[International expert consensus on gene therapy for hereditary hearing loss: based on clinical trials].
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Journal Article↗
Biomedical subjects
W Yuan
Publications and source records attributed to W Yuan.
Increased glycophorin A somatic cell variant frequency in arsenic-exposed patients of Guizhou, China.
Exposure to arsenic through domestic burning arsenic-containing coal causes various tumors in a population of Guizhou, China. The glycophorin A (GPA) assay is a human mutation assay detecting somatic variation in erythrocytes expressing the MN blood type, and was used to assess genotoxicity of arsenic-exposed patients. Peripheral blood was collected from 18 adult healthy subjects and 40 arsenic-exposed patients in heparin-treated tubes. Erythrocytes were isolated, fixed in formalin and immuno-labeled with fluorescent antibodies against GPA, followed by flow cytometry analysis. Arsenic exposure increased the variant frequency (expressed as the number of variant red cells per 10(6) erythrocytes): NN, 3.7 in healthy subjects versus 21.2 in arsenic-exposed patients; N phi, 12.6 versus 33.1; MM, 13.1 versus 110; and M phi, 5.2 versus 20.3. The total GPA variant frequency was increased about five-fold (34.7 in healthy subjects versus 185 in arsenosis patients). Furthermore, the variant frequency was significantly higher in skin tumor-bearing patients: NN, 19.4 in arsenic-exposed non-tumor patients versus 31.5 in tumor-bearing patients; N phi, 29.5 versus 54.5; MM, 102 versus 159; M phi, 15.9 versus 45.1. Total GPA variant frequency in arsenic-exposed patients bearing skin tumors was significantly increased compared to patients without skin tumors (167 versus 290). The relationship between arsenic exposure history and GPA variant frequency was less evident. These data demonstrate that arsenic exposure is associated with mutations at the GPA locus, an effect exaggerated in patients bearing arsenic-induced skin tumors. The variant frequency of GPA could be a useful biomarker for arsenic exposure and arsenic carcinogenesis.
Adult↗
The high integration and differentiation potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus.
Cell therapy is thought to have a central role in restorative therapy, which aims to restore function to the damaged nervous system. The purpose of this study was to establish an autologous neural stem cell (NSC) transplantation model using adult rats and to compare survival, migration, and differentiation between this system and allogeneic NSC transplantation. Furthermore, we compared the immunologic response of the host tissue between autologous and allogeneic transplantation. NSCs were removed from the subventricular zone of adult Fischer 344 rats using stereotactic methods. NSCs were expanded and microinjected into normal hippocampus in the autologous brain. Allogeneic NSC (derived from adult Wistar rats) transplantation was performed using the same procedure, and hippocampal sections were analyzed immunohistologically 3 weeks post-transplantation. The cell survival and migration rate were higher for autologous transplantation than for allogeneic transplantation, and the neuronal differentiation rate in the autologous transplanted cells far exceeded that of allogeneic transplantation. Furthermore, there was less astrocyte and microglia reactivity in the host tissue of the autologous transplantation compared with allogeneic transplantation. These findings demonstrate that immunoreactivity of the host tissue strongly influences cell transplantation in the CNS as the autologous transplantation did not induce host tissue immunoreactivity; the microenvironment was essentially maintained in an optimal condition for the transplanted cells.
Animals↗
Fertilization by intracytoplasmic sperm injection (ICSI) does not impair subsequent pregnancy outcome following frozen embryo transfer (ET) as determined by a large retrospective analysis.
PURPOSE: To determine if fertilization by intracytoplasmic sperm injection (ICSI) adversely affects pregnancy outcome following frozen embryo transfer (ET). METHODS: Retrospective analysis of frozen ETs where the oocytes were fertilized by conventional insemination vs ICSI was carried out. RESULTS: No difference in pregnancy outcome was found in women up to age 42. There was a non-significant trend for lower pregnancy rates in women age 43 and older. CONCLUSIONS: In the largest series to date by far these data convincingly show that fertilization by ICSI does not impair outcome following frozen ET.
Adult↗
A comparison of luteal phase support in graduated estradiol/progesterone replacement cycles using intramuscular progesterone alone versus combination with vaginal suppositories on outcome following frozen embryo transfer.
