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Biomedical subjects

J Xu

Publications and source records attributed to J Xu.

At least 685 records · Page 38Linked to original sources
PubMed1998

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Adult↗
PubMed1998

Exclusion of chromosome 11q and the FcepsilonRI-beta gene as aetiological factors in allergy and asthma in a population of Dutch asthmatic families.

BACKGROUND: The beta subunit of the high-affinity receptor for IgE (FcepsilonRI-beta) is localized to chromosome 11q13 and has been reported by Cookson et al. to be in close genetic linkage with a gene for atopy. A maternally inherited association was found between the presence of a variant of FcepsilonRI-beta, Ile181Leu, and high total serum IgE levels (IgE > 100 IU). In a previous study of 20 Dutch families, we found no evidence for linkage of atopy or bronchial hyperresponsiveness (BHR) to chromosome 11q. OBJECTIVE: Recently segregation analysis in 92 families has given us evidence for two independent major loci accounting for 78% of the observed variance in total serum IgE levels, and linkage analysis using both sib-pair and LOD score methods has identified one major locus for regulation of IgE levels and BHR near the cytokine gene complex on chromosome 5q. The objective of this study is to pursue the identification of the second major locus. METHODS: We have studied markers in the area of the high affinity IgE receptor (FcepsilonRI-beta) on chromosome 11q (D11S1314, FcepsilonRI-beta and D11S987) in 83 families for whom DNA was available. Furthermore, our families have been examined for variance in the FcepsilonRI-beta gene, specifically for Leu181 and Leu181/Leu183 mutations. RESULTS: By sib-pair analysis, there is no evidence for linkage of total serum IgE levels or number of positive skin tests to these markers in our population. Similar negative results were obtained for affected sib-pair analysis of BHR, with the exception of D11S1314, which was significant at P=0.046. The FcepsilonRI-beta gene in 36 female probands, 44 male probands and 46 female spouses was sequenced for these mutations. For each of these 126 individuals sequencing of FcepsilonRI-beta demonstrated a wild-type sequence pattern, with no mutations found in anyone, male or female. CONCLUSION: We are unable to confirm the presence of significant mutations in FcepsilonRI-beta gene in our population, and we cannot confirm that the FcepsilonRI-beta gene is crucial to the pathogenesis of allergic inflammation in asthma.

Asthma↗
PubMed1998

Genetics of complex human diseases: genome screening, association studies and fine mapping.

Positional cloning has been applied successfully to many Mendelian disorders. Because of the public health significance, there is strong interest in mapping susceptibility genes for common disorders, such as asthma and allergy, that have a genetic component. Genome-wide screening has been very useful in detecting regions of the genome likely to contain susceptibility genes. There are multiple chromosomal regions implicated in asthma and now the difficult process of finding the genes and relevant mutations is underway. Two approaches that are being utilized are those of association studies in candidate genes, and haplotype sharing or identical by descent (IBD) mapping. Although these are useful approaches, it is important to realize the strengths and limitations of each. The level of significance needed for an initial study or a replication study should be considered in light of the prior evidence for studying a specific gene polymorphism. Haplotype-sharing approaches, although difficult to use in outbred heterogeneous populations, may provide important insight into fine mapping and gene localization.

Asthma↗
PubMed1998

Cloning and characterization of a mouse sigma1 receptor.

A cDNA clone (S2-1a) isolated from a mouse brain cDNA library, using a guinea pig sigma1 cDNA as probe, has high homology to the predicted protein sequence of the guinea pig (88%) and human (90%) sigma1 receptors. Northern analysis revealed a major mRNA of approximately 1.8 kb in a wide range of mouse tissues, with highest levels in brain, liver, kidney, and thymus. Southern analysis and chromosomal mapping in the mouse suggested a single-copy gene in region A5-B2 of chromosome 4. Expression of the clone in MCF-7 and CHO cells led to a pronounced increase in (+)-[3H]pentazocine binding with a selectivity profile consistent with sigma1 receptors. In vitro translation yielded a protein of approximately 28 kDa, as did transfection of a probe containing the hemagglutinin (HA) epitope (S2-1a.HA) into CHO cells, as determined by western analysis using an antibody directed against HA. (+)-[3H]-Pentazocine binding to immunopurified HA-tagged receptor demonstrated conclusively that S2-1a.HA encodes a high-affinity (+)-[3H]pentazocine binding site with characteristics of a murine sigma1 receptor. An antisense oligodeoxynucleotide designed from S2-1a potentiated opioid analgesia in vivo.

Amino Acid Sequence↗
PubMed1998

Nerve wrapping with vein grafts in a rat model: a safe technique for the treatment of recurrent chronic compressive neuropathy.

