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Exclusively breastfed infants are at a high risk of vitamin D deficiency. Few studies have evaluated the effects of vitamin D supplementation. Hence, we conducted a prospective randomized controlled trial investigating the effects of oral vitamin D3 400 IU/d supplementation in exclusively breastfed newborns. Serum 25-hydroxy-vitamin D (25[OH]D) levels in pregnant women and their newborns were evaluated. Breastfed newborns were randomized to one of two regimens at age 10 days. One group received vitamin D3 supplementation at a dose of 400 IU/d (vD-400 group), whereas the placebo group received a liquid product without vitamin D3. Outcomes were assessed at 4 months of age. A total of 92 pregnant women and their infants were enrolled, and the data of 72 infants (37 in the vD-400 group and 35 in the placebo group) who completed the study at 4 months of age were assessed. The results showed severe vitamin D deficiency in 15.2% of mothers before delivery, while 54.3% had vitamin D deficiency. Moreover, 15.2% of newborns presented with severe vitamin D deficiency at birth, while 52.2% had vitamin D deficiency. Maternal vitamin D levels were significantly correlated with infant vitamin D levels at birth (r = 0.816, p 0.001). At 4 months of age, weight, head circumference, serum 25(OH)D, phosphorus, and intact parathyroid hormone levels significantly differed between the vD-400 and placebo groups. However, the body length and bone mineral density of the two groups did not differ significantly. Regardless of vitamin D supplementation, participants with severe vitamin D deficiency had significantly higher intact parathyroid hormone levels and lower bone mineral content. In conclusion, among exclusively breastfed infants, oral supplementation with vitamin D3 at a dose of 400 IU/d from age 10 days increased 25(OH)D concentrations at 4 months of age, but it did not affect bone mineralization. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Background/purpose: This study aimed to clarify whether brain-derived neurotrophic factor (BDNF) is a biomarker for cognitive dysfunction in children with type 1 diabetes. Methods: We conducted a cross-sectional case–control study of children aged between 6 and 18 years with type 1 diabetes and healthy volunteers. Serum BDNF level was measured in all of the studied children, and they all underwent intelligence tests with the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We further compared the cognitive function and BDNF levels in the diabetic children with positive glutamic acid decarboxylase 65 antibody (GAD65-Ab) and those with negative GAD65-Ab. Results: Forty-five children with type 1 diabetes (mean age 14.0 ± 2.6 years, 42% male) and 50 normal controls (mean age 13.2 ± 2.3 years, 54% male) were recruited. The serum BDNF level was significantly lower in the diabetes group than in the controls (15.92 ± 7.2 vs. 18.5 ± 5.1 ng/mL, respectively, t = −2.03, p = 0.045) and much lower in the subgroup with GAD65-Ab positive type 1 diabetes. The average Full-Scale IQ, verbal comprehension, perceptual reasoning and working memory scores in the diabetes group were significantly lower than in the controls (all p

Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology that affects infants and young children. Considerable evidence supports the hypothesis that there is a genetic basis for KD susceptibility. Genome-wide association studies (GWAS) have identified several genetic variants associated with KD. This study aims to replicate three novel KD-associated single nucleotide polymorphisms (SNPs), identified by GWAS in Japanese, in a Taiwanese population. Associations between these SNPs and development of coronary artery lesions (CALs) were also investigated. The rs2254546 A/G, rs2857151 A/G, and rs4813003 C/T SNPs were genotyped in 681 children with KD and 563 ethnically-matched healthy controls using TaqMan Assay or DNA sequencing. We found rs2254546 and rs4813003 SNPs were significantly associated with KD (G allele, odds ratio [OR] = 1.54, P = 1.0 × 10–5; C allele, OR = 1.32, P = 8.1 × 10–4). However, no evidence for associations with CAL development was observed. Our study successfully validates associations of the rs2254546 and rs4813003 SNPs with KD in a Taiwanese population. Further functional studies of the SNPs are important in understanding the pathogenesis of KD.

Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown. We screened 532 Taiwanese T1DM patients for CD biomarkers including anti-tissue transglutaminase (TGM2), anti-gliadin and anti-neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs. We report that 3.76% of Taiwanese patients had TGM2-Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2-Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti-gliadin or anti-neoepitope Abs coexisted with ~3/4 of TGM2-Abs positive patients that were likely due to gluten-ingestion, while the cause of TGM2-Abs production for other ~1/4 of patients was unknown. Purified anti-TGM2 IgA (TGA) and anti-TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2's transamidation activity by up to 80% but TGG had no effects. Epitope mapping of all TGM2-Abs positive sera demonstrated that TGM2-Abs had heterogeneity in specificities. This is the first study on the differences between Taiwanese Han group and Caucasian in HLA genotypes and properties of TGM2-Abs.

Background The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for confirming the activation of the hypothalamic–pituitary–gonadal axis in central precocious puberty (CPP). However, it is time-consuming and costly. Our aim was to search for a simpler diagnostic modality for CPP by 1) evaluating the performance of basal serum luteinizing hormone (LH), 2) constructing a practical scoring system, and 3) determining the optimal single sampling time for serum LH in the GnRH stimulation test. Methods Data of girls aged between 3 and 9 years at the time of the GnRH stimulation test, who attended our endocrine clinic at the MacKay Children's Hospital for signs of puberty between July 2014 and June 2019, were analyzed retrospectively. We recorded patients' age, height, weight, breast Tanner stage (BS), bone age, serum LH, and follicle-stimulating hormone (FSH). Receiver operating characteristic (ROC) curves and the Youden index were used to obtain the optimal basal serum LH level. Binary logistic regression was employed to construct a practical scoring system. Cross-sectional, cumulative frequency, and ROC curves were used to simplify the GnRH stimulation test. Results Overall, 381 sets of GnRH stimulation tests were performed in 313 patients. Basal serum LH ≥ 0.2 IU/L demonstrated 70% sensitivity and 70% specificity for predicting positive GnRH stimulation test results. The practical scoring system (3 × BS + 3 × LH + 4 × FSH) showed 76% sensitivity and 72% specificity. The serum LH level at 30 min after intravenous gonadorelin exhibited 99% sensitivity and 100% specificity. Conclusion Single sampling of serum LH at 30th minute post-injection of GnRH demonstrated a diagnostic performance equivalent to the traditional GnRH stimulation test in diagnosing CPP. Therefore, this approach could become the simplest diagnostic modality.