PURPOSE: To compare pregnancy outcome following frozen embryo transfer according to type of progesterone (P) support given in the luteal phase. METHODS: Retrospective cohort analysis of frozen embryo transfer (ET) cycles in which ovulation was suppressed by graduated estradiol in the follicular phase. Two P regimens in the luteal phase were compared: P vaginal suppositories and intramuscular P vs intramuscular alone. RESULTS: The clinical and viable pregnancy rates were significantly higher for the women receiving only intramuscular P (57.6% and 43.7%) vs those receiving combined therapy (45.9% and 35.6%, respectively). The implantation rates were not significantly different (22.6% vs 19.5%). CONCLUSION: The increased pregnancy rates with intramuscular P may have been related to a higher number of embryos transferred (3.69 vs 3.26). Nevertheless, intramuscular P alone is at least as effective, if not more effective, than combined therapy for frozen embryo transfers.
Adult↗
Evidence using a shared oocyte pool that the sperm rather than the oocyte in some cases may be responsible for the production of embryos with a high percentage of fragmented blastomeres--case report.
PURPOSE: Hypothesis--a sperm defect rather than an oocyte problem may occasionally be responsible for blastomere fragmentation. METHODS: The morphology of embryos in pairs of women producing embryos from a common pool of oocytes but fertilized by two different sperm sources was performed to see if a pair could be detected where one woman produced embryos with very little blastomere fragmentation vs the other woman having embryos with extensive fragmentation. RESULTS: An oocyte donor was identified who produced 49 oocytes resulting in 17 embryos for the infertile donor to evaluate and 13 for the recipient. Almost all of the donor embryos showed extensive fragmentation vs very little for the recipient embryos. CONCLUSION: The sperm, in some cases at least, may be the etiologic factor for blastomere fragmentation.
Adult↗
A comparison of in vitro fertilization outcome by culture media used for developing cleavage-stage embryos.
PURPOSE: To determine whether removing glucose and phosphate from media used for developing cleavage-stage embryos improves outcome following transfer of fresh or frozen embryos. Furthermore the study would evaluate the efficacy of adding nonessential amino acids and glutamate to media. METHODS: Embryo development was rotated on a weekly basis in human tubal fluid (HTF), versus two media relatively devoid of glucose and phosphate (e.g., P1), with one having the addition of essential amino acids and glutamate (Quinn's Advantage Medium). RESULTS: For fresh cycles, the implantation rate was significantly higher for Quinn's. There was less fragmentation with P1 and Quinn's. For frozen cycles, the viable pregnancy, implantation rates and embryo quality were higher for Quinn's and P1 than HTF. CONCLUSION: Removal of glucose and phosphate for day-2 embryos improves in vitro fertilization outcome after embryo transfer. It is not clear if adding certain non-essential amino acids and glutamate provides further improvement.
Adult↗
Development of sustainability indicators by communities in China: a case study of Chongming County, Shanghai.
Public participation as a means of identifying sustainability indicators for Chongming County, Shanghai, China was evaluated by an international group drawing on established best practice. An initial 'long list' of 86 sustainability indicators, based on previous indicator systems developed in China, was identified. This 'long list' was reduced via consultations with local academics and local-government officers from Shanghai City and Chongming County to a 'short list' of 17 indicators. This short-list was subjected to further community consultation involving 159 local-government officers, teachers, students (aged 12-14 years), farmers and workers. Data from the consultations indicated differences in the understanding of sustainable development among the different sectors. By combining the data from the different sectors it was possible to identify a consensus around 4 core and 7 additional indicators. These are proposed as indicators which could be used to steer local activities directed towards sustainable development. The list of indicators produced by the people of Chongming Island was compared to local indicator systems in Europe. In comparison with European lists the Chongming list was found to have a greater emphasis on economic development but a similar level of concern for environmental matters. This study has special significance as it reports on the implementation of a process involving local resident participation in the process of sustainable development in China.
Adolescent↗
Effect of transferring frozen-thawed embryos resulting from fertilization of immature oocytes matured one day in culture prior to intracytoplasmic sperm injection (ICSI) on implantation rates.
