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Low-grade endometrial stromal sarcoma and ossifying fibromyxoid tumors are two types of mesenchymal tumors that share no similarities in terms of site, sex, and morphological characteristics. They are rare, low grade tumors of uncertain lineage, with no definite immunological markers. Interestingly, a common PHF1 gene- related rearrangement was observed in these two tumors. Here, we report a case of endometrial stromal sarcoma with distinct ossification. Microscopically, the tumor is composed of bland-looking ovoid cells with low cellularity in the fibromyxoid stroma. Foci of metaplastic bone formation were noted. Using a combination of FISH, transcriptome sequencing, and molecular techniques, we identified a new PHF1-BRD8 fusion transcript, which was previously described, but in its reciprocal fusion form. This case expands the current understanding of low-grade endometrial stromal sarcoma and emphasizes the importance of molecular characterization of unique fusion, which may be related to its distinct morphological features and the possibly chemosensitive target.

Highlights • Performance of serological tests detecting SARS-CoV-2 antibodies is disease course dependent. • Detection sensitivity of rapid antibody tests with lateral flow immunoassay for COVID-19 reached 100% after 3 weeks of symptom onset. • COVID-19 patients with pneumonia exhibited earlier seroconversion than those without pneumonia. • Prolonged viral shedding after seroconversion with a median duration of 14 days was observed. • Serological testing may be a useful tool in addition to rRT-PCR for the diagnosis of COVID-19., SUMMARY Objectives: We aimed to evaluate the role of rapid serological tests in the management of coronavirus disease 2019 (COVID-19) patients. Methods: This retrospective study enrolled 16 real-time reverse transcription polymerase chain reaction-confirmed symptomatic patients with COVID-19 and 58 COVID-19 negative patients at a medical center in Taiwan over a 3-month period. Serial serum samples were collected and tested for antibody response using four point-of-care (POC) lateral flow immunoassays (LFIA) (ALLTEST 2019-nCoV IgG/IgM Rapid Test, Dynamiker 2019-nCoV IgG/IgM Rapid Test, ASK COVID-19 IgG/IgM Rapid Test, and Wondfo SARS-CoV-2 Antibody Test). Time-dependent detection sensitivity and timeliness of seroconversion were determined and compared between the four POC rapid tests. Results: The overall sensitivity and specificity of the four tests for detecting anti-SARS-CoV-2 antibodies after 3 weeks of symptom onset were 100% and 100%, respectively. There was no significant difference between the rapid tests used for detection of IgM and IgG separately and those used for detection of combined total antibody (mainly IgM/IgG). There was no significant difference between the four POC rapid tests in terms of time required for determining seroconversion of COVID-19. Patients with COVID-19 with pneumonia demonstrated shorter seroconversion time than those without pneumonia. Conclusion: Though the POC antibody rapid tests based on LFIA showed reliable performance in the detection of SARS-CoV-2-specific antibodies, the results of these tests should be interpreted and applied appropriately in the context of antibody dynamic of COVID-19 infection. COVID-19 patients complicated with pneumonia exhibited earlier anti-SARS-CoV-2 antibody response than COVID-19 patients without pneumonia.

In Taiwan, the vaccination program started in March 2021, with ChAdOx1-S being the first available WHO-approved COVID-19 vaccine, followed by Moderna vaccine. This study aimed to investigate the immunogenicity and safety of homologous and heterologous prime-boost regimens with ChAdOx1-S and mRNA-1273.From March to November 2021, homologous or heterologous regimens with ChAdOx1-S and mRNA-1273 vaccination (ChAdOx1-S/ChAdOx1-S, mRNA-1273/mRNA-1273, ChAdOx1-S/mRNA-1273) were given to 945 healthy participants. Serum samples were collected at designated time points. The anti-RBD/S1 antibody titers and neutralizing ability were measured by three different immunoassays: Elecsys® Anti-SARS-CoV-2 S (Roche Diagnostics, Mannheim, Germany), AdviseDx SARS-CoV-2 IgG II (Abbott Diagnostics Division, Sligo, Ireland), and cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit (GenScript, New Jersey, USA).We found that heterologous vaccination with ChAdOx1-S/mRNA-1273 had an acceptable safety profile and induced higher total anti-RBD/S1 antibody production (p 0.0001), yet lower anti-RBD/S1 IgG titer (p 0.0001) and neutralizing ability (p = 0.0101) than mRNA-1273/mRNA-1273 group. Both regimens showed higher antibody titers and superior neutralizing abilities than ChAdOx1-S/ChAdOx1-S. An age-dependent antibody response to ChAdOx1-S/mRNA-1273 was shown after both the priming and the booster doses. Younger age was associated with higher antibody production and neutralizing ability.Heterologous ChAdOx1-S/mRNA-1273 vaccination regimen is generally safe and induces a robust humoral immune response that is non-inferior to that of mRNA-1273/mRNA-1273.

BackgroundHereditary maculopathy is a group of clinically and genetically heterogeneous disorders. With distinctive clinical features, subtypes of macular atrophy may correlate with their genetic defects.MethodsSeven patients from six families with adolescent/adult-onset maculopathy were examined in this clinical case series. A detailed medical history and eye examination were performed. Genomic DNA sequencing was performed using whole exome sequencing or direct sequencing of retinol dehydrogenase 12 (RDH12) coding exons.ResultsSeven patients, including one male and six female patients, with pseudocoloboma-like maculopathy had biallelic missenseRDH12mutations. The most common mutant allele found in six of the seven patients was p.Ala269Gly. The average disease onset was at age 19.3 years, and visual acuity ranged from count fingers to 1.0. Most of the patients had mild myopic refraction. Common findings on fundus examination and spectral-domain optical coherence tomography include discrete margins of pseudocoloboma-like macular lesions with variable degrees of chorioretinal atrophy, excavation of retinal tissue and pigmentary changes mainly in the macular area. The electroretinograms were relatively normal to subnormal in all participants.ConclusionsProgressive macular degeneration with a relatively normal peripheral retina and subsequent development of a pseudocoloboma-like appearance were the main clinical features in patients with compound heterozygousRDH12missense mutations. Genetic testing may be crucial for early diagnosis and may play a key role in the development of future treatment strategies.