// Bi-Wen Cheng 1, 8, * , Fu-Sung Lo 2, 3, * , An-Mei Wang 4, 6 , Chen-Mei Hung 5 , Chi-Yu Huang 1, 6 , Wei-Hsin Ting 1, 6 , Mei-Ore Yang 7 , Chao-Hsu Lin 8 , Chia-Ching Chen 9 , Chiung-Ling Lin 10 , Yi-Lei Wu 11 and Yann-Jinn Lee 1, 10, 12, 13, 14 1 Department of Pediatric Endocrinology, MacKay Children's Hospital, Taipei, Taiwan 2 Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan 3 College of Medicine, Chang Gung University, Taoyuan, Taiwan 4 Department of Nuclear Medicine, MacKay Memorial Hospital, Taipei, Taiwan 5 Department of Pediatrics, Hsinchu Cathay General Hospital, HsinChu, Taiwan 6 MacKay Medicine, Nursing and Management College, New Taipei City, Taiwan 7 Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei, Taiwan 8 Department of Pediatrics, MacKay Memorial Hospital HsinChu Branch, HsinChu, Taiwan 9 Department of Pediatrics, Chiayi Christian Hospital, Chiayi, Taiwan 10 Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan 11 Department of Pediatric Endocrinology and Metabolism, Chuanghua Christian Children’s Hospital, Chuanghua, Taiwan 12 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan 13 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 14 Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Yann-Jinn Lee, email: yannlee@mmh.org.tw Keywords: autoantibodies; glutamic acid decarboxylase 65 (GAD) autoantibody; insulinoma-associated protein 2 autoantibody; insulin autoantibody; type 1 diabetes mellitus; Immunology Received: December 12, 2016 Accepted: February 13, 2018 Epub: February 19, 2018 Published: March 27, 2018 ABSTRACT We investigated the prevalence of glutamic acid decarboxylase 65 autoantibody (GADA), insulinoma-associated protein 2 autoantibody (IA2A), and insulin autoantibody (IAA) in 750 children with type 1 diabetes (T1D) living in Taiwan. GADA, IA2A, and IAA were measured by radioimmunoassay. The data were assessed by χ 2 test, binary logistic regression, and Spearman rank correlation. Of the 750 T1D patients, 66.3% had GADA, 65.3% IA2A, 35.7% IAA, and 17.2% no autoantibodies. The prevalence of GADA and IA2A significantly decreased along T1D duration. The positivity of either GADA or IA2A was 89.4% within the first year of disease and decreased to 36.7% after 9 years ( P = 1.22 × 10 –20 ). Female patients had significantly higher prevalence of GADA compared with male patients (72.3% vs. 59.7%, P = 0.00027). The patients diagnosed before 12 years of age had a positive rate of 92.2% for either GADA or IA2A. Patients diagnosed at age 12 or above had a significantly lower positive rate of 81.6% ( P = 0.011). GADA and IA2A significantly correlated with each other (rs = 0.245, P = 1.09 × 10 –11 ). We concluded that autoantibodies were detectable in 89.4% of T1D patients within one year after diagnosis. Their prevalence declined with disease duration. GADA was more prevalent in female patients. GADA and IA2A weakly correlated with each other.

Backbroud/Purpose: Microalbuminuria and macroalbuminuria are markers of diabetic nephropathy (DN). The purpose of this study was to unravel the risk factors for DN in the young patients with type 1 diabetes (T1D). Methods: 341 patients (160 males) with T1D diagnosed at the age 7.6 ± 4.0 years with disease duration 11.5 ± 6.5 years were assessed. Among them, 185 were young adults (aged 18.0â36.2 years). Urinary albumin creatinine ratio (UACR) was checked on morning spot urine. Microalbuminuria and macroalbuminuria were defined as a UACR of 30â300 mg/g and >300 mg/g, respectively, in at least 2 consecutive specimens. Results: 50 (14.7%) patients were classified as microalbuminuria and 13 (3.8%) as macroalbuminuria. In all patients, multivariate logistic regression revealed that the most significant risk factors were average HbA1c (%), OR (95% CI) = 1.76 (1.37â2.25), P = 0.002); and male sex, OR = (odd ratio 2.31 (1.19â4.46), P = 0.013). In adult patients, the most significant factors were average HbA1c, OR = 1.74 (1.32â2.31), P = 0.003; and systolic blood pressure, OR = 1.06 (1.01â1.11), P = 0.011. Survival analysis showed average HbA1c levels significantly influenced the development of DN. Conclusion: The most important risk factors for DN were average HbA1c and age. When microalbuminuria is detected, proper treatment with ACEIs or ARBs and improving glycemic control can delay progression of DN. Keywords: Type 1 diabetes, Diabetic nephropathy, Microalbuminuria, Macroalbuminuria, HbA1c