PURPOSE: To evaluate whether it is efficacious to allow immature (metaphase I or germinal vesicle stage) oocytes to incubate one more day and then perform ICSI. METHOD: A retrospective study of frozen embryo transfers (ET) of deselected frozen embryos was performed to see if inclusion of a higher percentage of embryos derived from in vitro maturation of oocytes resulted in lower implantation rates. RESULTS: The implantation rate following transfer of frozen-thawed embryos, where embryos derived from immature oocytes constituted < or = 40% of the embryos (group 1) was similar to group 2 with > 40% (11.3% vs 9.8%). However, group 1 had a 10.2% implantation rate for viable (past first trimester) sacs vs only 4.3% for group 2. CONCLUSIONS: Pregnancies from transfer of frozen-thawed embryos derived from in vitro cultured immature oocytes are as likely to implant as the other deselected frozen-thawed embryos.
Cryopreservation↗
Evolution of the Shanghai city region 1978-1998: an analysis of indicators.
Building on a description of the present situation in Shanghai, a series of ten regionally relevant indicators are identified and described. Using data from 1978-1998, relationships between these economic, social and environmental indicators are explored using correlation and regression analysis. The analysis indicated that, in Shanghai, conflict between economy and environment existed throughout the research period and the evolution of the city region system seems to lack regularity. The key elements affecting trends in the development of the Shanghai city region are Gross Domestic Product, Total Investment and Urban Living Area per Head. The city region system seemed more sustainable, indicated by an improvement in environmental quality and relative lower investment growth rate, when the annual change rate of Gross Domestic Product was less than 7-8%.
China↗
Association between protease-specific proteolytic cleavage of brevican and synaptic loss in the dentate gyrus of kainate-treated rats.
Proteolytic fragments generated by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs)-mediated cleavage of the aggregating chondroitin sulfate proteoglycan, brevican, have been identified, but not localized in the CNS. The purpose of this study, using kainate-induced CNS lesion, was to examine the spatial and quantitative relationship between ADAMTS1 and 4 mRNA expression and ADAMTS-mediated cleavage of brevican (as determined by the abundance of the neo-epitope QEAVESE at the C-terminal of the cleaved brevican G1 domain). In untreated rats, in situ hybridization and reverse transcriptase polymerase chain reaction indicated that ADAMTS4 expression was higher than ADAMTS1 and was localized to hippocampus, temporal lobe and other areas of cortex, striatum and hypothalamus. ADAMTS4 mRNA expression in these regions correlated with the presence of the QEAVESE neo-epitope, which was concentrated in perineuronal nets and in neuropil. In rats that seized after kainate, there was a dramatic elevation in ADAMTS1 and ADAMTS4 transcript that correlated and co-localized with a robust elevation in an extractable, 55-kDa fragment of brevican in temporal lobe and hippocampus. This fragment consisted, at least in part, of the ADAMTS-cleaved epitope G1-QEAVESE. The kainate-induced elevation in this ADAMTS-cleaved fragment was localized to amygdaloid and thalamic nuclei, hippocampus, caudate-putamen, cingulate cortex, and the outer molecular layer of the dentate gyrus where it was accompanied by a robust elevation in ADAMTS1 and 4 mRNA and a 28% decline in synaptic density 5 days after kainate.Thus, complexes of extracellular matrix proteins that exist in perineuronal nets and in the neuropil are cleaved by specific matrix-degrading proteases at early time points during excitotoxic neurodegeneration. The observed ADAMTS-induced cleavage of brevican in the dentate outer molecular layer is closely associated with diminished synaptic density, and may, therefore, contribute to synaptic loss and/or reorganization in this region.
ADAM Proteins↗
Evidence that the adverse effect of controlled ovarian hyperstimulation on successful pregnancy outcome following embryo transfer may be related to premature trophoblast invasion.
PURPOSE: To determine if premature trophoblast invasion may be a contributing factor to lower fecundity associated with controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF). METHODS: Blood samples were obtained three-five days after ET to measure expression by lymphocytes of a 34 kDa protein known as the progesterone-induced blocking factor (PIBF) using an immunocytochemistry technique. Clinical and viable pregnancy rates were determined according to whether PIBF was detected or not. RESULTS: Progesterone-induced blocking factor was positive in 14 of 67 (21%). Clinical pregnancy rates following fresh ET were 7.1% for those positive for PIBF versus 43.4% for those negative for PIBF. CONCLUSIONS: Progesterone-induced blocking factor production requires allogeneic induction of progesterone receptors in gamma/delta T-cells. This suggests early detection of PIBF may be related to premature trophoblast invasion possibly into an endometrium not yet prepared for the trophoblast, thus possibly leading to early immune rejection of the fetus.