To the Editor:We read with interest the article by Yang and colleagues.1 The authors argued that in their series of 29 families with RCBTB1 variants, none had FEVR syndrome, in contrast to what we ...

Background: After angioplasty, veins are more prone to intimal hyperplasia than arteries. Veins tend to produce less nitric oxide (NO), which could lead to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and contributes to cardiovascular disease. In humans, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme for ADMA degradation. In this study, we aim to determine whether venous intimal hyperplasia in hemodialysis (HD) vascular access is influenced by common polymorphisms in the DDAH1 genes. Methods: This is a prospective observational cohort study. A total of 473 HD patients referred for the angioplasty of vascular access were enrolled. There were 190 arteriovenous grafts (AVG) and 283 arteriovenous fistulas (AVF). The follow-up lasted for 2 years after the interventions. Seven single nucleotide polymorphisms (SNPs) in DDAH1 were genotyped and ADMA were measured at baseline. The primary outcome was restenosis after angioplasty. Results: Among the 7 SNPs, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA + GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19 μM, p = 0.03) and rs1498373 (CT + TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, p = 0.02) genotypes. The AVF group with GG + GA genotype of rs233112 and CT + TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In the AVG group, only GG + GA genotype of rs233112 was associated with early restenosis. A combined analysis of AVG and AVF groups showed that patients with rs233112 GA + GG genotype and rs1498373 CT + TT genotype had higher risks of early restenosis (both p < 0.001). The multivariate analysis results showed that the association of these genotypes with early restenosis is independent of clinical, access, or biochemical factors. Conclusions: Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.

Arsenic exposure is a global health concern. Several studies have focused on chronic arsenic exposure in adults; however, limited data are available regarding the potential adverse effects of prenatal exposure on fetuses and neonates.To assess which time point maternal arsenic exposure may influence the fetus during pregnancy and birth outcomes.In this study, total arsenic concentrations were analyzed in urine samples collected from 130 women with singleton pregnancies (22-45years old) in Taiwan from March to December of 2010. All fetal biometric measurements in each trimester period and birth outcomes at delivery were obtained. We applied a generalized estimating equation model and multivariate regression models to evaluate the associations between maternal urinary total arsenic (UtAs) exposure during pregnancy, fetal biometric measurements, and neonatal birth outcomes.We observed statistically significant correlations between maternal UtAs levels and the fetal biparietal diameter over all three trimesters (β=-1.046mm, p0.05). Multiple regression analyses showed a negative association between maternal UtAs levels and chest circumference in the first trimester (β=-0.721cm, p0.05), and second-trimester UtAs exposure was associated with decreases in birth weight (β=-173.26g, p0.01), head circumference (β=-0.611cm, p0.05), and chest circumference (β=-0.654cm, p0.05). Dose-response relationships were also observed for maternal UtAs exposure and birth outcomes.We identified a negative relationship between maternal UtAs levels during pregnancy, fetal development, and neonatal birth outcomes. These findings should be confirmed in future studies with large sample sizes.

Objective The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. Methods This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene ( DRD4 ) were identified. Results Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69 nmol/g cre. vs. 186.84 nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95 µg/g cre. vs. 16.55 µg/g cre., p value DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24–0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13–1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12–65.04). Conclusion This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected.

Background/Aims: Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired acute renal failure. However, the pathogenesis of CIN remains unclear. This study evaluated the role of anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) gene polymorphisms as CIN susceptibility markers after percutaneous coronary intervention (PCI). Methods: Four IL-10 tag SNPs (rs1554286, rs3021094, rs3790622, rs1800896) and three TNF-α tag SNPs (rs1799964, rs1800630, rs1800629) were analyzed by MALDI-TOF mass spectrometry in 53 CIN patients and 455 control subjects. Serum IL-10 and TNF-α were detected using ELISA. Results: When compared to controls, the CIN patients showed increased frequencies of CC (rs1554286) and AG+GG (rs1800896) genotypes in IL-10 and GA+AA (rs1800629) genotype in TNF-α (OR = 2.24 (1.13–4.44), p = 0.018; OR = 2.61 (1.30–5.26), p = 0.005, and OR = 2.11 (1.08–4.09), p = 0.025, respectively). Baseline serum IL-10 levels in CIN patients were significantly lower (1.02 ± 1.14 vs. 2.78 ± 4.73 pg/ml, p = 0.008). Patients with CIN had a higher rate of decline in renal function than those without CIN (0.89 ± 1.67 vs. 0.30 ± 0.95 ml/min/1.73 m2 per month, p = 0.002). Significantly higher rates of decline in creatinine clearance were noted in patients with TNF-α (rs1800629) GA+AA than GG genotype (0.88 ± 1.83 vs. 0.36 ± 0.70, p = 0.03), and with IL-10 (rs1800896) AG+GG than AA genotype (1.28 ± 2.14 vs. 0.33 ± 0.90, p < 0.001). Conclusions: Gene polymorphisms of IL-10 and TNF-α are associated with CIN risk and long-term renal outcome after PCI. More prospective studies are needed to confirm our results.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Evidence of the negative effects of sugar-sweetened beverages (SSBs) on mental health has not been convincing, although a few studies have found an association between high SSB levels and attention problems in children. This study aimed to test the hypothesis that SSB consumption is associated with ADHD among children. Doctor-diagnosed ADHD cases (n = 173) and non-ADHD controls (n = 159) between age 4 to 15 were recruited. SSB consumption, socio-demographic and lifestyle characteristics of the children, as well as of their mothers’ characteristics during pregnancy, were collected using a questionnaire. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. There was a dose-response relationship between SSB consumption and ADHD. After covariates were adjusted, children who consumed SSBs at moderate levels and high levels had 1.36 and 3.69 odds, respectively, of having ADHD, compared with those who did not consume SSBs (p for trend < 0.05). Similar results were obtained when females were excluded. Our findings highlighted the adverse correlation between SSB consumption and ADHD and indicated a dose-response effect even after covariates were adjusted.

