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B Xu

Publications and source records attributed to B Xu.

At least 55 records · Page 3Linked to original sources

An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles.

We developed genotyping assays for CYP2A6*7 (Ile471Thr) and CYP2A6*8 (Arg485Leu). We found higher allelic frequencies in Japanese and Chinese versus Caucasians and identified an allele in which both substitutions occur together (CYP2A6*10). We created a homology model for predicting the impact of allelic variants on enzymatic activity and subsequently tested this in vivo in a pilot kinetic study. Consistent with our homology model predictions, we found (i) that CYP2A6*7 produces an enzyme that has decreased (not inactive) activity for metabolizing nicotine and coumarin; (ii) that CYP2A6*8 is unlikely to affect catalytic activity in vivo; and (iii) that having both substitutions together on an allele (CYP2A6*10) dramatically reduces function and may be fully inactive for some substrates. In conclusion, this study identifies, at relatively high frequency in Asians, an allele with decreased activity (may be substrate selective), a fully functional allele, and an allele containing both substitutions in which function is dramatically reduced.

Alleles↗

Continuous infusion of neurotrophin-3 triggers sprouting, decreases the levels of TrkA and TrkC, and inhibits epileptogenesis and activity-dependent axonal growth in adult rats.

Neurotrophin-3 (NT-3), a member of the neurotrophin family of neurotrophic factors, is important for cell survival, axonal growth and neuronal plasticity. Epileptiform activation can regulate the expression of neurotrophins, and increases or decreases in neurotrophins can affect both epileptogenesis and seizure-related axonal growth. Interestingly, the expression of nerve growth factor and brain-derived neurotrophic factor is rapidly up-regulated following seizures, while NT-3 mRNA remains unchanged or undergoes a delayed down-regulation, suggesting that NT-3 might have a different function in epileptogenesis. In the present study, we demonstrate that continuous intraventricular infusion of NT-3 in the absence of kindling triggers mossy fiber sprouting in the inner molecular layer of the dentate gyrus and the stratum oriens of the CA3 region. Furthermore, despite this NT-3-related sprouting effect, continuous infusion of NT-3 retards the development of behavioral seizures and inhibits kindling-induced mossy fiber sprouting in the inner molecular layer of the dentate gyrus. We also show that prolonged infusion of NT-3 leads to a decrease in kindling-induced Trk phosphorylation and a down-regulation of the high-affinity Trk receptors, TrkA and TrkC, suggesting an involvement of both cholinergic nerve growth factor receptors and hippocampal NT-3 receptors in these effects. Our results demonstrate an important inhibitory role for NT-3 in seizure development and seizure-related synaptic reorganization.

Animals↗

Correlates of pregnancy oestrogen, progesterone and sex hormone-binding globulin in the USA and China.

The objective of this study is to examine perinatal correlates of oestradiol (E2), oestriol (E3), progesterone and sex hormone-binding globulin (SHBG) among pregnant women in the USA and China. Three hundred and four Caucasian women in Boston and 335 Chinese women in Shanghai were studied. Levels of E2, E3, progesterone and SHBG were measured in maternal blood at weeks 16 and 27 of gestation, and correlated with maternal, gestational and perinatal characteristics. Height, weight and body mass index (BMI) before pregnancy is inversely associated with E2 and SHBG, whereas E3 is inversely associated with height and progesterone is inversely associated with weight and BMI. A previous live birth is associated with lower E2 and SHBG in the index pregnancy. Total gestation duration is inversely associated with E2, E3 and progesterone, whereas weight gain during pregnancy is inversely associated with progesterone and SHBG. In the US, pregnancies with female fetuses are characterized by significantly reduced progesterone. Pregnancy hormones are associated with several maternal, gestational and neonatal characteristics.

Adult↗

High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6.