// Yuh-Cheng Yang 1, 4, * , Tzu-Yang Chang 3, * , Tze-Chien Chen 1 , Wen-Shan Lin 3 , Shih-Chuan Chang 3 , Yann-Jinn Lee 2, 3, 5, 6, 7 1 Department of Gynecology and Obstetrics, MacKay Memorial Hospital, Taipei City 2 Department of Pediatric Endocrinology, MacKay Children’s Hospital, Taipei City 3 Department of Medical Research, MacKay Memorial Hospital, New Taipei City 4 Department of Gynecology and Obstetrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 5 Departments of Gynecology and Obstetrics, Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 6 Institute of Biomedical Sciences Mackay Medical College, New Taipei City, Taiwan 7 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan * These authors contributed equally to this work. Correspondence to: Yann-Jinn Lee, email: yannlee@mmh.org.tw , kylechang@mmh.org.tw Keywords: cervical cancer, HPV, immunity, ITPR3, polymorphism Received: June 15, 2016 Accepted: December 15, 2016 Published: December 28, 2016 ABSTRACT Host immunogenetic background plays an important role in human papillomavirus (HPV) infection and cervical cancer development. Inositol 1,4,5-triphosphate receptor type 3 (ITPR3) is essential for both immune activation and cancer pathogenesis. We aim to investigate if ITPR3 genetic polymorphisms are associated with the risk of cervical cancer in Taiwanese women. ITPR3 rs3748079 A/G and rs2229634 C/T polymorphisms were genotyped in a hospital-based study of 462 women with cervical squamous cell carcinoma (CSCC) and 921 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. No significant association of individual ITPR3 variants were found among controls, CSCC, and HPV-16 positive CSCC. However, we found a significant association of haplotype AT between CSCC and controls (OR = 2.28, 95% CI 1.31–3.97, P = 2.83 × 10 −3 ) and the OR increased further in CSCC patients infected with HPV-16 (OR = 2.89, 95% CI 1.55–5.37, P = 4.54 × 10 −4 ). The linkage disequilibrium analysis demonstrated that ITPR3 association with CSCC was independent of HLA-DRB1 alleles. In conclusion, these findings suggest that AT haplotype in the ITPR3 gene may serve as a potential marker for genetic susceptibility to CSCC.

Background: Graves disease (GD) is the most common cause of thyrotoxicosis in children and adolescents, accounting for 15% of all thyroid diseases during childhood. Anti-thyroid drugs (ATD) are recommended as the first-line treatment in children and adolescents. However, the remission rate is lower in children than in adults, and the optimal treatment duration and favorable factors associated with remission remain unknown. We aimed to investigate long-term outcomes of pediatric GD patients receiving ATD. Methods: We retrospectively reviewed medical charts of 396 GD subjects from 1985 to 2017 at MacKay Children's Hospital. Ninety–six patients were excluded from the analyses, including 71 patients followed for less than one year, 6 patients who received radioactive therapy and 19 patients who received surgery. The remaining 300 patients initially treated with ATD and followed up for more than 1 year constituted our study population. Results: The 300 patients comprised 257 (85.7%) females and 43 (14.3%) males. Their median age at diagnosis was 11.6 (range 2.7–17.8) years with 11 patients (3.7%) younger than 5 years. Their median follow-up period was 4.7 (range 1.1–23.9) years. Overall, 122 patients achieved the criteria for discontinuing ATD treatment, and seventy-nine (39.9%) patients achieved remission, with a median follow-up period of 5.3 (range 1.5–20.1) years. Patients in the remission group were more likely to be aged