To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034GT p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034GT p.G345V, c.1013TC p.V338E, and c.1130CT p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings.Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.

Background The association between genetic polymorphisms of ADRβ2, IL-4, and ADAM3 and asthma remains undetermined. Furthermore, it is not clear as to whether these three gene polymorphisms combined produce a correlative increase in asthmatic risk. Methods A total of 476 asthmatic patients and 115 healthy volunteers were enrolled. Single nucleotide polymorphisms (SNPs) of the C-589T IL-4 promoter (rs2243250), the ADRβ2 gene [at nucleic acid 46 (rs1042713) and 79 (rs1042714)] and the ADAM33 gene [at rs2280091 (T1), rs3918396 (S1), rs3918391 (D1), and rs615436] were analyzed. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE for inhalant allergens and total eosinophil counts were assessed. Results The T allele for the IL-4 gene promoter (C-589T locus), the C allele frequency for ADRβ2 (Gln27Glu locus), and the A allele for the ADAM33 gene (rs2280091, T1) were higher in asthma patients than in normal individuals. In asthmatic patients, the A allele of ADAM33 (rs2280091) was associated with higher eosinophil count and increased hyperresponsiveness compared to the C allele. Combination of the three risk genes SNP had an additive effect on the risk of asthma (OR: 3.46; CI: 1.51–7.93) and increased the diagnostic sensitivity and specificity of asthma. Conclusion Genetic polymorphism in the IL-4 promoter, ADRβ2, and ADAM33 is associated with asthma. Furthermore, ADAM33 genetic polymorphism modifies the phenotype of asthma in atopy and hyperresponsiveness. Asthma is a complex polygenic disease, and combinations of polymorphisms of various genes have an additive effect on the risk of asthma.

Elevated plasma level of asymmetric dimethylarginine (ADMA) was reported to be associated with endothelial dysfunction and atherosclerotic risk factors. We assessed the prognostic value of plasma ADMA levels in 997 consecutive individuals referred for coronary angiography from July 2006 to June 2009.ADMA was measured by high performance liquid chromatography. All subjects were followed for a median period of 2.4years for the occurrence of all-cause mortality, major adverse cardiovascular events (MACE, defined as cardiovascular death, non-fatal myocardial infarction and stroke), and MACE plus clinically-driven target vessel revascularization (TVR).Plasma ADMA levels were significantly higher in patients with significant coronary artery disease (CAD) (≥50% stenosis, n=655) than those with insignificant CAD (20-50% stenosis, n=272) and normal coronary artery (20% stenosis, n=70) (0.47±0.10μmol/l vs 0.44±0.10μmol/l vs 0.42±0.08μmol/l, p0.001). By multivariate analysis, plasma ADMA level was identified as a significant independent risk factor of significant CAD (OR: 1.29, 95% CI: 1.10-1.50; p=0.002). Moreover, multivariate Cox regression analysis showed that, comparing with the ADMA tertile I, the highest ADMA tertile was a significant independent predictor for all adverse long-term clinical outcomes. Notably, plasma ADMA level remained associated with the long-term outcomes in non-diabetic individuals, but not in those with diabetes (interaction p=0.04 for MACE plus TVR).Our findings suggest that elevated plasma ADMA level might be a risk factor of significant CAD, and might predict worse long-term clinical outcomes in subjects referred for cardiac catheterization, especially in non-diabetic individuals.

Posttraumatic stress disorder (PTSD) is a severely debilitating anxiety disorder. Over 80% of patients with PTSD also exhibit other psychiatric condition, such as bipolar disorder (BP) or major depression (MDD). Previously, it has been found that p11 mRNA expression was significantly changed in post mortem cortex of patients with PTSD and depression. We hypothesize that p11 mRNA levels in the peripheral blood cells will be a potential biomarker for PTSD with heterogeneity in terms of type of trauma, time since trauma and duration of illness. We examined the peripheral blood mononuclear cell (PBMC) P11 mRNA of patients with PTSD (n=13), major depressive disorder (MDD, n=16), bipolar disorder (BP, n=24), and schizophrenia (SCZ, n=12) or controls (n=14) using quantitative real-time PCR and the circulating levels of cortisol in blood plasma and saliva of PTSD using radioimmunoassay kit CORT-CT2. The Hamilton Rating Scale for Depression (HAMD) and Anxiety (HARS), the Chinese version of the Davidson Trauma Scale-Frequency (CDTS-F) and the Chinese version of the Davidson Trauma Scale-Severity (CDTS-S), and Impact of Event Scale-Revised (IES-R) were administered. We found that patients with PTSD had lower levels of p11 mRNA than control subjects, while those with MDD, BP and SCZ had significantly higher p11 levels than the controls. P11 mRNA levels were positively correlated with the scores of HAMD (r=0.62, p