The surgical outcome in recurrent chronic nerve compression remains unsatisfactory. Clinically, it has been reported that vein grafts can be used to wrap the nerve, following nerve decompression, to improve the functional recovery of the nerve. In order to determine the safety and feasibility of the technique of vein wrapping of nerve, this study assessed the effect of vein-graft wrapping around normal nerve. In each of 30 rats, a segment of femoral vein was wrapped around the sciatic nerve. Functional, electrophysiologic, and histologic testing was performed at 9, 12 and 15 weeks postoperatively, and the results showed no significant differences between the experimental and control groups. Neither scar tissue between the nerve and the vein graft, nor demyelinization or degeneration of the nerve fibers were identified histologically. The study demonstrated that autogenous vein-graft wrapping did not result in any pathologic nerve entrapment. The technique of vein wrapping of nerve appears to be safe, feasible, and reliable. The results supported further study for the use of vein-graft wrapping in the surgical management of recurrent chronic nerve compression.

Action Potentials↗
PubMed1998

Arp2/3 complex from Acanthamoeba binds profilin and cross-links actin filaments.

The Arp2/3 complex was first purified from Acanthamoeba castellanii by profilin affinity chromatography. The mechanism of interaction with profilin was unknown but was hypothesized to be mediated by either Arp2 or Arp3. Here we show that the Arp2 subunit of the complex can be chemically cross-linked to the actin-binding site of profilin. By analytical ultracentrifugation, rhodamine-labeled profilin binds Arp2/3 complex with a Kd of 7 microM, an affinity intermediate between the low affinity of profilin for barbed ends of actin filaments and its high affinity for actin monomers. These data suggest the barbed end of Arp2 is exposed, but Arp2 and Arp3 are not packed together in the complex exactly like two actin monomers in a filament. Arp2/3 complex also cross-links actin filaments into small bundles and isotropic networks, which are mechanically stiffer than solutions of actin filaments alone. Arp2/3 complex is concentrated at the leading edge of motile Acanthamoeba, and its localization is distinct from that of alpha-actinin, another filament cross-linking protein. Based on localization and actin filament nucleation and cross-linking activities, we propose a role for Arp2/3 in determining the structure of the actin filament network at the leading edge of motile cells.

Acanthamoeba↗
PubMed1998

237Np: oxidation state in vivo and chelation by multidentate catecholate and hydroxypyridinonate ligands.

Chemically, 237Np(V) is as toxic as U(VI), and radiologically, about as toxic as 239Pu. Depending on redox conditions in vivo, 237Np exists as weakly complexing Np(V) (NpO2+) or as Np(IV), which forms complexes as stable as those of Pu(IV). Ten multidentate catecholate (CAM) and hydroxypyridinonate (HOPO) ligands with great affinity for Pu(IV) were compared with CaNa3-DTPA for in vivo chelation of 237Np. Mice were injected intravenously with 237NpO2Cl: those in a kinetic study were killed 1 to 2880 min; in ligand studies, fed mice were injected intraperitoneally with a ligand 5, 60, or 1440 min after 237Np(V) (molar ratio 5.6 to 73), mice fasted for 16 h were gastrically intubated with a ligand 3 min after 237Np(V) (molar ratio 5.6 to 274), and all were killed 24 h after ligand administration; tissues and excreta were radioanalyzed. Rapid plasma clearance and urinary excretion of 237Np(V) resemble U(VI); deposition and early retention in skeleton and liver resemble Pu(IV). The x-ray absorption near edge structure spectroscopy (XANES) spectra of femora of 237Np(V)-injected mice, compared with spectra of Np(V) and Np(IV) from reference solids, showed predominantly Np(IV). Significant in vivo 237Np chelation was obtained with all of the HOPO and CAM ligands injected at molar ratio 22; the HOPO ligands reduced 237Np in skeleton, liver, and other soft tissue, on average, to 72, 25, and 25% of control, respectively, while CaNa3-DTPA was ineffective. Two HOPO ligands injected 60 min after 237Np (molar ratio 5.6) significantly reduced body and liver 237Np, and three HOPO ligands given orally (molar ratio > or = 73) significantly reduced body and liver 237Np, compared with controls. Combined with earlier work, these results indicate that: the dominant neptunium species circulating and excreted in urine is Np(V), while that in bone and liver deposits is Np(IV); Np(V) must be reduced to Np(IV) before it can be stably chelated; efficient decorporation of neptunium requires multidentate ligands that form exceptionally stable actinide(IV) chelates and facilitate Np(V) reduction.

Administration, Oral↗
PubMed1998

A cepstral method for analysis of acoustic transmission characteristics of respiratory system.

The generation and transmission process of transmitted sound signals (TSS) is analyzed and a mathematical model of TSS is established in this paper. The power cepstral characteristics of TSS are studied based on the mathematical model and a new analysis method of acoustic transmission of respiratory system using homomorphic processing technique is proposed. The experimental results show that the normal respiratory system has only one formant, while the abnormal respiratory system presenting lung consolidation has two formants and the second formant plays important role in that system. This new method is a simple and effective one.

