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Abstract: Background: Dravet syndrome (DS) is a rare form of intractable epilepsy. Children with DS often start having seizures in infancy, and gradually develop other seizure types. Several studies have demonstrated that certain gene mutations and submicroscopic copy number variations (CNV) in DS patients are strongly associated with intractable epilepsy. In this study, directed DNA sequencing and microarray technology were used to investigate genomic variations in DS patients. Methods: A total of nine DS patients were enrolled in this genetic study. A detailed medical history was obtained from each participant, and appropriate neurological examinations performed. Seizure types and epilepsy syndromes were classified according to ILAE criteria. The complete coding regions of SCN1A, SCN1B, SCN2A, GABRG2, and GABRD, including the intron/exon boundaries, were sequenced using DNA samples drawn from participants. In addition, whole genome CNV analysis was conducted via SNP microarray analysis. Results: DNA sequencing revealed a mutation in the SCN1A gene in five (55.6%) of the DS patients, within which three missense mutations, c.719T>C (p.Leu240Pro), c.2807A>T (p.Asp936Val), c.4349A>C (p.Gln1450Pro), and two frameshift mutations, c.2277insAACA (p.His759fsX772) and c.3972insT (p.Leu1324fsX1331) were observed. Upon CNV analysis, a novel duplication region, 4q13.1–q13.2, was detected in one DS patient; this variant region contained a gene, EPHA5, related to cerebral neuron development. Conclusion: This study extended the spectrum of SCN1A mutations in Taiwanese DS patients and confirms the high sensitivity of SCN1A for the DS phenotype. In addition, a novel duplication region identified within EPHA5 should be considered in future screening procedures for DS. [Copyright &y& Elsevier]

Abstract: Background: Membranous glomerulonephritis (MGN) is one of common causes of idiopathic nephrotic syndrome in adults, and 25% of MGN patients proceed to end-stage renal disease. STAT4 gene polymorphisms have been reported to be associated with many inflammatory diseases. The objective of this study was to clarify the relationship between STAT4 gene polymorphisms and the pathogenesis of MGN. Methods: We investigated the association of three STAT4 gene polymorphisms (rs3024912, rs3024908, and rs3024877) with the susceptibility to MGN in 403 Taiwanese populations (138 MGN patients and 265 controls). Results: The results indicated that the statistically significant difference in genotype frequency distribution was found at rs3024908 SNP in MGN patients and control groups (p =0.014). In addition, the individuals with the GG genotype at rs3024912 SNP may have a higher risk in kidney failure of MGN patients (adjusted odds ratio [OR]=3.255; 95% confidence interval [CI]=1.155–9.176, p =0.026). Conclusions: Our data provide a new information that the STAT4 (rs3024912 and rs3024908) polymorphisms may be the underlying cause of MGN, and these polymorphisms revealed by this study warrant further investigation. [Copyright &y& Elsevier]

Abstract: Background: The national hepatitis B (HB) vaccination program in Taiwan that began in 1984 has resulted in a significant reduction in the carrier rate among children. However, a significant proportion of Taiwanese neonatal HB immunization recipients have exhibited low anti-HBs titers that fall to non-protective or undetectable levels. Methods: We recruited 1677 entering freshman and graduate student participants at a Taiwanese university health center, grouped them into three age groups representing three stages of Taiwan''s HB vaccination program, then conducted hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) serological surveillances for each individual. Univariate and multivariate regression analyses of clinical characteristics and Interleukin-10 (IL-10) genetic variations were also conducted. Results: A trend toward a decreasing HBsAg carrier rate was observed over the starting dates of the vaccination program (11.7%, 1.6% and 1.7% for age groups 1, 2 and 3, respectively), but we also observed an increasing rate of non-protective anti-HBs titers (15%, 26% and 50.3% for cohorts 1–3, respectively). The percentage of students with non-protective anti-HBs titers increased from 23.1% for students born in 1984, to 25.2% for those born in 1985, to 39.4% for birth-year 1986 students, to 45.7% for birth-year 1987 students, and to 56.5% for birth-year 1988 students. The risk for low anti-HBs titers increased concurrently with increases in systolic blood pressure (BP), the IL-10 ATA/ACC haplotype, and the IL-10 ATA present haplotype. Risk for low anti-HBs titers decreased with concurrent decreases in glucose ante cibum (AC, before meals) and the IL-10 ACC/ACC haplotype. Conclusions: These results suggest that the genetic determinants may also contribute to variations in anti-HBs titers in immune responses to HB vaccination. [Copyright &y& Elsevier]