The aim of this study was to examine the feasibility of (123)I-ADAM to image the serotonin transporter (SERT) in Asian (Taiwanese) subjects. Single photon emission computed tomography (SPECT) scans were performed on nine healthy volunteers who were s-allele carriers at the polymorphism within the serotonin transporter promoter region (SERTPR) after intravenous bolus injection of (123)I-ADAM. Quantification of (123)I-ADAM binding was performed using the ratio equilibrium method (REM) with specific uptake ratio (SUR) and a simplified reference tissue model (SRTM). Curve-fitting techniques were used to obtain the peak equilibrium point from 241 to 301 min (average 264+/-20 min) after injection of (123)I-ADAM for the midbrain and from 215 to 270 min (average 235+/-18 min) after injection of (123)I-ADAM for the striatum. Two sets of SUR were obtained by either curve fitting (estimated values) or integrated period from 240 to 270 min (observed values). The estimated values of SUR were 2.11+/-0.51 for the midbrain and 1.50+/-0.44 for the striatum, whereas the observed values were 2.11+/-0.83 for the midbrain and 1.24+/-0.31 for the striatum. The SRTM showed that the binding potential (BP) was 2.10+/-0.66 for the midbrain and 1.35+/-0.25 for the striatum. There was a good correlation between estimated SUR, observed SUR and SRTM in the midbrain but not in the striatum. The optimal scanning duration for both the midbrain and the striatum should be 220 to 280 min similar to that suggested by previous studies in Caucasians. However, due to the low signal-to-noise ratio in the striatum, (123)I-ADAM could be an ideal tracer for imaging SERT in the midbrain but not in the striatum.

OBJECTIVE:Nonylphenol (NP) belongs to the family of endocrine disruptors, and it is widely used in industrial applications and is ubiquitous in daily foods. Animal studies have suggested that NP exposure might promote motor hyperactivity, likely by causing deficits in dopaminergic neurons. However, research assessing NP exposure and epidemiology studies on human populations are limited. The aim of this study was to explore the association between child NP exposure and ADHD while considering particular covariants, such as lead levels and dopamine-related gene variations. METHODS:A case-control study was conducted on patients with clinically diagnosed ADHD; the Swanson, Nolan and Pelham, Fourth Revision (SNAP-IV) questionnaire was used to identify normal controls aged 4-15 years. Participants were examined for urinary NP concentrations, blood lead levels, and select single-nucleotide polymorphisms of two dopamine-related genes (D4 dopamine receptor, DRD4, and dopamine transporter, DAT1). Socio-demographic variables, maternal lifestyle factors during pregnancy and family medical history were obtained using a questionnaire. RESULTS:A total of 97 children with doctor-diagnosed ADHD and 110 normal controls were enrolled. The blood lead levels in both groups were similar (1.57±0.73 vs. 1.73±0.77 μg/dL, p = 0.15). No significant difference in urinary NP concentration was found between the children with ADHD and the control subjects (4.52±3.22 μg/g cr. vs. 4.64±2.95 μg/g cr., p = 0.43). ADHD was significantly more prevalent among males in this study (male to female ratio: 5:1 for the ADHD group and 1.3:1 for the control group, p

Heme oxygenase-1 (HO-1) gene, which encodes an oxidative response protein, plays a role in cytoprotection. A (GT)n dinucleotide repeat in HO-1 promoter is polymorphic and modulates the transcriptional activity of the gene. A HO-1 gene promoter polymorphism was reported to be associated with the risks of lung adenocarcinoma and oral squamous cancer. In this study, the correlation between the HO-1 gene promoter polymorphism and the clinicopathological characteristics, along with the risk of gastric cancer, was analyzed.We examined the genotypic frequencies of (GT)n repeats in 183 gastric cancer patients and 250 control subjects by PCR-based genotyping and DNA sequencing. The length polymorphisms of (GT)n repeats were classified into short (S) component (nor= 25), medium (M) component (26or= nor= 30) and long (L) component (nor= 31). The distribution of S, M and L components in patient and control groups were evaluated to determine the correlation with susceptibility and clinicopathological characteristics of gastric adenocarcinoma.Higher frequencies of L-allele, L-allele carrier (S/L, M/L, L/L) and S/L genotype were found in gastric cancer patients. The frequencies of M-allele, M-allele carrier (M/M, M/L, M/S) and M/M genotype were significantly lower in patients with gastric cancer than controls. Furthermore, the frequency of lymphovascular tumor invasion was significantly lower in M-allele carriers compared to non-M-allele carriers (S/S, S/L, L/L) (p = 0.009).These findings suggest that the long (GT)n repeat of HO-1 gene promoter was associated with a higher frequency of gastric adenocarcinoma, and the medium (GT)n repeat might possess protective effect against gastric adenocarcinoma with a lower frequency of lymphovascular invasion in tumors.

The mammalian nitrilase (Nit) protein is a member of the nitrilase superfamily whose function remains to be characterized. We now show that the nitrilase family member 2 gene (NIT2) is ubiquitously expressed in multiple tissues and encodes protein mainly distributed in the cytosol. Ectopic expression of Nit2 in HeLa cells was found to inhibit cell growth through G2 arrest rather than by apoptosis. Consistent with this, proteomic and RT-PCR analyses showed that Nit2 up-regulated the protein and mRNA levels of 14-3-3σ, an inhibitor of both G2/M progression and protein kinase B (Akt)-activated cell growth, and down-regulated 14-3-3β, a potential oncogenic protein. Genotype analysis in four types of primary tumor tissues showed 12.5–38.5% allelic imbalance surrounding the NIT2 locus. The results demonstrated that NIT2 plays an important role in cell growth inhibition and links to human malignancies, suggesting that Nit2 may be a potential tumor suppressor candidate.