AIM: Sera of patients with autoimmune liver diseases were investigated for the presence of autoantibodies binding to human biliary epithelial cells (BECs). Furthermore, their functional capacity was investigated by testing their capacity to fix complement as well as induce expression of various adhesion molecules and production of cytokines. METHODS: Sera from patients with various stages of primary sclerosing cholangitis (PSC; n=30), primary biliary cirrhosis (PBC; n=29), autoimmune hepatitis (AIH; n=25), and normal controls (n=12) were investigated for the presence of antibodies that reacted with unstimulated and cytokine stimulated BECs isolated from a normal healthy liver. To demonstrate organ specificity, lung epithelial cells (LECs) were used as control cells. Antibodies were tested for their functional capacity. RESULTS: Compared with controls (8%), significantly higher numbers of PSC patients (63%, p=0.001), but not PBC (37%, NS) or AIH (16%, NS) patients, had anti-BEC antibodies. In 90% of PSC patients, the autoantibodies reacted only with cytokine stimulated target cells. Lower numbers of PSC (6%), PBC (10%), and AIH (0%) patients had LEC antibodies. Other significant findings were that anti-BEC antibodies were found in (i) PSC patients with either the HLA-DRB1*0301 or DR2 allele compared with those without (p=0.007); and (ii) in PBC patients with end stage disease compared with those without (p=0.018). Furthermore, anti-BEC antibodies from PSC and PBC but not AIH patients induced BECs to produce high levels of the cytokine interleukin 6. IgM and IgG fractions isolated from PSC but not PBC and AIH sera induced significantly increased expression of the cell adhesion molecule CD44. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blot analysis of BEC membranes demonstrated a specific band of 40 kDa with PSC sera and 45, 42, 30, and 33 kDa bands with PBC sera, which were absent in control groups. CONCLUSION: Thus for the first time we have demonstrated the presence of functionally important autoantibodies to cell surface expressed antigens on the relevant target cells of destruction, namely BECs, in PSC and PBC. These finding have important implications for the pathogenesis of bile duct destruction in these patients.

Adult↗

Biological effects of hyperbaric oxygen on human severe periodontitis.

This paper reports the effects of Hyperbaric Oxygen (HBO2) in a controlled study of periodontitis in 24 patients. The patients received either HBO2 or no HBO2, and study teeth were divided into 4 groups based on treatment: 1-HBO2 therapy, 2-HBO2 + scaling, 3-scaling, 4-control. We measured indices of periodontal disease and gingival blood flow (GBF). The microorganisms in a periodontal pocket were stained and the percentage of straight rods (Rods), curved rods (Cur), fusiforms (Fusi) and spirochetes (Spiro) were observed. The numbers of anaerobic organisms were measured by routine anaerobic culture. Highly significant differences in Gingival Indices (GI), Sulcus Bleeding Indices (SBI), Probing Depth (PD), Attachment Loss (AL), Plaque Index (PLI), and GBF were seen in the HBO2, the HBO2 + Scaling and the Scaling Groups compared to the Control Group (P < 0.01). The number of subgingival anaerobes as well as the number of Rods, Cur, Fusi, and Spiro were reduced markedly in these three treatment groups. Statistically greater differences in clinical indices, GBF, subgingival anaerobe number and number of Rods, Cur, Fusi and Spiro were found by comparison of HBO2 + Scaling and HBO2 Groups, as well as between the HBO2 + Scaling and Scaling Groups, but no significant differences were observed in GI, SBI, PD, or AL between the HBO2 and Scaling Groups. In conclusion, HBO2 had beneficial therapeutic effects on severe periodontitis. HBO2 therapy combined with scaling and root planing was the most beneficial in the treatment of periodontitis. Clinical follow-up suggests that this treatment effect could last more than 1 year.

Adolescent↗

The influence of interpatient and intrapatient rectum variation on external beam treatment of prostate cancer.