Abstract: Objective: The insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and human growth hormone (h-GH) have been recognized as therapeutic targets for the heart disease therapy. The bioavailability and actions of insulin-like growth factors-II (IGF-II) and matrix metalloproteinase-9 (MMP9) are important for embryonic development and cardiomyocyte differentiation as well. However, the clinical manifestations following the change in the serum IGF-II and MMP9 in infants with isolated ventricular septal defect (VSD) undergoing surgical repair have not been clearly defined. Study design: Serum samples were collected from 72 infants: Twenty normal infants (group I) and 51 consecutive infants with echocardiography established isolated VSD (aged from 3months to 1year) were investigated. Among the 51 infants with VSD, 28 with shunt fraction, Qp/Qs< or =1.5 were free of congestive heart failure symptoms (group II); 23 with shunt fraction, Qp/Qs> or =2.0 were in congestive heart failure (group IIIa); and 23 of these 23 infants had undergone VSD repair 6months before their second study (group IIIb). All insulin-like growth factors-II (IGF-II) and human growth hormone (h-GH), insulin like growth factor binding protein-3 (IGFBP-3) and its specific serum protease-MMP9 concentration were analyzed using ELISA and zymography, respectively. Results: Serum IGF-II and MMP9 exhibited significant decreasing trends among the three groups and significantly lower concentrations of IGF-II, IGF-II/IGFBP-3 ratio and MMP9, were found only in the severe group whereas h-GH/IGF-II ratio became significantly higher in this group. Moreover, there were no significant differences in these parameters between the infants after surgical correction and the normal ones. Conclusions: The improvement in IGF-II and MMP9 serum concentration was identified in infants with VSD after surgical repair. These findings also indicate a significant relationship between IGF-II, MMP9 and VSD which might be used as diagnosis and prognosis indicators for this defect. Slight reductions in IGF-II/IGFBP3 ratio and slight increase in the h-GH/IGF-II ratio indicate mild VSD. The reductions in the MMP9, IGF-II, and IGF-II/IGFBP3 ratio plus high increase in the h-GH/IGF-II ratio indicate severe VSD. [Copyright &y& Elsevier]

Abstract: Background: Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in adults. NPHS1 encoding nephrin is a transmembrane protein of the immunoglobulin family. We clarified the relationship between NPHS1 gene polymorphisms and the susceptibility or progression of MGN. Methods: We recruited a cohort of 132 biopsy-diagnosed MGN patients and 257 healthy subjects. Genotyping of three SNPs (rs401824, rs437168 and rs3814995) at chromosome positions 41034749 (5′UTR), 41026259(exon17) and 41034052 (exon 3) was performed using a Taqman SNP genotyping assay. Results: There was a significant difference in genotype frequency distribution of rs437168 polymorphism between MGN patients and controls. The results also showed that the frequency of the G allele was significantly higher in the patient group. Among the polymorphisms rs437168, rs401824 and rs3814995, no significant haplotype was shown in MGN patients. A stratified analysis revealed that a high disease progression in the AA genotype of rs401824 and GG genotype of rs437168 patients were associated with a low rate of remission. Conclusions: The presence of the different genotypes of NPHS1 was associated with susceptibility of MGN and the remission of proteinuria during disease progression after the therapy. [Copyright &y& Elsevier]

Abstract: Background: Oral cancer is a worldwide problem. It is a universal aggressive disease in the population of smoking and drinking. The oral cancer mortality has been ranked 5th place in Taiwan in male cancer patients. A number of protein markers for oral cancer are still not applicable in large populations. Proteomic technologies provide excellent tools for rapid screening of a large number of potential biomarkers in malignant cells. Method: Proteomics and real-time quantitative RT-PCR were used to analyze over-expressed proteins in 10 OSCC patients. Result: Forty-one proteins were identified as commonly over-expressed in OSCC tissues. In OSCC tissues, αB-crystallin, tropomyosin 2, myosin light chain 1, heat shock protein 27 (HSP27), stratifin, thioredoxin-dependent peroxide reductase, flavin reductase, vimentin, rho GDP-dissociation inhibitor 2 (rho GDI-2), glutathione S-transferase Pi (GST-pi) and superoxide dismutase [Mn] (MnSOD) were significantly over-expressed (an average of 7.2, 6.0, 5.7, 4.3, 3.6, 3.4, 3.0, 3.0, 2.6, 2.5, 2.1-fold, respectively). In real-time quantitative RT-PCR analysis, the gene expressions of αB-crystallin, HSP27 and MnSOD were also increased in the cancer tissues, consistent with proteomic results. Conclusion: The identified proteins in this experiment may be used in future studies of carcinogenesis or as diagnostic markers and therapeutic targets for OSCC. [Copyright &y& Elsevier]