[International expert consensus on gene therapy for hereditary hearing loss: based on clinical trials].
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Journal Article↗
Biomedical subjects
Y Zhao
Publications and source records attributed to Y Zhao.
Recurrence of clonal hematopoiesis after discontinuing pegylated recombinant interferon-alpha 2a in a patient with polycythemia vera.
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Amino Acid Substitution↗
Health-related behaviours as predictors of mortality and morbidity in Australian Aborigines.
OBJECTIVE: To examine predictors of coronary heart disease (CHD) and all-cause mortality in Aboriginal Australians. METHOD: In 1988-89, a survey of Western Australian Aborigines (256 women, 258 men) aged 15-88 years documented diet, alcohol and smoking habits. Linkage to mortality and hospital admissions to the end of 2002 provided longitudinal data for modelling of coronary heart disease endpoints and all-cause mortality using Cox regression. RESULTS: Coronary heart disease risk increased with smoking (HR 2.62, 95% CI: 1.19, 5.75), consumption of processed meats >once/week (HR 2.21, 95% CI: 1.05, 4.63), eggs >twice/week (HR 2.59, 95% CI: 1.11, 6.04) and using spreads on bread (HR 3.14. 95% CI: 1.03, 9.61). All-cause mortality risk was lower with exercise >once/week (HR 0.51, 95% CI 0.26, 1.05), increased in ex-drinkers (HR 3.66, 95% CI: 1.08, 12.47), heavy drinkers (HR 5.26, 95% CI: 1.46, 7.52) and with consumption of take away foods >nine times/month (HR 1.78, 95% CI 0.96, 3.29). Greater alcohol intake, smoking and adverse dietary choices clustered in 53% of men and 56% of women and increased risk of coronary heart disease (HR 2.1, 95% CI: 1.1, 4.0) and all-cause mortality (HR 2.3, 95% CI: 1.2, 4.2). CONCLUSION: Lifestyle in Aboriginal Australians predicts coronary heart disease and all-cause mortality. Clustering of adverse behaviours is common and increases risk of coronary heart disease and death.
Adolescent↗
Liver test abnormalities in multiple sclerosis: findings from placebo-treated patients.
The risk of an abnormal liver test in 813 patients with multiple sclerosis or clinically isolated syndrome enrolled in placebo arms of clinical trials was greater than expected for alanine aminotransferase (ALT) (relative risk [RR] 3.7; 95% CI: 2.3 to 6.0) and aspartate aminotransferase (AST) (RR 2.2; 95% CI: 1.3 to 3.6), although not alkaline phosphatase (AP) or total bilirubin, at first presentation. Abnormal test results were associated with higher body mass index (ALT only), male gender (ALT only), and a relapsing-remitting (vs secondary-progressive) course (ALT and AST only).
Adolescent↗
Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells.
The initiation and propagation of the early processes of bystander signaling induced by low-dose alpha-particle irradiation are very important for understanding the underlying mechanism of the bystander process. Our previous investigation showed that the medium collected from cell culture exposed to low-dose alpha-particle rapidly induced phosphorylated form of H2AX protein foci formation among the non-irradiated medium receptor cells in a time-dependent manner. Using N(G)-methyl-L-arginine, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate and N(omega)-nitro-L-arginine (L-NNA) treatment before exposure to 1 cGy alpha-particle, we showed in the present study that nitric oxide (NO(*)) produced in the irradiated cells was important and necessary for the DNA double strand break inducing activity (DIA) of conditioned medium and the generation of NO(*) in irradiated confluent AG1522 cells is in a time-dependent manner and that almost all NO(*) was generated within 15 min post-irradiation. Concurrently, the kinetics of NO(*) production in the medium of irradiated cells after irradiation was rapid and in a time-dependent manner as well, with a maximum yield observed at 10 min after irradiation with electron spin resonance analysis. Furthermore, our results that 7-Nitroindazole and L-NNA, but not aminoguanidine hemisulfate, treatment before exposure to 1 cGy alpha-particle significantly decrease the DIA of the conditioned medium suggested that constitutive NO(*) from the irradiated cells possibly acted as an intercellular signaling molecule to initiate and activate the early process (<or=30 min) of bystander response after low-dose irradiation.
Alpha Particles↗
The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence.