OBJECTIVES The CYP19 gene encodes aromatase—a key enzyme involved in the conversion of androstenedione/testosterone to estrone/estradiol. In this study, we analyzed the association between the TCT insertion (Ins)/deletion (Del) and TTTA repeat polymorphisms of CYP19 and prostate cancer (PCa). METHODS Automated sequencer with GeneScan software was used to determine the CYP19 gene polymorphisms in peripheral blood mononuclear cell DNA from 244 patients with PCa and 261 age-matched healthy male controls. The distribution of Stage I to IV was 3.4%, 23.8%, 19.6%, and 53.2%, respectively. The Gleason score was 2 to 5 in 22.9%, 6 to 7 in 53.2%, and 8 to 10 in 23.8%. RESULTS The frequency of the TCT Del/Del genotype in the Taiwanese patients with PCa (12.3%) was significantly greater than that in the controls (5.4%; P 0.015, odds ratio [OR] 2.43, 95% confidence interval [CI] 1.23 to 4.80). Individuals with a homozygous A1 (seven TTTA repeats) genotype had a significantly greater risk of developing PCa (OR 1.59, 95% CI 1.04 to 2.44, P 0.044). The frequency of the Ins-A6 (12 TTTA repeats) haplotype was significantly greater in the control group than in the patient group (9.8% versus 6.1%, OR 0.61, 95% CI 0.38 to 0.97). The OR of developing PCa for men with the homozygous Del-A1 diplotype was 2.31 (95% CI 1.10 to 4.83). CONCLUSIONS The results of our study have shown that the CYP19 TCT Del/Del genotype might be a susceptibility marker for PCa. Men with the Ins-A6 haplotype had a lower risk of developing PCa. UROLOGY 69: 996 –1000, 2007. © 2007 Elsevier Inc.

Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer. Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients. Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues. Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.

Background and objectives: Recent family-based studies have revealed a linkage between human chromosome 5q31 and asthma, elevated serum IgE levels and airway hyperresponsiveness (AHR). Among the candidate genes in this region is the gene encoding IL-4. This gene could be a candidate gene for asthma. The aim of this prospective case-control study was to assess the frequency of polymorphisms in the IL-4 gene promoter among asthmatic patients from Taiwan. Methods: The study consisted of 167 patients with asthma and 111 healthy subjects. PCR amplification followed by Bsm F1 restriction digestion were used to assign genotypes at the IL-4 promoter C-589T locus. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE antibodies against common inhalant allergens and total eosinophil counts were assessed in asthmatic patients. Results: The T allele frequency for the C-589T IL-4 gene promoter in asthma patients was higher than for normal subjects (P

Familial exudative vitreoretinopathy (FEVR) belongs to a group of genetically and clinically heterogeneous disorders in retinal vascular development. To date, in approximately 50% of patients with FEVR, pathogenic mutations have been detected in FZD4, LRP5, TSPAN12, NDP and ZNF408. In this study, we identified two heterozygous frameshift mutations in RCBTB1 from three Taiwanese cases through exome sequencing. In patient-derived lymphoblastoid cell lines (LCLs), the protein level of RCBTB1 is approximately half that of unaffected control LCLs, which is indicative of a haploinsufficiency mechanism. By employing transient transfection and reporter assays for the transcriptional activity of β-catenin, we demonstrated that RCBTB1 participates in the Norrin/FZD4 signaling pathway and that knockdown of RCBTB1 by shRNA significantly reduced nuclear accumulation of β-catenin under Norrin and Wnt3a treatments. Furthermore, transgenic fli1:EGFP zebrafish with rcbtb1 knockdown exhibited anomalies in intersegmental and intraocular vessels. These results strongly support that reduced RCBTB1 expression may lead to defects in angiogenesis through the Norrin-dependent Wnt pathway, and that RCBTB1 is a putative genetic cause of vitreoretinopathies.

Objective Several genetic variants have been found to increase the risk of restless legs syndrome (RLS). The aim of the present study was to determine if these genetic variants were also associated with the comorbidity of RLS and migraine in patients. Methods Thirteen single-nucleotide polymorphisms (SNPs) at six RLS risk loci ( MEIS1, BTBD9, MAP2K5, PTPRD, TOX3, and an intergenic region on chromosome 2p14) were genotyped in 211 migraine patients with RLS and 781 migraine patients without RLS. Association analyses were performed for the overall cohort, as well as for the subgroups of patients who experienced migraines with and without aura and episodic migraines (EMs) vs. chronic migraines (CMs). In order to verify which genetic markers were potentially related to the incidence of RLS in migraine patients, multivariate regression analyses were also performed. Results Among the six tested loci, only MEIS1 was significantly associated with RLS. The most significant SNP of MEIS1, rs2300478, increased the risk of RLS by 1.42-fold in the overall cohort ( p = 0.0047). In the subgroup analyses, MEIS1 augmented the risk of RLS only in the patients who experienced EMs (odds ratio (OR) = 1.99, p = 0.0004) and not those experiencing CMs. Multivariate regression analyses further showed that rs2300478 in MEIS1 (OR = 1.39, p = 0.018), a CM diagnosis (OR = 1.52, p = 0.022), and depression (OR = 1.86, p = 0.005) were independent predictors of RLS in migraine. Conclusions MEIS1 variants were associated with an increased risk of RLS in migraine patients. It is possible that an imbalance in iron homeostasis and the dopaminergic system may represent a link between RLS incidence and migraines.

Nitric oxide (NO) is a pivotal vasoactive substance modulating arteriovenous fistula (AVF) patency for hemodialysis (HD). Since genetic background could be the predicting factor of AVF malfunction, we aimed to investigate whether the NO-related genotype polymorphisms determine AVF survival rates.This is a retrospective, observational, multi-center study involving eight HD units in Taiwan, enrolled 580 patients initiating maintenance HD via AVFs. Genotype polymorphisms of NO-biosynthesis regulating enzymes (DDAH-1, DDAH-2, eNOS and PRMT1) were compared between HD patients with (n = 161) and without (n = 419) history of AVF malfunction. Subgroup analyses by gender were performed to evaluate the genetic effect in difference sexes.In overall population, statistically significant associations were not found between AVF malfunction and the genetic polymorphisms. In the male subgroup (n = 313), a single nucleotide polymorphism (SNP) of PRMT1, rs10415880 (IVS9-193 A/G), showed a significant association with AVF malfunction. Male patients with AA/AG genotype had inferior AVF outcomes compared to GG genotype, regarding primary patency (70.6% vs. 40.9%, p = 0.001), assisted primary patency (81.0% vs. 58.4%, p 0.001) and secondary patency (83.7% vs. 63.3%, p 0.001) at a 5-year observation period. From multivariate Cox regression model, the AA/AG genotypes of PRMT1 were an independent risk factor for AVF malfunction in men (HR: 4.539, 95% CI 2.015-10.223; p 0.001). However, such associations were not found in women.rs10415880, the SNP of PRMT1 could be a novel genetic marker associated with AVF malfunction risk in male HD patients. Those with AA and AG genotypes of rs10415880 may predict a poorer long-term patency of AVF.