// Yuh-Cheng Yang 1, 4, * , Tzu-Yang Chang 3, * , Tze-Chien Chen 1 , Wen-Shan Lin 3 , Shih-Chuan Chang 3 , Yann-Jinn Lee 2, 3, 5, 6, 7 1 Department of Gynecology and Obstetrics, MacKay Memorial Hospital, Taipei City, Taiwan 2 Department of Pediatric Endocrinology, MacKay Children’s Hospital, Taipei City, Taiwan 3 Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan 4 Department of Gynecology and Obstetrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 5 Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan 6 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan 7 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan * The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors Correspondence to: Yann-Jinn Lee, email: yannlee@mmh.org.tw , kylechang@mmh.org.tw Keywords: cervical cancer, HPV, immunity, P2RX7 , polymorphism Received: June 30, 2016 Accepted: September 28, 2016 Published: October 13, 2016 ABSTRACT Human papillomavirus (HPV) infection and the fate of HPV infected cervical epithelial cells are strictly associated with cervical cancer development. P2X7 receptor has been implicated in both the regulation of immune responses and apoptosis of cervical cancer cells. The study aims to investigate if polymorphisms in the P2RX7 gene are associated with the risk of cervical cancer in Taiwanese women. P2RX7 253 T/C , 835 G/A , and 1513 A/C loss-of-function polymorphisms were genotyped in a hospital-based study of 507 women with cervical squamous cell carcinoma (CSCC) and 1619 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. The frequency of 253 C/C genotype was found to increase significantly in patients with HPV-16 positive CSCC compared with controls (odds ratio = 10.2, 95% confidence interval 1.39–87.8, P c = 0.03). No significant associations were found for other 2 polymorphisms. Analysis of haplotypes also revealed no significant differences among women with CSCC, those with HPV-16 positive CSCC and controls. In conclusion, inheritance of the C/C genotype at position 253 in the P2RX7 gene may contribute to the risk of HPV-16 associated CSCC in Taiwanese women.

Monogenic diabetes is caused by mutations that reduce β-cell function. While Sanger sequencing is the standard method used to detect mutated genes. Next-generation sequencing techniques, such as whole exome sequencing (WES), can be used to find multiple gene mutations in one assay. We used WES to detect genetic mutations in both permanent neonatal (PND) and type 1B diabetes (T1BD). A total of five PND and nine T1BD patients were enrolled in this study. WES variants were assessed using VarioWatch, excluding those identified previously. Sanger sequencing was used to confirm the mutations, and their pathogenicity was established via the literature or bioinformatic/functional analysis. The PND and T1BD patients were diagnosed at 0.1–0.5 and 0.8–2.7 years of age, respectively. Diabetic ketoacidosis was present at diagnosis in 60% of PND patients and 44.4% of T1BD patients. We found five novel mutations in five different genes. Notably, patient 602 had a novel homozygous missense mutation c.1295C > A (T432 K) in the glucokinase (GCK) gene. Compared to the wild-type recombinant protein, the mutant protein had significantly lower enzymatic activity (2.5%, p = 0.0002) and Vmax (1.23 ± 0.019 vs. 0.33 ± 0.016, respectively; p = 0.005). WES is a robust technique that can be used to unravel the etiologies of genetically heterogeneous forms of diabetes. Homozygous inactivating mutations of the GCK gene may have a significant role in PND pathogenesis.

Genetic epidemiological studies show that genetic factors contribute significantly to cervical cancer carcinogenesis. Several genome-wide association studies (GWAS) have revealed novel genetic variants associated with cervical cancer susceptibility. We aim to replicate 4 GWAS-identified single nucleotide polymorphisms (SNPs), which were associated with invasive cervical cancer in Chinese women, in a Taiwanese population. The rs13117307 C/T, rs8067378 A/G, rs4282438 G/T, and rs9277952 A/G SNPs were genotyped in 507 women with cervical squamous cell carcinoma (CSCC) and 432 age/sex matched healthy controls by using TaqMan PCR Assay. Human papillomavirus (HPV) DNA test and typing were performed in CSCC patients. Only the rs4282438 SNP was found to be significantly associated (G allele, odds ratio [OR] = 0.67, P = 1.5 × 10−5). This protective association remained in HPV-16 positive CSCC subgroup (G allele, OR = 0.60, P = 1.2 × 10−5). In conclusion, our study confirms the association of rs4282438 SNP with CSCC in a Taiwanese population. However, larger sample sets of other ethnic groups are required to confirm these findings.