Evidence of LRRK2 haplotypes associated with Parkinson's disease (PD) risk was recently found in the Chinese population from Singapore, and a common LRRK2 missense variant, Gly2385Arg, was independently detected as a putative risk factor for PD in the Chinese population from Taiwan. To test the association between the Gly2385Arg variant in a large case-control sample of Chinese ethnicity from Singapore, and to perform functional studies of the wild type and Gly2385Arg LRRK2 protein in human cell lines. In a case-control study involving 989 Chinese subjects, the frequency of the heterozygous Gly2385Arg genotype was higher in PD compared to controls (7.3 vs. 3.6%, odds ratio = 2.1, 95% CI: 1.1-3.9, P = 0.014); these values yield an estimated population attributable risk (PAR) of approximately 4%. In a multivariate logistic regression analysis with the disease group (PD vs. controls) as the dependent variable and the genotype as an independent factor with adjustments made for the effect of age and gender, the heterozygous Gly2385Arg genotype remained associated with an increased risk of PD compared to wild type genotype (odds ratio = 2.67, 95% CI: 1.43-4.99, P = 0.002). The glycine at position 2385 is a candidate site for N-myristoylation, and the Gly2385Arg variant replaces the hydrophobic glycine with the hydrophilic arginine, and increases the net positive charge of the LRRK2 WD40 domain. In transfection studies, we demonstrated that both the wild type and Gly2385Arg variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under condition of oxidative stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis. Our study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the Chinese population. Our bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant is biologically relevant and it might act through pro-apoptotic mechanisms.
Aged↗
Using physiological models and decision theory for selecting appropriate ventilator settings.
OBJECTIVE: To present a decision support system for optimising mechanical ventilation in patients residing in the intensive care unit. METHODS: Mathematical models of oxygen transport, carbon dioxide transport and lung mechanics are combined with penalty functions describing clinical preference toward the goals and side-effects of mechanical ventilation in a decision theoretic approach. Penalties are quantified for risk of lung barotrauma, acidosis or alkalosis, oxygen toxicity or absorption atelectasis, and hypoxaemia. RESULTS: The system is presented with an example of its use in a post-surgical patient. The mathematical models describe the patient's data, and the system suggests an optimal ventilator strategy in line with clinical practice. CONCLUSIONS: The system illustrates how mathematical models combined with decision theory can aid in the difficult compromises necessary when deciding on ventilator settings.
Carbon Dioxide↗
Nonlinear imaging of embedded microstructures inside transparent materials with laser-induced ionization microscopy.
We present a novel nonlinear imaging method that utilizes femtosecond laser-induced plasma emission to probe microscopic structures embedded inside transparent materials. This nonlinear diagnostic tool can resolve either elemental or structural variations of the sample of interest and provide significant improvements over the ordinary linear microscopes by having much higher contrast ratios for the observed areas of different refractive indices. Examples of using this technique to examine the microstructures fabricated by ultrashort laser pulses inside optical glass are presented.
Journal Article↗
Exploring an interaction of adenosine A2A receptor variability with coffee and tea intake in Parkinson's disease.
Caffeine is an adenosine receptor A1 and A2A receptor antagonist and a putative functional genetic variant of the A2A receptor (2592C > Tins) mediates caffeine-induced anxiety. Here we investigated the potential interaction of this A2A genetic variant with the quantity of coffee and tea intake and their relationship with the risk of PD. A total of 441 subjects consisting of 222 PD and 219 race, gender and age matched controls were included. A multivariate analysis of the variables including the 2592C > Tins A2A genotypes, age of onset, gender, and the quantity of tea and coffee intake, interaction of the A2A genotypes with coffee intake, interaction of A2A genotypes with tea intake demonstrated the quantity of coffee intake to be significantly associated with PD (P < 0.0005, OR = 0.922, 95% CI: 0.881, 0.964). However, there was no significant interaction of the A2A genotypes with the quantity of coffee and tea intake in modulating the risk of PD. The dose dependent protective effect of coffee intake in PD was independent of the 2592C > Tins A2A genotype suggesting that the pharmacogenetic action of caffeine in PD may be mediated differently from other caffeine-induced neurologic syndromes.
Base Sequence↗
Computational evaluation of the roles of Na+ current, iNa, and cell death in cardiac pacemaking and driving.