PURPOSE: The rectal dose/volume relationship and inherent variations thereof are fundamental parameters to guide dose escalation in prostate cancer treatment. This study evaluates the effect of rectal dose/volume variation on the risk of rectal complication for different planning target volume (PTV) constructions. METHODS AND MATERIALS: Thirty prostate patients with multiple daily CT scans obtained during the treatment course were included in this retrospective study. The dose distribution was calculated based on the pretreatment CT image alone. Treatment plans were generated by applying the four-field-box beam arrangement to each of three different PTVs: PTVs with 0.5-cm and 1.0-cm uniform margins, and a patient-specific PTV constructed using treatment imaging feedback. For each of the 30 patients, the rectal wall as manifested on each of multiple CT images was delineated after image bony registration to the pretreatment CT image, and applied to the corresponding treatment plan to obtain the rectal wall dose-volume histogram (DVH). Interpatient and intrapatient rectal dose/volume variations were quantified accordingly. The corresponding uncertainty and sensitivity of the risk of rectal complication to the variations were evaluated for each of the three PTVs. Finally, the efficacy of using multiple CT images to reduce uncertainty in planning evaluation was examined. RESULTS: Sensitivity of the risk of rectal complication to rectal dose/volume variation strongly depends on the clinical target volume (CTV)-to-PTV margin or prescription dose, or both. Compared to the conventional two-dimensional (2D) prostate cancer treatment, the sensitivity for a conformal treatment can be 3 times higher or more. Due to the interpatient rectal dose/volume variation, the individual normal tissue complication probability (NTCP) was distributed from 10% to 37% when a common prescription dose was applied for all patients. The intrapatient rectal dose/volume variation introduces at least +/- 25% uncertainty in the NTCP calculation for at least 10% or 25% of the patients treated with the PTV of 1.0- or 0.5-cm margin, respectively. These uncertainties were larger for the smaller PTV, with the standard deviation up to 20%. By applying multiple CT image feedback, the NTCP uncertainty could be reduced by a factor of 2. CONCLUSIONS: Shape and position variation of rectum has less influence on treatment planning in the conventional 2D treatment of prostate cancer. However, this influence is quickly growing with high treatment dose or small CTV-to-PTV margins. To reduce the variation and uncertainties in the treatment planning evaluation associated with the inter- and intrapatient rectal dose/volume variation, the iso-NTCP model and treatment image feedback technique can be applied in dose escalation trials of prostate cancer treatment.

Algorithms↗

Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice.

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At approximately 5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

Animals↗

A novel growth suppressor gene on chromosome 17p13.3 with a high frequency of mutation in human hepatocellular carcinoma.

Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89-93, 1991; H. Nagai et al., Oncogene, 14: 2927-2933, 1997; V. Boige et al., Cancer Res., 57: 1986-1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177-1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full-length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene.

3T3 Cells↗

Cortical localization of reading in normal children: an fMRI language study.

BACKGROUND: fMRI provides a noninvasive means of identifying the location and organization of neural networks that underlie cognitive functions. OBJECTIVE: To identify, using fMRI, brain regions involved in processing written text in children. METHODS: The authors studied nine normal right-handed native English-speaking children, aged 10.2 years (range 7.9 to 13.3 years), with two paradigms: reading Aesop's Fables and "Read Response Naming" (reading a description of an object that was then silently named). Data were acquired using blood oxygen level-dependent fMRI. Group data were analyzed with statistical parametric mapping; individual data sets were analyzed with a region-of-interest approach from individual study t maps. The number of activated pixels was determined in brain regions and an asymmetry index (AI = [L - R]/[L + R]) calculated for each region. RESULTS: The authors found strong activation in the left middle temporal gyrus and left midfrontal gyrus and variable activation in left inferior frontal gyrus for both reading tasks in the group analysis (z > 5.5 to 9.1). All subjects had strong left-sided lateralization for both tasks in middle/superior temporal gyrus, inferior frontal gyrus, and middle frontal gyrus (AI = 0.76 to 1.0 for t = 4). Reading Fables activated twice as many pixels in temporal cortex as the Read Response Naming task; activation in dorsolateral prefrontal cortex was similar for both tasks. Small homologous right middle temporal region activation was seen with reading a fable. CONCLUSIONS: The neural networks that process reading appear to be lateralized and localized by middle to late childhood. Reading text paradigms may prove useful for identifying frontal and temporal language-processing areas and for determining language dominance in children experiencing epilepsy or undergoing tumor surgery.

Brain Mapping↗

Determination of the maximum specific uptake capacities for glucose and oxygen in glucose-limited fed-batch cultivations of Escherichia coli.

A simple pulse-based method for the determination of the maximum uptake capacities for glucose and oxygen in glucose limited cultivations of E. coli is presented. The method does not depend on the time-consuming analysis of glucose or acetate, and therefore can be used to control the feed rate in glucose limited cultivations, such as fed-batch processes. The application of this method in fed-batch processes of E. coli showed that the uptake capacity for neither glucose nor oxygen is a constant parameter, as often is assumed in fed-batch models. The glucose uptake capacity decreased significantly when the specific growth rate decreased below 0.15 h(-1) and fell to about 0.6 mmol g(-1) h(-1) (mmol per g cell dry weight and hour) at the end of fed-batch fermentations, where specific growth rate was approximately 0.02 h(-1). The oxygen uptake capacity started to decrease somewhat earlier when specific growth rate declined below 0.25 h(-1) and was 5 mmol g(-1) h(-1) at the end of the fermentations. The behavior of both uptake systems is integrated in a dynamic model which allows a better fitting of experimental values for glucose in fed-batch processes in comparison to generally used unstructured kinetic models.