Glycemic control and quality of life (QoL) are both considered indicators of health adaptation among adolescents with type 1 diabetes (T1D). The purpose of this study was to construct a path model addressing the influences of individual characteristics, school support, resilience, and self-care behaviors on glycated hemoglobin (HbA1c) and QoL among adolescents with T1D in Taiwan. This was a cross-sectional design study. A structured questionnaire was used to collect information on individual characteristics, school support, resilience, self-care behaviors, and QoL. The latest HbA1c was collected from medical records. Data from 238 adolescents with T1D were analyzed using structural equation modeling to test the hypothesized path model. The findings indicated that self-care behaviors and resilience both directly influenced HbA1c and QoL. School support directly influenced QoL but indirectly influenced HbA1c. We suggest that improving self-care behaviors and resilience could be considered an appropriate intervention for enhancing the health adaptation of adolescents with T1D. Increasing school support might be a strategy to improve QoL among adolescents with T1D.

Background The mere presence of human papillomavirus (HPV) is not enough for cervical cancer development and immunogenetic background may play an important role. Human leucocyte antigen (HLA)-G acts as a negative regulator of immune responses and its expression in tumour cells may enable them to avoid immune attack. We aim to study if polymorphisms in the HLA-G gene are associated with cervical cancer risk in Taiwanese women. Methods +1537 A/C , 14-bp deletion/insertion ( Del/Ins ), and +3142 G/C polymorphisms were genotyped in a hospital-based study of 317 women with cervical squamous cell carcinoma (CSCC) and 400 healthy control women frequency matched by age. The presence and genotypes of HPV in CSCC were determined. Results We found the +3142 C/C genotype and C allele were associated with increased risk for CSCC (adjusted odds ratio [OR] = 1.78, P = 0.004; adjusted OR = 1.31, P = 0.014, respectively). In subgroup analysis based on HPV type 16 positivity, significant associations with higher adjusted ORs were found in +3142 C/C genotype and C allele (adjusted OR = 2.19, P = 0.001; adjusted OR = 1.48, P = 0.003, respectively) and +1537 C/C genotype and C allele frequencies increased significantly (adjusted OR = 2.88, P = 0.004; adjusted OR = 1.69, P = 0.0005, respectively). Furthermore, the C-Del-C haplotype conferred increased risk of both CSCC and HPV-16 positive CSCC women (adjusted OR = 1.41, P = 0.009; adjusted OR = 1.94, P = 0.0001, respectively). Conclusion These findings suggest that HLA-G gene is involved in the susceptibility to CSCC.

Cervical cancer is strongly associated with infection of oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for progression to cervical cancer. It is now recognized that host immunogenetic background participates in the control of HPV infection and development of cervical cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays a central role in antitumor immunity. The aim of this study is to determine if potentially functional polymorphisms in IL-18 gene are associated with risk of HPV-induced cervical cancer in Taiwanese women. Pre-Developed TaqMan Allelic Discrimination Assay was used to genotype IL-18 − 1297 T / C , − 607 C / A , − 380 C / G , − 137 G / C , and + 105 A / C polymorphisms in a hospital-based study of 470 women with cervical squamous cell carcinoma (CSCC) and 722 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined by PCR. None of the polymorphisms or any haplotype was found to have significant differences in distribution among all subjects with CSCC, those with HPV-16 positive CSCC, and controls. Our results suggest that the IL-18 − 1297 T / C , − 607 C / A , − 380 C / G , − 137 G / C , and + 105 A / C polymorphisms are not associated with susceptibility to CSCC in Taiwanese women.