Voltage-dependent sodium (Na(+)) channels are heterogeneously distributed through the pacemaker of the heart, the sinoatrial node (SA node). The measured sodium channel current (i(Na)) density is higher in the periphery but low or zero in the center of the SA node. The functional roles of i(Na) in initiation and conduction of cardiac pacemaker activity remain uncertain. We evaluated the functional roles of i(Na) by computer modeling. A gradient model of the intact SA node and atrium of the rabbit heart was developed that incorporates both heterogeneities of the SA node electrophysiology and histological structure. Our computations show that a large i(Na) in the periphery helps the SA node to drive the atrial muscle. Removal i(Na) from the SA node slows down the pacemaking rate and increases the sinoatrial node-atrium conduction time. In some cases, reduction of the SA node i(Na) results in impairment of impulse initiation and conduction that leads to the SA node-atrium conduction exit block. Decrease in active SA node cell population has similar effects. Combined actions of reduced cell population and removal of i(Na) from the SA node have greater impacts on weakening the ability of the SA node to pace and drive the atrium.
Action Potentials↗
Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US.
The efficacy and safety of tadalafil, dosed once a day for the treatment of erectile dysfunction, was assessed in a randomized, double-blind, placebo-controlled, parallel-design study at 15 US centers. Following a 4-week treatment-free run-in period, patients (>or=18 years of age) were randomly assigned to 24 weeks treatment with tadalafil 2.5 mg, tadalafil 5 mg or placebo. Primary efficacy endpoints were change at 24 weeks in International Index of Erectile Function Erectile Function (EF) Domain score and mean per-patient percentage 'yes' responses to Sexual Encounter Profile diary questions 2 and 3. Tadalafil significantly improved erectile function compared with placebo for all three co-primary efficacy endpoints. Few patients discontinued because of adverse events (2.1%, placebo; 6.3%, tadalafil 2.5 mg; 4.1%, tadalafil 5 mg). Common treatment-emergent adverse events (>or=5%) were nasopharyngitis, influenza, viral gastroenteritis and back pain. Tadalafil 2.5 mg and 5 mg, dosed once a day for 24 weeks, was well tolerated and significantly improved erectile function.
Adult↗
Zebrafish dax1 is required for development of the interrenal organ, the adrenal cortex equivalent.
Mutations in the human nuclear receptor, DAX1, cause X-linked adrenal hypoplasia congenita (AHC). We report the isolation and characterization of a DAX1 homolog, dax1, in zebrafish. The dax1 cDNA encodes a protein of 264 amino acids, including the conserved carboxy-terminal ligand binding-like motif; but the amino-terminal region lacks the unusual repeats of the DNA binding-like domain in mammals. Genomic sequence analysis indicates that the dax1 gene structure is conserved also. Whole-mount in situ hybridization revealed the onset of dax1 expression in the developing hypothalamus at approximately 26 h post fertilization (hpf). Later, at about 28 hpf, a novel expression domain for dax1 appeared in the trunk. This bilateral dax1-expressing structure was located immediately above the yolk sac, between the otic vesicle and the pronephros. Interestingly, weak and transient expression of dax1 was observed in the interrenal glands (adrenal cortical equivalents) at approximately 31 hpf. This gene was also expressed in the liver after 3 dpf in the zebrafish larvae. Disruption of dax1 function by morpholino oligonucleotides (MO) down-regulated expression of steroidogenic genes, cyp11a and star, and led to severe phenotypes similar to ff1b (SF1) MO-injected embryos. Injection of dax1 MO did not affect ff1b expression, whereas ff1b MO abolished dax1 expression in the interrenal organ. Based on these results, we propose that dax1 is the mammalian DAX1 ortholog, functions downstream of ff1b in the regulatory cascades, and is required for normal development and function of the zebrafish interrenal organ.
Adrenal Cortex↗
Green luminescence band in ZnO: fine structures, electron-phonon coupling, and temperature effect.
The green emission band of ZnO has been investigated by both experimental and theoretical means. Two sets of equally separated fine structures with the same periodicity (close to the longitudinal optical (LO) phonon energy of ZnO) are well resolved in the low-temperature broad green emission spectra. As the temperature increases, the fine structures gradually fade out and the whole green emission band becomes smooth at room temperature. An attempt to quantitatively reproduce the variable-temperature green emission spectra using the underdamped multimode Brownian oscillator model taking into account the quantum dissipation effect of the phonon bath is done. Results show that the two electronic transitions strongly coupled to lattice vibrations of ZnO lead to the observed broad emission band with fine structures. Excellent agreement between theory and experiment for the entire temperature range enables us to determine the dimensionless Huang-Rhys factor characterizing the strength of electron-LO phonon coupling and the coupling coefficient of the LO and bath modes.