Adult↗
Assessment of equivalence on multiple endpoints.
Some clinical trials aim to demonstrate therapeutic equivalence on multiple primary endpoints. For example, therapeutic equivalence studies of agents for the treatment of osteoarthritis use several primary endpoints including investigator's global assessment of disease activity, patient's global assessment of response to therapy, and pain. In this paper, thoughts on simultaneous equivalence assessment on three endpoints are presented. As pointed out by Berger and Hsu (1996), the conventional intersection-union test can be conservative. Simulation and computation are conducted to provide an insight on the conservativeness. We also provide a method to lower the confidence level and at the same time maintain the type I error when endpoints have normal distributions and are independent. If, in a particular analysis, the goal is to demonstrate equivalence on as many endpoints as possible, a step-up procedure can be used for selecting those endpoints for which equivalence may be demonstrated. This step-up procedure at the same time controls experimentwise error rate. The techniques are illustrated by a data example.
Biometry↗
Class I and III polyhydroxyalkanoate synthases from Ralstonia eutropha and Allochromatium vinosum: characterization and substrate specificity studies.
Class I and III polyhydroxyalkanoate (PHA) synthases catalyze the conversion of beta-hydroxybutyryl coenzyme A (HBCoA) to polyhydroxybutyrate. The Class I PHA synthase from Ralstonia eutropha has been purified by numerous labs with reported specific activities that vary between 1 and 160 U/mg. An N-terminal (His)6-PHA synthase was constructed and purified with specific activity of 40 U/mg. The variable activity is shown to be related to the protein's propensity to aggregate and not to incomplete post-translational modification by coenzyme A and a phosphopantetheinyl transferase. The substrate specificities of this enzyme and the Class III PHA synthase from Allochromatium vinosum have been determined with nine analogs of varied chain length and branching, OH group position within the chain, and thioesters. The results suggest that in vitro, both PHA synthases are very specific and provide further support for their active site structural similarities. In vitro results differ from studies in vivo.
Acyltransferases↗
Neurophysiological evidence of spared upper motor conduction fibers in clinically complete spinal cord injury: discomplete SCI in rats.
Motor evoked potentials (MEP) were recorded and characterized by epidural electrodes (scMEP) and extracellular microelectrodes (exMEP) on T(13) level from 10 normal rats and 40 rats with chronic spinal cord injury (SCI). The spinal cord of 40 anesthetized rats were injured with various severity (sham, 35, 70, and 100 g/cm impact injury) at T(8)-T(9) cord using Allen's drop model. The incline plane and Tarlov techniques were investigated to assess clinical neurological function. MEPs in the normal rats elicited by applying transcortical suprathreshold stimulation consisted of 3-4 early negative peaks (N(1), N(2), N(3), N(4)) followed by several late waves. The N(1) and N(2) peaks had their maximal amplitudes in the anterior and ventrolateral funiculus, respectively, irrespective of the polarity of stimulation, which indicated that these impulses were conducted mostly through the extrapyramidal pathways. The 100 g/cm impact injury or transection of the cord caused abolishment of the MEP signals distal to the lesion, whereas the 35 g/cm injury resulted in a latency shift and amplitude decrement of the MEP peaks. Out of 20 rats with 70 g/cm injuries, 18 showed clinically paraplegia. Among them, seven had neurophysiological evidence of residual conduction pathways through the injured cord segment, such as the presence of N(1) and N(2) peaks in scMEP or exMEP. After 4-aminopyridine (4-AP) administration (1 mg/kg), the amplitude of spared exMEP increased significantly and spread more widely. These results suggest that MEPs evoked by transcortical stimulation travel mostly in the extrapyramid tract. The present study provides further direct and objective electrophysiological evidences of spared functional axons after discomplete SCI, since many other studies on this field have achieved similar results previously. Furthermore, pharmaceutical treatment with 4-AP or other K(+) channel blocking agents proved to be a potential therapeutic strategy for patient with chronic SCI.