Background and Aim Symptomatic gallstone disease (SGSD) induced several inflammatory responses and affected extrahepatic bile ducts. Although the pathology and environmental risk factors of gallstone disease are well documented, immune or inflammatory responses in SGSD development are still inconclusive. Interleukin 18 (IL18) is a pro-inflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of the induction of interferon-γ. In this study, we investigated whether polymorphisms of the IL18 gene were associated with SGSD susceptibility. Methods Genomic DNA was isolated from the whole blood samples of 445 patients with SGSD and 1121 gallstone-free controls. The IL18 rs549908T>G, rs5744247C>G, rs187238G>C, rs1946518T>G, and rs360719A>G polymorphisms were genotyped using predeveloped TaqMan allelic discrimination assay. Results We found IL18 rs5744247G allele conferred protection against SGSD in female patients (odds ratio = 0.75, corrected P-value = 0.015). Haplotype analysis revealed that TGGTA protected females from SGSD development (odds ratio = 0.75, corrected P-value = 0.02). Conclusions Based on our findings, IL18 rs5744247C>G polymorphism could be a potential genetic marker to predict SGSD susceptibility in Han Chinese women.

Hashimoto disease (HD) is an autoimmune thyroid disease resulting from complex interactions between genetic and environmental factors. The human leukocyte antigen (HLA) gene has been established to be involved in the susceptibility to HD. We aim to investigate the associations between HLA-B alleles and Han Chinese children with HD by both case-control and family-based studies. A total of 108 unrelated children with HD, 380 unrelated healthy controls, 58 trios of affected patients and their parents, and 75 trios of unaffected siblings and their parents were recruited. HLA-B genotyping was performed by polymerase chain reaction and detected with a sequence-specific oligonucleotide probes system. We found that B*46:01 allele (OR = 2.31, 95% CI 1.60-3.34, P(c) = 9.99 × 10(-5)) and carrier (OR = 3.28, 95% CI 2.10-5.11, P(c) = 1.35 × 10(-6)) were associated with HD risk. Transmission/disequilibrium test further confirmed an overtransmission of the B*46:01 (OR 2.55, 95% CI 1.36-6.10, P = 6.5 × 10(-3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-B*46:01 confers susceptibility to HD in Han Chinese children. Further studies with larger children cohort are required to confirm the role of B*46:01 in the development of HD.

Graves disease (GD) is an autoimmune thyroid disease with a female preponderance and a wide range of ages at onset, and human leukocyte antigen (HLA) gene plays a primary role in the susceptibility to GD. We aim to investigate the associations between HLA-DRB1 alleles and Taiwanese children with GD by both case-control and family-based studies. A total of 241 unrelated children with GD, 539 healthy controls, 115 trios of affected patients and their parents, and 121 trios of unaffected siblings and their parents were recruited. HLA-DRB1 genotyping was performed by polymerase chain reaction and sequence-based typing assays. We found that DRB1*09:01 (OR = 2.60, 95% CI 2.02–3.35, Pc = 6.55 × 10−13) was associated with GD risk, while DRB1*12:02 (OR = 0.32, 95% CI 0.20–0.53, Pc = 4.55 × 10−5) was protective against GD. Transmission/disequilibrium test further confirmed an overtransmission of the DRB1*09:01 (OR 3.37, 95% CI 2.13–6.22, Pc = 1.0 × 10−5) and an undertransmission of the DRB1*12:02 (OR 0.21, 95% CI 0.05–0.42, Pc = 1.7 × 10−3). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-DRB1*09:01 confers susceptibility to GD and DRB1*12:02 exerts protection against GD development in Taiwanese children.

Cervical cancer is caused primarily by infection with oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for the progression to cervical cancer. Host immunogenetic factors may involve in the development of this disease. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is recently shown to act as a negative regulator of T-cell activation. We aim to study if polymorphisms in the ITPKC gene are associated with the risk of cervical cancer in Taiwanese women. ITPKC rs28493229 C/G, rs890934 G/T, rs2303723 C/T, and rs10420685 A/G polymorphisms were genotyped in a hospital-based study of 465 women with cervical squamous cell carcinoma (CSCC) and 800 age-matched healthy control women. The presence and genotypes of HPV in CSCC were determined. The frequency of G/G genotype and G allele of the ITPKC rs28493229 polymorphism was significantly higher in patients with CSCC compared with controls (OR = 1.81, 95 % CI 1.20–2.73, P = 0.005, P c = 0.02; OR = 1.70, 95 % CI 1.14–2.54, P = 0.008, P c = 0.03, respectively). No significant associations were found for other 3 polymorphisms. Haplotype analysis revealed the distribution of haplotype CGTA was significantly reduced in women with CSCC (OR = 0.59, 95 % CI 0.40–0.89, P = 0.01, P c = 0.04). In conclusion, we found the G/G genotype and G allele of the ITPKC rs28493229 polymorphism may contribute to the risk of CSCC in Taiwanese women. This finding provides new insights into the mechanisms of immune activation in cervical cancer.