Since the mid-1990s, novel G9 rotaviruses have been detected in many countries, suggesting that G9 is a globally important serotype. The molecular epidemiology of G9 rotaviruses in Taiwan from 2000 to 2002 was investigated in this study. G9 rotavirus first appeared in 2000 with 4 cases and constituted 33.8% and 54.8% of the rotavirus-positive samples in 2001 and 2002, respectively. These G9 strains belonged to P[8]G9, subgroup II, and long electropherotype, except one belonged to P[4]G9, subgroup II, and short electropherotype. Nucleotide sequencing and phylogenetic analysis of 52 Taiwanese G9 rotaviruses showed that the VP7 genes shared a high degree of identity to overseas G9 rotaviruses detected after 1993 and that the VP8* portions of the VP4 genes were more closely related to those of local rotaviruses of other G types. The two P[8]G9 strains with high nucleotide identities in the VP7 and the partial VP4 genes, 01TW591 of Taiwan from 2001 and 95H115 of Japan from 1995, varied in four genes, genes 2, 3, 7, and 8, which was revealed by RNA-RNA hybridization. Representative strains for different RNA patterns were also analyzed in the partial VP2 and VP3 genes; the nucleotide identities were high between Taiwanese G9 strains and local G3 or G2 strains. These results suggested that Taiwanese G9 rotaviruses possibly had evolved through reassortment between overseas G9 strains and circulating rotaviruses of other G types.

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n)or=30 and S allele means (GT)n30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)(n)or=30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.

Areca (betel) chewing is associated with the high incidence of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) in Asians. Heme oxygenase-1 (HO-1), encoding an oxidative response protein, plays protective roles in cells. A (GT)n microsatellite repeat in HO-1 promoter shows polymorphisms and modulates the level of gene transcription. We examined allelotypic frequencies of (GT)n repeats in 83 controls, 147 OSCC and 71 OSF. All subjects were male areca chewers. Logistic regression was used to adjust the age confounding for odds ratio (OR). (GT)n repeat polymorphism was classified into short (S), medium (M) and long (L) alleles. The adjusted OR in OSCC subjects carrying L allelotype relative to S allelotype was 1.75. Buccal squamous cell carcinoma (BSCC) is the most common OSCC subset in areca chewers. L allelotype implied the risk of BSCC with adjusted OR of 2.05, whereas M allelotype appeared protective for non-BSCC with adjusted OR of 0.49. Our findings indicated that longer (GT)n repeat allele in HO-1 promoter is associated with the risks of areca-related OSCC, while the shorter (GT)n repeat allele may have protective effects for OSCC.

Background: Oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF), which are highly associated with areca use, are prevalent in most Asian countries. Matrix metalloproteinases (MMPs) are superfamily of metal-dependent proteolytic enzymes, mediating the degradation of extracellular matrix. Insertion/deletion (−1607 2G1G) polymorphism has been described in the promoter region of the human matrix metalloproteinases-1 (MMP-1) genes, which cause an alteration in the transcriptional activity. This genotype is associated with risks of cancer genesis and metastasis. In this paper, we studied the relationship between such genotype and areca-associated oral diseases. Methods: Genomic DNA from the blood of OSCC (n = 121), OSF (n = 58) cases and controls (n = 147) were amplified by polymerase chain reaction (PCR)-based genotyping. The OSCC were further grouped into buccal squamous cell carcinoma (BSCC) and non-buccal suqmaous cell carcinoma (NBSCC), in accord with the site of involvement. The significance of the differences was assessed by Fisher's exact test. Results: The 2G genotype in MMP-1 promoter was observed with a higher frequency in both OSCC (0.69, P = 0.06) and NBSCC (0.76, P = 0.03) cases compared with controls (0.63), with an odds ratio of 2.17 and 4.58, respectively. This genotype was not related to the risk of OSF. No other clinicopathologic parameter was associated with the genotypes in OSCC cases. Conclusion: The results showed that 2G genotype in MMP-1 promoter was associated with the risk of OSCC.

Background and aims Elevated plasma asymmetric dimethylarginine (ADMA) levels have been observed in patients with insulin resistance and diabetes, and have been reported to predict adverse cardiovascular events in type 2 diabetic patients. However, the relationship between ADMA and glycemic control in patients with type 2 diabetes remained controversial. Methods and results We evaluated 270 patients with type 2 diabetes and measured their plasma ADMA and hemoglobin A1c (HbA1c) levels by high performance liquid chromatography. The mean age was 67 ± 12 years. The mean plasma ADMA and HbA1c level were 0.46 ± 0.09 μmol/l and 7.8 ± 1.6%, respectively. There was no significant correlation between plasma ADMA level and HbA1c level (r = −0.09, p = 0.13). During the median follow-up period of 5.7 years (inter-quartile range: 5.0 − 7.3 years), major adverse cardiovascular event (MACE, including cardiovascular death, myocardial infarction and stroke) was observed in 55 patients (20.4%). Multivariate Cox regression analysis revealed that the ADMA tertile was an independent risk factor for MACE (ADMA tertile III versus ADMA tertile I: p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). The prognosis predictive power of ADMA disappeared in patients with well glycemic control (HbA1c ≤6.5%), and the ADMA-HbA1c interaction p value was 0.01. Conclusions In patients with type 2 diabetes, ADMA might be an independent risk factor for long-term adverse cardiovascular events. However, ADMA was not correlated with serum HbA1c level, and in diabetic patients with HbA1c ≤6.5%, elevated ADMA level was no longer associated with increased risk of long-term prognosis. Our findings suggested that the prognosis predictive value of ADMA in type 2 diabetes might be modified by the glycemic control.