Adult↗
PubMed1998

Factors affecting biosynthesis by Xanthomonas albilineans of albicidin antibiotics and phytotoxins.

Albicidins are important factors in systemic pathogenesis by Xanthomonas albilineans, which causes the devastating leaf scald disease of sugar cane. They are also of substantial interest as antibiotics that selectively block prokaryote DNA replication. Albicidin biosynthesis is highly sensitive to medium composition. An optimized, chemically defined medium (SMG3) yielded 30-fold more albicidin from half the accumulated biomass, relative to sucrose peptone (SP) medium. Phosphate starvation stimulated albicidin production in SMG3 and SP media. Addition of other amino acids, ammonium ions or peptones to the defined medium increased the growth rate of X. albilineans XA3, but differentially inhibited albicidin biosynthesis. Knowledge of these factors indicates new approaches to understanding mechanisms of pathogenesis and resistance to sugar cane leaf scald disease, and to strain improvement for production of albicidin antibiotics.

Amino Acids↗
PubMed1998

Prenatal identification of de novo marker chromosomes using micro-FISH approach.

Chromosome microdissection combined with polymerase chain reaction (PCR) and reverse chromosome painting ('micro-FISH') is a powerful technique for the unequivocal identification of complex or subtle chromosomal aberrations. We have applied this technique to the prenatal diagnosis of three fetuses with de novo marker chromosomes. One small supernumerary satellited marker chromosome was shown to have originated from the fusion of the centromeric heterochromatin of one or both of chromosomes 14 and 22. The second marker was identified as i(9)(p10) while the third marker chromosome was shown to have been derived from the 1p13.1-1q21.3 region. At birth, the clinical outcome correlated well with that expected from the prenatal cytogenetic findings. Our study highlights the importance of the application of 'micro-FISH' to prenatal diagnosis.

Adolescent↗
PubMed1998

Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Trials Group.

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.

AIDS-Related Opportunistic Infections↗
PubMed1998

Selectivity of ferric enterobactin binding and cooperativity of transport in gram-negative bacteria.

The ligand-gated outer membrane porin FepA serves Escherichia coli as the receptor for the siderophore ferric enterobactin. We characterized the ability of seven analogs of enterobactin to supply iron via FepA by quantitatively measuring the binding and transport of their 59Fe complexes. The experiments refuted the idea that chirality of the iron complex affects its recognition by FepA and demonstrated the necessity of an unsubstituted catecholate coordination center for binding to the outer membrane protein. Among the compounds we tested, only ferric enantioenterobactin, the synthetic, left-handed isomer of natural enterobactin, and ferric TRENCAM, which substitutes a tertiary amine for the macrocyclic lactone ring of ferric enterobactin but maintains an unsubstituted catecholate iron complex, were recognized by FepA (Kd approximately 20 nM). Ferric complexes of other analogs (TRENCAM-3,2-HOPO; TREN-Me-3,2-HOPO; MeMEEtTAM; MeME-Me-3,2-HOPO; K3MECAMS; agrobactin A) with alterations to the chelating groups and different net charge on the iron center neither adsorbed to nor transported through FepA. We also compared the binding and uptake of ferric enterobactin by homologs of FepA from Bordetella bronchisepticus, Pseudomonas aeruginosa, and Salmonella typhimurium in the native organisms and as plasmid-mediated clones expressed in E. coli. All the transport proteins bound ferric enterobactin with high affinity (Kd </= 100 nM) and transported it at comparable rates (>/=50 pmol/min/10(9) cells) in their own particular membrane environments. However, the FepA and IroN proteins of S. typhimurium failed to efficiently function in E. coli. For E. coli, S. typhimurium, and P. aeruginosa, the rate of ferric enterobactin uptake was a sigmoidal function of its concentration, indicating a cooperative transport reaction involving multiple interacting binding sites on FepA.

Bacterial Outer Membrane Proteins↗
PubMed1998

Colony size can be used to determine the MIC of fluconazole for pathogenic yeasts.

This report describes a new statistical method for estimating the MIC of fluconazole for yeasts pathogenic to humans. This method is based on comparison of the colony sizes on solid media containing different concentrations of fluconazole. By this method, the MICs of fluconazole for 10 yeast strains were comparable to results obtained by the standard method recommended by the National Committee for Clinical Laboratory Standards. This method is simple to perform and easy to interpret. The turnaround time is faster than other methods. The method should be applicable to the determination MICs of other antifungal drugs for yeasts.

Antifungal Agents↗
PubMed1998

Identification of the cytoplasmic regions of fibroblast growth factor (FGF) receptor 1 which play important roles in induction of neurite outgrowth in PC12 cells by FGF-1.