Animals↗
Transforming growth factor-beta repression of matrix metalloproteinase-1 in dermal fibroblasts involves Smad3.
Enhanced production of matrix metalloproteinase-1 (MMP-1, collagenase-1) is implicated in pathological tissue destruction. Transforming growth factor-beta (TGF-beta) prevents cytokine-induced MMP-1 gene expression in fibroblasts. In these studies, we examined the hypothesis that repression of MMP-1 may be mediated through the Smad signaling pathway. The results showed that Smad3 and Smad4, but not Smad1 or Smad2, mimicked the inhibitory effect of TGF-beta and abrogated interleukin-1beta (IL-1beta)-induced stimulation of MMP-1 promoter activity and NFkappaB-specific gene transcription in dermal fibroblasts. Experiments with truncation mutants indicated that both MH1 and MH2 domains of Smad3 were necessary for inhibitory activity. Dominant negative mutants of Smad3 or Smad4 and antagonistic Smad7, which disrupts ligand-induced Smad3 phosphorylation, abrogated the repression of MMP-1 transcription by TGF-beta. Similar results were obtained using immunoblot and Northern analysis. Furthermore, TGF-beta failed to repress MMP-1 promoter activity in Smad3-deficient murine embryonic fibroblasts. These results implicated cellular Smads in mediating the inhibitory effects of TGF-beta. Overexpression of the transcriptional co-activator p300, but not its histone acetyltransferase (HAT)-deficient mutant, was able to relieve repression of MMP-1 gene expression, suggesting that Smad-dependent inhibition may be due to increased competition between Smad proteins and IL-1beta signaling pathways for limiting amounts of cellular p300. Together, these results demonstrate that MMP-1 is a target for negative regulation by TGF-beta through cellular Smad3 and Smad4. Smad-mediated repression of MMP-1 gene expression may be important for preventing excessive matrix degradation induced by inflammatory cytokines; disruption of Smad signaling, as occurs in certain cancer cells, may thus be causally linked to uncontrolled tissue destruction mediated through MMP-1.
Animals↗
Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness.
Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na(+)-Ca(2+) exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca(2+) stores, reducing Ca(2+) transients and contractile function. Whereas beta-adrenergic receptors (beta-ARs) are progressively downregulated in HF, residual beta-AR responsiveness at this critical HF stage allows SR Ca(2+) load to increase, causing spontaneous SR Ca(2+) release and transient inward current carried by NaCaX. A given Ca(2+) release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and approximately 50% less Ca(2+) release is required to trigger an action potential in HF. The inward rectifier potassium current (I(K1)) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I(K1) in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I(K1), and residual beta-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.
Adrenergic beta-Agonists↗
PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats.
The aim of the present work was to assess the merits of PEGylated poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles as protein and peptide drugs (PPD) carriers. PEG-PLGA copolymer, which could be used to prepare the stealth nanoparticles or long-circulating nanoparticles, was synthesized with methoxypolyethyleneglycol (MePEG) and PLGA. The structure of PEG-PLGA was confirmed with (1)H NMR and Fourier transform infrared (FTIR) spectrum, and molecular weight was determined by gel permeation chromatography (GPC). Bovine serum albumin (BSA), chosen as model protein, was encapsulated within the stealth nanoparticles with the double emulsion method. The particles were characterized in terms of size, zeta potential and in vitro release of the protein. The biological fate of the BSA-loaded nanoparticles following intravenous administration was determined over 24 h in rats. The experimental results showed that PEG-PLGA could be obtained by ring-opening polymerization of lactide and glycolide in the presence of MePEG. (1)H NMR and FTIR spectrum were consistent with the structure of PEG-PLGA copolymer. Molecular weight determined by GPC was 50800. The stealth nanoparticles loading BSA could be prepared by the double emulsion technique. The entrapment efficiency was 48.6%, particle size about 200 nm and zeta potential -16.1 mV. BSA release from the stealth nanoparticles showed an initial burst release and then sustained release. PEG-PLGA nanoparticles could extend half-life of BSA from 13.6 min of loaded in PLGA nanoparticles to 4.5 h and obviously change the protein biodistribution in rats compared with that of PLGA nanoparticles. Thus, PEG-PLGA nanoparticles could be an effective carrier for PPD delivery.
Animals↗