Monozygotic twins with chromosome 22q11 microdeletions offer an ideal situation to observe the association of microdeletion and disrupted cardiovascular patterning. We report monozygotic twins concordant for 22q11.2 microdeletion but discordant for cardiovascular patterning. Both twins showed identical intracardiac defects including tetralogy of Fallot with pulmonary atresia. Nevertheless, their great vessel patternings were variable. These twins show that the mispatterning of the great vessels may not correlate with intracardiac morphogenesis. The discordant development of the great vessels, especially in the pulmonary vascular system, has clinical significance for prognosis. The phenotypic variability of cardiovascular anomalies seen in 22q11 microdeletion cannot be explained on the basis of genotypic difference.

Objective. Tetralogy of Fallot is a common cardiac anomaly that is associated with chromosome 22q11 microdeletion. In this study we examined the mode of transmission as well as the parental origin of microdeletion in patients with tetralogy of Fallot. Methods. Eighty-four children with sporadic tetralogy of Fallot (40 boys and 44 girls; mean age, 34 months) were analyzed for microdeletion at chromosome 22q11 by genotype analysis, using five microsatellite markers, D22S427, D22S941, D22S944, D22S264 and D22S311, and confirmed by quantitative polymerase chain reaction, using TUPLE1 and D22S264. All parents of these subjects consented to their own participation and their child's participation in the clinical evaluation and molecular study. To provide a molecular characterization of microdeletion, we isolated DNA from the parents and typed their DNA with each of the five polymorphic markers. Results. Sixty-six patients were associated with pulmonary stenosis; and 8 of these cases (12%) had microdeletion. Eighteen patients were associated with pulmonary atresia, and 6 (33%) of these cases had microdeletion. The parental origins of the 14 patients with microdeletion were paternal in 3 cases and maternal in 11 cases. The most common mode of transmission was de novo without parental hemizygosity (93%). Transmission by autosomal dominant heredity was uncommon (7%). Conclusions. Biased parental origin was consistently found in tetralogy of Fallot patients with chromosomal 22q11 microdeletion. Our results indicated a higher prevalence of microdeletion because of inheritance of maternal microdeletion (78%).

Of 193 emergency department workers exposed to severe acute respiratory syndrome (SARS), 9 (4.7%) were infected. Pneumonia developed in six workers, and assays showed anti-SARS immunoglobulin (Ig) M and IgG. The other three workers were IgM-positive and had lower IgG titers; in two, mild illness developed, and one remained asymptomatic.

BACKGROUND The objective of this study was to evaluate the interaction between the length polymorphism of the guanosine thymidine repeat [(GT)n] in the heme oxygenase-1 (HO-1) gene and far-infrared (FIR) therapy on access flow (Qa) and arteriovenous fistula (AVF) patency in hemodialysis (HD) patients. METHODS A total of 280 HD patients were randomized into a control group (n = 141) and the FIR group (n = 139) who received 40 min of FIR therapy three times weekly for a year during the study period from May 2005 to December 2007. Access flow was measured during HD. The [(GT)n] was determined with the definition of long (L) allele as [(GT)n] ≥ 30 and short (S) allele as [(GT)n] < 30. RESULTS The Qa decreased from S/S to S/L and further to the L/L group but increased by FIR therapy with the highest Qa increase in the S/S group. The incidence of AVF malfunction decreased both from the L/L, S/L to S/S group (32.4 versus 17.2 versus 10.9%, P = 0.007) and from the control group to FIR group (27.5 versus 12.6%, P = 0.004). Significant associations were found between AVF malfunction and the following factors (hazard ratio, P-value): a past history of AVF malfunction (2.45, P = 0.044), FIR therapy (0.369, P = 0.03) and L/L genotypes of HO-1 (2.531 versus S/S + S/L genotypes). The 1-year unassisted patency decreased from 91.9 and 77.6% in S/S and S/L subgroups with and without FIR therapy to 75.8 and 60% for L/L subgroup with and without FIR therapy, respectively (P < 0.001). CONCLUSIONS FIR therapy improves Qa and patency of AVF in HD patients, with the best protective effect in those with S/S genotype of HO-1.

We investigated the microsatellite alterations in mitochondrial DNA (mtDNA) and in TP53 in thoracic esophageal squamous cell carcinomas (TESCC). Using laser microdissection, 66 paired non-cancerous esophageal muscles, non-cancerous esophageal mucosa, cancerous TESCC nests plus 35 metastatic lymph nodes harvested from 66 resected esophagi of TESCC patients were subjected to DNA extrac- tion. D310 and D17S960 were chosen as markers to address microsatellite alterations in mtDNA, including changes in copy number and homoplasmic/heteroplasmic mutations of mtDNA, and in TP53, including loss of heterozygosity (LOH) and microsatellite instability (MI). From non-cancerous esophageal mucosa to cancerous TESCC nests and then metastatic lymph nodes, a trend of homoplasmic D310 muta- tion (10.6, 25.8, 31.4%; P=0.023), an ever increase of mtDNA copy ratios (0.892, 1.128, 1.183; P=0.018) and an elevated incidence of TP53 LOH (19.7, 34.8, 37.1%; P=0.010) were observed. From T1, T2, T3 to T4 TESCC, the incidence of TP53 LOH (12.5, 16.7, 34.8, 52.2%; P=0.011) was increased, in a stepwise fashion. Furthermore, we observed an association of TP53 LOH with an increased mtDNA copy ratio (P=0.022) and TP53 MI with heteroplasmic D310 mutation (P=0.069) in TESCC. Concurrent and associated microsatellite alterations in mtDNA and in TP53 in TESCC support the cancer clonal expansion theory and imply a possible relationship between the mitochondria and p53 in TESCC.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat. In this study, we describe the identification and characterization of the gene harbouring this repeat. The SCA1 transcript is 10,660 bases and is transcribed from both the wild type and SCA1 alleles. The CAG repeat, coding for a polyglutamine tract, lies within the coding region. The gene spans 450 kb of genomic DNA and is organized in nine exons. The first seven fall in the 5' untranslated region and the last two contain the coding region, and a 7,277 basepairs 3' untranslated region. The first four non-coding exons undergo alternative splicing in several tissues. These features suggest that the transcriptional and translational regulation of ataxin-1, the SCA1 encoded protein, may be complex.