Culture Media↗

Apoptosis in chronic rejection of human cardiac allografts.

BACKGROUND: We investigated the role of apoptosis (programed cell death) in the pathogenesis of chronic rejection. METHODS: Epicardial coronary arteries from cardiac allografts with chronic rejection were examined for apoptosis by the TUNEL assay. Double labeling was carried out using anti-CD3, anti-CD68, and anti-von Willenbrand factor (vWF) monoclonal antibodies. Additional immunostaining was carried using anti-Fas, anti-Fas-L, and anti-Bcl-2 monoclonal antibodies. Apoptosis-associated oligonucleosomal DNA degradation was assessed by DNA agarose gel electrophoresis. The transcription level of apoptosis-related caspase genes were determined using microarrays. RESULTS: Apoptotic cells (TUNEL+) were detected within the arterial wall and in perivascular areas. Double labeling demonstrated that apoptotic cells included T cells (CD3+), monocyte/macrophages (CD68+), and vascular endothelial cells (VWF+). Numbers and densities of TUNEL+ cells did not correlate with the degree of arterial stenosis. Apoptosis-associated oligonucleosomal DNA degradation was assessed by agarose gel electrophoresis of DNA, which showed DNA fragments of approximately 180 bp and multimers thereof (DNA laddering gel), which are characteristic for DNA fragmentation in apoptotic cells. Microarray analysis demonstrated that the apoptosis related caspases 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, were all transcribed (caspases 8, 9, and 10 were highly up-regulated). These results are consistent with the involvement of apoptosis in chronic rejection. Immunoreactivity for Fas/Fas-L was present at the sites of apoptotic cells. Immunoreactivity for Bcl-2 was present in areas with very few apoptotic cells. CONCLUSIONS: Apoptotic cells include T cells, monocyte/macrophages, and endothelial cells. Apoptosis, likely through the Fas/Fas-L system, is involved in the pathogenesis of chronic rejection in cardiac allografts.

Adult↗

Chromatographic behavior of poly(styrene-divinybenzene) encapsulated packing material for capillary electrochromatography.

Poly(styrene-divinylbenzene) encapsulated silica (PS-DES) was synthesized and its characteristics as capillary electrochromatography stationary phase were studied. On capillary columns packed with this stationary phase, the effects of acetonitrile concentration as well as pH values on electroosmotic flow, and the effect of the latter on column efficiency were evaluated. Aromatic hydrocarbons, polar and basic medicinal compounds were successfully separated by using reversed-phase elution. It was evident that selectivity based on pi-pi electronic interaction between solute and stationary phase molecules contributed to the separation. Peaks in the chromatograms obtained were generally symmetrical. At a pH of the mobile phase as high as 11.2, the stationary phase was still stable after more than 160 h of exposure.

Adsorption↗

Physiological responses to mixing in large scale bioreactors.

Escherichia coli fed-batch cultivations at 22 m3 scale were compared to corresponding laboratory scale processes and cultivations using a scale-down reactor furnished with a high-glucose concentration zone to mimic the conditions in a feed zone of the large bioreactor. Formate accumulated in the large reactor, indicating the existence of oxygen limitation zones. It is suggested that the reduced biomass yield at large scale partly is due to repeated production/re-assimilation of acetate from overflow metabolism and mixed acid fermentation products due to local moving zones with oxygen limitation. The conditions that generated mixed-acid fermentation in the scale-down reactor also induced a number of stress responses, monitored by analysis of mRNA of selected stress induced genes. The stress responses were relaxed when the cells returned to the substrate limited and oxygen sufficient compartment of the reactor. Corresponding analysis in the large reactor showed that the concentration of mRNA of four stress induced genes was lowest at the sampling port most distant from the feed zone. It is assumed that repeated induction/relaxation of stress responses in a large bioreactor may contribute to altered physiological properties of the cells grown in large-scale bioreactor. Flow cytometric analysis revealed reduced damage with respect to cytoplasmic membrane potential and integrity in cells grown in the dynamic environments of the large scale reactor and the scale-down reactor.

Acetic Acid↗

The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease.