Journal Article↗
Genetic analysis of SCA2, 3 and 17 in idiopathic Parkinson's disease.
Recent reports of SCA2 and SCA3 patients who presented with levodopa responsive parkinsonism have generated considerable interest as they have implications for genetic testing. It is unclear whether ethnic race alone or founder effects within certain geographical region explain such an association. In this study, we conducted genetic analysis of SCA2, 3, 17 in an ethnic Chinese cohort with early onset and familial Parkinson's disease (PD) and healthy controls. A total of 191 subjects comprising of 91 PD and 100 healthy controls were examined. We identified one positive case of SCA2 in an early-onset sporadic PD patient who had CAG 36 repeats, yielding a prevalence of 2.2% in early-onset sporadic PD patients and less than 1.0% in our study PD population. The size of the repeats was lower than the expanded repeats (38-57) in SCA2 patients with ataxia in our population. All the children of the patient were physically normal even though some of them carried the repeat expansion of similar size. No cases and controls were positive for SCA3 and SCA17. We do not think routine screening of SCA2, SCA3 and SCA17 for all idiopathic PD patients is cost-effective in our ethnic Chinese population. However, SCA2 should be a differential diagnosis in young onset sporadic PD when genetic mutations of other known PD genes have been excluded.
Adult↗
A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.
X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, -77T>C) in the XRCC1 gene 5' untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that -77T>C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T>C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between -77T>C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the -77T>C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18-1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20-2.21) than in non-smokers (OR=1.28, 95% CI=0.94-1.76). Taken together, these results showed that the functional SNP -77T>C in XRCC1 5'UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.
Adult↗
The fragmentation mechanism of beta-(N-alkyl/arylamino)-alpha,beta-unsaturated carboxylates under electrospray ionization conditions.
The positive ion mass spectrometric behavior of six beta-(N-alkyl/arylamino)-alpha,beta-unsaturated carboxylates, alpha-(1-alkyl/arylaminoethylidene)-gamma-lactones, has been studied under electrospray ionization conditions. Their fragmentation pathways are described and supported by tandem mass spectrometry. The protonated compounds are apt to eliminate a water, and a water plus a oxacyclopent-2-yne molecule. Some of the compounds show a tendency to undergo a four-membered ring contraction rearrangement to lose a carbon dioxide. The fragmentation patterns of these compounds exhibit a strong substituent dependency.
Carboxylic Acids↗
A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma.
We constructed a novel hepatocellular carcinoma-specific conditionally replicative adenovirus (CRAd). This adenovirus, designated Ad.HS4.AFP.E1A/TRAIL, expresses E1A to mediate viral replication and TRAIL to enhance HCC-killing efficacy under the control of a modified AFP promoter. An insulator HS-4 was placed in front of the AFP promoter to enhance the fidelity of the heterologous promoter. This virus was shown to have specific cytolytic activity in AFP-expressing HCC cells in vitro. Furthermore, the replication efficiency of Ad.HS4.AFP.E1A/TRAIL correlated well with AFP expression of the host cells, showing a 100-fold and 1 000 000-fold decrease in the low-and non-AFP-expressing HCC cells, respectively, compared to the high AFP-expressing HCC cells. An increase in mRNA of TRAIL and the elevated Caspase-3 activity were also observed in Ad.HS4.AFP.E1A/TRAIL-infected HCC cells. These results indicated that TRAIL expression from the viral vector activated the Caspase-3 enzymatic capacity and the HCC cells were sensitive to TRAIL. In vivo, Ad.HS4.AFP.E1A/TRAIL effectively prevented the growth of low AFP-expressing BEL-7404 xenografts. These results indicate that Ad.HS4.AFP.E1A/TRAIL could provide a new strategy of gene therapy for HCC.
Adenoviridae↗
Neighborhood detection using mutual information for the identification of cellular automata.
Extracting the rules from spatio-temporal patterns generated by the evolution of cellular automata (CA) usually requires a priori information about the observed system, but in many applications little information will be known about the pattern. This paper introduces a new neighborhood detection algorithm which can determine the range of the neighborhood without any knowledge of the system by introducing a criterion based on mutual information (and an indication of over-estimation). A coarse-to-fine identification routine is then proposed to determine the CA rule from the observed pattern. Examples, including data from a real experiment, are employed to evaluate the new algorithm.
Algorithms↗