Fibroblast growth factor 1 (FGF-1) induces neurite outgrowth in PC12 cells. Recently, we have shown that the FGF receptor 1 (FGFR-1) is much more potent than FGFR-3 in induction of neurite outgrowth. To identify the cytoplasmic regions of FGFR-1 that are responsible for the induction of neurite outgrowth in PC12 cells, we took advantage of this difference and prepared receptor chimeras containing different regions of the FGFR-1 introduced into the FGFR-3 protein. The chimeric receptors were introduced into FGF-nonresponsive variant PC12 cells (fnr-PC12 cells), and their ability to mediate FGF-stimulated neurite outgrowth of the cells was assessed. The juxtamembrane (JM) and carboxy-terminal (COOH) regions of FGFR-1 were identified as conferring robust and moderate abilities, respectively, for induction of neurite outgrowth to FGFR-3. Analysis of FGF-stimulated activation of signal transduction revealed that the JM region of FGFR-1 conferred strong and sustained tyrosine phosphorylation of several cellular proteins and activation of MAP kinase. The SNT/FRS2 protein was demonstrated to be one of the cellular substrates preferentially phosphorylated by chimeras containing the JM domain of FGFR-1. SNT/FRS2 links FGF signaling to the MAP kinase pathway. Thus, the ability of FGFR-1 JM domain chimeras to induce strong sustained phosphorylation of this protein would explain the ability of these chimeras to activate MAP kinase and hence neurite outgrowth. The role of the COOH region of FGFR-1 in induction of neurite outgrowth involved the tyrosine residue at amino acid position 764, a site required for phospholipase C gamma binding and activation, whereas the JM region functioned primarily through a non-phosphotyrosine-dependent mechanism. In contrast, assessment of the chimeras in the pre-B lymphoid cell line BaF3 for FGF-1-induced mitogenesis revealed that the JM region did not play a role in this cell type. These data indicate that FGFR signaling can be regulated at the level of intracellular interactions and that signaling pathways for neurite outgrowth and mitogenesis use different regions of the FGFR.

Amino Acid Sequence↗
PubMed1998

Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin.

The relationship among gender, lipopolysaccharide (LPS), and liver disease is complex. Accordingly, the effect of estrogen on activation of Kupffer cells by endotoxin was studied. All rats given estrogen intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by pretreatment with gadolinium chloride, a Kupffer cell toxicant. Peak serum tumor necrosis factor-alpha (TNF-alpha) values as well as TNF-alpha mRNA in the liver after LPS were twice as high in the estrogen-treated group as in the untreated controls. Plasma nitrite levels and inducible nitric oxide synthase in the liver were also elevated significantly in estrogen-treated rats 6 h after LPS. Furthermore, Kupffer cells isolated from estrogen-treated rats produced about twice as much TNF-alpha and nitrite as controls did in response to LPS. In addition, Kupffer cells from estrogen-treated rats required 15-fold lower amounts of LPS to increase intracellular Ca2+ than controls did, and Kupffer cells from estrogen-treated animals expressed more CD14, the receptor for LPS/LPS binding protein, than controls. Moreover, estrogen treatment increased LPS binding protein mRNA dramatically in liver in 6-24 h. It is concluded that estrogen treatment in vivo sensitizes Kupffer cells to LPS, leading to increased toxic mediator production by the liver.

Acute-Phase Proteins↗
PubMed1998

Synergistic cytotoxicity from nitric oxide and hyperoxia in cultured lung cells.

Exogenous nitric oxide (NO) is being tested clinically for the treatment of pulmonary hypertension in infants and children. In most cases, these patients receive simultaneous oxygen (O2) therapy. However, little is known about the combined toxicity of NO + hyperoxia. To test this potential toxicity, human alveolar epithelial cells (A549 cells) and human lung microvascular endothelial lung cells were cultured in room air (control), hyperoxia (95% O2), NO (derived from chemical donors), or combined hyperoxia + NO. Control cells grew normally over a 6-day study period. In contrast, cell death from hyperoxia was evident after 4-5 days, whereas cells neither died nor divided in NO alone. However, cells exposed to both NO and hyperoxia began to die on day 2 and died rapidly thereafter. This cytotoxic effect was clearly synergistic, and cell death did not occur via apoptosis. As an indicator of peroxynitrite formation, nitrotyrosine-containing proteins were assayed using anti-nitrotyrosine antibodies. Two protein bands, at molecular masses of 25 and 35 kDa, were found to be increased in A549 cells exposed to NO or NO + hyperoxia. These results indicate that combined NO + hyperoxia has a synergistic cytotoxic effect on alveolar epithelial and lung vascular endothelial cells in culture.

Cells, Cultured↗