Summary Background and objectives Elevated plasma level of asymmetric dimethylarginine (ADMA) have been reported to be associated with endothelial dysfunction and atherosclerosis risk factors, and may predict cardiovascular events in patients with ESRD. In this study, we aimed to assess the association between plasma ADMA and long-term outcome in a cohort of patients with stage 3 to 4 chronic kidney disease (CKD). Design, setting, participants, & measurements From July 2006 to June 2009, 298 consecutive patients with stage 3 to 4 CKD scheduled to undergo coronary angiography were recruited. Plasma ADMA levels were determined using HPLC. Results The mean age was 73 ± 10 years. Approximately half of the patients had diabetes and 88 patients had proteinuria. The baseline estimated GFR (eGFR) was 44 ± 13 ml/min per 1.73 m2. The plasma ADMA levels of the patients with proteinuria were significantly higher than those without. The plasma ADMA levels correlated significantly with eGFR. During the median follow-up period of 2.7 years, we observed 26 all-cause deaths, 12 nonfatal myocardial infarctions, and 2 strokes. Multivariate Cox analysis revealed that an increase of 0.1 μmol/L in plasma ADMA level was associated with a 37% increased risk of the composite outcomes of all-cause deaths, nonfatal myocardial infarctions, and strokes. Conclusions In this elder and high-risk population with stage 3 to 4 CKD, high plasma ADMA level was associated with low eGFR and macroalbuminuria. Furthermore, high plasma ADMA level appeared to be an independent predictor of long-term outcome.

Background: Bipolar disorder (BD) is a common mental disorder, subdivided into BD-I and BD-II. Currently, few biomarkers differentiate BD-I from BD-II. However, it is suggested that peripheral blood mononuclear cell (PBMC) mRNA levels of p11 and positron emission tomography (PET) might be potential biomarkers for BD. Methods: Healthy controls (HCs), BD-I, and BD-II patients in remission (n ¼ 20 in each group) underwent a resting PET study with the radiotracer [ 18 F]-2-deoxy-2-fluoro-D-glucose ( 18 F-FDG). PBMC p11 mRNA levels were determined by quantitative real-time PCR. Results: Comparing BD patients to HCs, normalized glucose metabolism (NGM) was higher in the hippocampus, parahippocampus, and amygdala, but lower in the anterior cingulate cortex (aCC), medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dlPFC), insula and thalamus. Compared to BD-II, BD-I had hypometabolism of glucose in the aCC, bilateral middle and inferior gyrus, insula and striatum, and hypermetabolism of glucose in the left parahippocampus. PBMC p11 mRNA was over-expressed in both BD-I and BD-II, although there was no significant difference in its expression levels between BD-I and B-II patients. Further, there were significant positive correlations between PBMC p11 mRNA and NGM in the mPFC, aCC, left insula, bilateral orbitofrontal cortex (OFC), and left middle, inferior and superior temporal gyri. Also, PBMC p11 mRNA was positively correlated to the number of depressive episodes in BD patients, especially in BD-I patients. Discussion: This study demonstrates that PBMC p11 mRNA expression is associated with neural activation in the brain of BD patients and warrants a larger translational study to determine its clinical utility. Published by Elsevier Ltd.

Background Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown. Methods From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Results Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04). Conclusions Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome.

Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat on chromosome 6p. Normal alleles range from 19-36 repeats while SCA1 alleles contain 43-81 repeats. We now show that in 63% of paternal transmissions, an increase in repeat number is observed, whereas 69% of maternal transmissions showed no change or a decrease in repeat number. Sequence analysis of the repeat from 126 chromosomes reveals an interrupted repeat configuration in 98% of the unexpanded alleles but a contiguous repeat (CAG)n configuration in 30 expanded alleles from seven SCA1 families. This indicates that the repeat instability in SCA1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the SCA1 (CAG)n to expansion.

Although suicide represents 1.8% of the global burden of disease, there are few objective assays for suicide risk. Being associated with depressive disorders, which have a high risk of suicide, the proteins P11, P2RX7, and S100β may be biomarkers for a suicidal disposition. We measured levels of p11 and P2RX7 mRNA in peripheral blood mononuclear cells (PBMCs) of 26 psychiatric patients (11 suicide attempters, 15 suicide non-attempters) with post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), and 14 normal controls, using quantitative real-time PCR. We also conducted a meta-analysis of microarray data of p11, P2RX7 and S100β from post-mortem prefrontal cortex (PFC) of patients who committed suicide (n = 56) and non-suicide controls (n = 61). We found that PBMC p11 mRNA levels were significantly lower in suicide attempters and higher in suicide non-attempters, when compared to normal controls. The PFC p11 mRNA levels in suicide completers were also lower than non-suicide controls (adjusted p = 0.007). Unlike p11, PBMC P2RX7 mRNA levels were significantly lower than normal controls in all patients including suicide attempters, suicide non-attempters, and suicide completers. In addition, levels of S100β in PFC did not differ between suicide completers and non-suicide controls. These results suggest that PBMC p11 mRNA levels may be a potential adjunctive biomarker for the assessment of suicide risk in mental disorders and warrants a larger translational study to determine its clinical utility.