterodimeric complex in which the C-terminal segment of Mad2 becomes folded. These results provide the first structural insight into mechanisms of the spindle assembly checkpoint.

Amino Acid Sequence↗
PubMed2000

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

Adipose Tissue↗
PubMed2000

Bing de ling, a Chinese herbal formula, stimulates multifaceted immunologic responses in mice.

Bing de ling is a Chinese herbal formula most commonly used in complementary medical settings against viral disorders. We have found that bing de ling potentiates upregulation of immune activity when administered to mice in dosages proportional to those used clinically. These mice demonstrated significant elevation of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production in splenocytes and enhancement of macrophage, natural killer cell, and lymphokine-activated killer cell cytotoxicity. These data are consistent with bing de ling's clinically observed efficacy against viruses and identify the formula as a promising candidate for clinical trials against diverse diseases that may respond to increased immunologic activity.

Adjuvants, Immunologic↗
PubMed2000

Hepatocyte encapsulation for enhanced cellular functions.

An efficient bioartificial liver-assisted device can sustain the lives of patients with acute liver failure. Among different configurations of the bioreactor design, hepatocyte encapsulation has important features that satisfy most requirements of the device. We have encapsulated rat hepatocytes in a two-layer polymeric membrane by complex coacervation using a simple setup and demonstrated enhanced cellular functions up to three times higher than those of the monolayer control. These microcapsules of the functioning hepatocytes have a 2- to 3-microm outer layer of synthetic polymer with 25% 2-hydroxyethyl methacrylate, 25% methacrylic acid, and 50% methyl methacrylate and an inner layer of positively charged modified collagen as a suitable substrate for the enhanced cellular functions. Permeable only to small molecules up to albumin, the microcapsules should allow unimpeded exchange of nutrients, oxygen, growth factors, and metabolites but prevent attack by immunoglobulins of the immune system, and no "skin effect" of the collagen has been observed. Mechanical properties of the microcapsules measured with a nano-indentation method suggest that the microcapsules should be suitable for use in a bioartificial liver-assisted device.

Animals↗
PubMed2000

Genetic analysis of nitric oxide and endothelin in end-stage renal disease.

BACKGROUND: Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans. METHODS: The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software. RESULTS: Significant evidence for association with ESRD was detected for alleles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies). CONCLUSION: Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.

Adult↗
PubMed2000

Patient compliance is critical for equivalent clinical outcomes for breast cancer treated by breast-conservation therapy.

OBJECTIVE: To determine the compliance with a standard breast-conservation therapy (BCT) program in a predominantly indigent, minority population of patients with early breast cancer (stage I and II) served by a rural state institution in the South; to compare the clinical outcomes of this group with those reported in clinical trials; and to examine the socioeconomic factors that may have contributed to the rate of compliance. SUMMARY BACKGROUND DATA: Disease-free survival and overall survival in early breast cancer treated by BCT versus modified radical mastectomy are reported to be equivalent in prospective randomized trials. However, patients enrolled in clinical trials may not be representative of patients living in the various diverse communities that make up the United States. The authors' hypothesis is that patients enrolled in clinical trials at the national level may not be representative of indigent patients in the rural South and that clinical trial results may not be directly applicable. METHODS: A retrospective review of 55 women with early-stage breast cancer treated from 1990 to 1995 was performed. Clinical data, compliance with treatment and clinical follow-up, and recurrence rates were examined. Statistical analysis performed include the Fisher exact test, Kaplan-Meier survival analysis, and log-rank test. RESULTS: Full compliance (defined as completion of the entire course of radiation therapy and clinical follow-up) with the BCT program was observed in only 36% of patients. Fifteen of the 35 noncompliant patients did not complete radiation therapy. A significantly higher local failure rate was observed: 8 of these 15 patients (53%) have had local failure. In contrast, patients who were either in full compliance with the BCT program or were deficient only in that they missed part of their clinical follow-up had local failure rates of 5% (1/20) and 10% (2/20), respectively. Age, race, stage of cancer, economic status (measured by availability of medical insurance), distance of patient's residence from the hospital, and education level were evaluated as potential predictors of compliance. None predicted patient compliance, although a trend toward higher compliance was noted in patients with a higher education level, as determined by literacy testing. CONCLUSIONS: Compliance with the BCT protocol at the authors' institution was worse than reported in clinical trials, and noncompliance translated into a significant increase in the local failure rate. Factors examined suggest that literacy may play a role in predicting compliance. Although BCT should be discussed with all breast cancer patients, the judicious application of clinical trial data to an institution's local population is warranted.

Breast Neoplasms↗
PubMed2000

Computer-based radiation safety training for hospital radiation workers.

Conducting a hospital-based radiation safety training class may lead to temporary technologist staffing shortages resulting in a reduction of patient services or even the cessation of all routine patient services. Use of an interactive computer-based radiation safety training software program may provide a practical alternative for hospital diagnostic and therapeutic radiation departments, as well as other hospital departments utilizing radiation sources, in meeting annual radiation safety training requirements for radiation workers. Medical radiation workers' participation in computer-based radiation safety training can make a positive impact on radiation safety awareness in the hospital, assist license holders in satisfying regulatory training requirements, ensure maximum participation of staff technologists, and reduce the burden of technologist staffing shortages caused by traditional methods of training.

Computer-Assisted Instruction↗
PubMed2000

Lattice boltzmann method for compressible flows with high mach numbers

In this paper we present a lattice Boltzmann model to simulate compressible flows by introducing an attractive force. This scheme has two main advantages: one is to soften sound speed effectively, which greatly raises the Mach number (up to 5); another is its relative simple procedure. Simulations of the March cone and the comparison between theoretical expectations and simulations demonstrate that the scheme is effective in the simulation of compressible flows with high Mach numbers, which would create many new applications.

Journal Article↗