Nerve growth factor (NGF) is important for regulation, differentiation, and survival of peripheral and central nervous system neurons, including basal forebrain cholinergic neurons (BFCN) which degenerate in Alzheimer's disease (AD). Mature NGF protein is processed from a larger precursor, proNGF. We demonstrate that proNGF is the predominant form of NGF in mouse, rat, and human brain tissue, whereas little or no mature NGF is detected. Previous reports showed NGF protein, measured by ELISA, is increased in AD BFCN target regions such as hippocampus and cortex. Using Western blotting, we demonstrate a twofold increase in proNGF in AD parietal cortex compared to controls, indicating that it is this precursor form, proNGF, that accumulates in AD. This increase may reflect either a role for biologically active proNGF or posttranslational disturbances in NGF biosynthesis that decrease the processing of proNGF to mature NGF in AD.

Aged↗

Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes.

Gene therapy targeted at the respiratory epithelium holds therapeutic potential for diseases such as cystic fibrosis and alpha-1 anti-trypsin deficiency. A variety of approaches such as intranasal or intratracheal instillation and aerosol delivery have been utilized to target genes to the airways. Polyethylenimine (PEI), a linear or branched polycationic polymer, has been used for delivery of genes to various organs. In this study, using fluorescein isothiocyanate (FITC)-labeled branched PEI, we initially examined the localization of PEI in the lungs after aerosol delivery to Balb/C mice. Further, after aerosol delivery of PEI-CAT DNA, in situ immunostaining for chloramphenicol acetyl transferase (CAT) protein was used to localize the transgene expression within the lungs. Immunohistochemistry for CAT, as well as localization of FITC-labeled PEI, revealed that after aerosol delivery, the PEI-DNA complexes deposit and subsequently transfect most of the epithelial cells in the conducting airways (including the peripheral airways). High levels of CAT were detected at 24 h after aerosol exposure and significant CAT expression was detected in the lungs up to 28 days after a single aerosol exposure. The data suggest that aerosol delivery of PEI-DNA complexes could be effective for the treatment of pulmonary diseases such as cystic fibrosis and alpha-1 anti-trypsin deficiency.

Administration, Inhalation↗

Developmental aspects of pediatric fMRI: considerations for image acquisition, analysis, and interpretation.

Functional MRI provides a powerful means to identify and trace the evolution, development, and consolidation of cognitive neural networks through normal childhood. Neural network perturbations due to disease and other adverse factors during development can also be explored. Studies performed to date suggest that normal children older than 5 years show activation maps comparable to adults for similar cognitive paradigms. Minor differences in adult and pediatric activation maps may reflect age dependent strategies or maturation of cognitive networks. However, there are important physiologic and anatomic differences in children, varying with age, that may affect the acquisition, analysis, and interpretation of pediatric fMRI data. Differences between children and adult fMRI comparison studies may reflect technical aspects of data acquisition as much as developmental and brain maturation factors.

Aging↗

Silent mixed corticotroph and somatotroph macroadenomas presenting with pituitary apoplexy.

We discuss three unique cases of pituitary macroadenoma presenting with pituitary hemorrhage but without typical endocrine symptomatology. Immunohistochemical analysis indicated positive reactivity for adrenocorticotropic hormone (ACTH) and growth hormone (GH), and in situ hybridization indicated the expression of proopiomelanocortin (POMC) and GH mRNA. We designated these cases silent mixed corticotroph and somatotroph adenoma. Patient 1 was a 30-year-old man, patient 2 was a 29-year-old woman, and patient 3 was a 59-year-old woman. All patients presented with a headache of sudden onset and visual disturbance. The patients did not exhibit typical Cushing's or acromegalic features. Serum ACTH level was remarkably elevated in patient 1, and slightly elevated in patients 2 and 3. In all patients, serum GH levels were within normal range and magnetic resonance imaging revealed an intra- and suprasellar mass with pituitary hemorrhage. Transnasal pituitary surgery in the three patients disclosed a pituitary adenoma producing ACTH and GH. In patient 2, the residual adenoma reappeared along with an intratumoral hemorrhage, and was resected by secondary transnasal surgery. Silent mixed corticotroph and somatotroph adenomas are characterized by the following: no endocrine symptoms; presentation dominated by mass effect symptoms; macroadenoma presenting with acute pituitary hemorrhage; and production of both ACTH and GH.

Adenoma↗