Background and Objective: Biliary atresia (BA) is a destructive inflammatory obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. Although the etiology is unknown, immunologically mediated injury of the bile ducts triggered by as yet unidentified infectious agents is likely to play a critical role. Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of its induction of interferon-gamma. In this study, we investigated whether polymorphisms of the IL18 gene were associated with susceptibility to BA. Patients and Methods: Genomic DNA was extracted from whole-blood samples of 50 Taiwanese children with BA and 1117 ethnically matched healthy controls. The IL18 ―1297 T/C, ―607 C/A, ―137 G/C, and +105 A/C polymorphisms were genotyped using the TaqMan assay. Results: No statistically significant differences of genotype, allele, carrier, and haplotype frequencies of these IL18 gene variants were found between children with BA and healthy controls. Conclusions: Our data suggest that the IL18 gene does not play a major role in BA predisposition in Taiwanese children.

Kawasaki disease (KD) is a systemic vasculitis caused by unknown infectious agents, host immune dysregulation and genetic susceptibility in children. Coronary artery lesions (CALs) complicate 15-25% of cases of untreated KD. The aim of this study was to investigate if the single-nucleotide polymorphism (SNP) rs28493229 of the ITPKC gene is associated with susceptibility to KD or with CALs in Taiwanese children. A total of 385 unrelated Taiwanese children (222 boys and 163 girls) with KD were included, 140 of whom had CALs. Mean age at diagnosis was 1.9 +/- 1.7 (0.1-10.2) years. Rs28493229 was genotyped in children with KD and 1158 ethnically matched healthy controls using the TaqMan Allelic Discrimination Assay. In 184 families with KD, both biological parents were available, constituting 184 trios with their children. They were assessed in a family-based study by means of a transmission/disequilibrium test (TDT). No significant differences in genotype (P = 0.29 and P = 0.29, respectively), allele (P = 0.14 and P = 0.22, respectively) and carrier (P = 0.22 and P = 0.25, respectively) frequencies of the SNP were found between healthy controls and children with KD or those with CALs. TDT in the 184 family trios and in 69 trios where the child had CALs did not reveal significant overtransmittion of the C allele. In conclusion, we did not find a statistically significant association between the ITPKC gene SNP rs28493229 and KD or CALs in Taiwanese children.

Biliary atresia (BA) is a devastating neonatal hepatobiliary disease characterized by bile duct inflammation and fibrosis. The pathogenesis remains unclear, but immunologically mediated injury to bile ducts following an infectious insult is likely to play a critical role. Interferon-gamma (IFN-gamma) is a key cytokine that affects immune-mediated inflammatory responses.This study aims to investigate whether polymorphisms of the IFN-gamma (IFNG) gene were associated with susceptibility to BA.The IFNG -1615 C/T, -183 G/T, +874 A/T, and +2197 A/G polymorphisms were genotyped using the TaqMan assay, and CA repeat microsatellite was analyzed using capillary electrophoresis in 50 children with BA and 788 ethnically matched healthy controls.The distribution of genotype, allele, and haplotype frequencies of these IFNG gene variants did not differ significantly between children with BA and controls.Polymorphisms of the IFNG gene do not appear to play a major role in the genetic predisposition to BA in Taiwanese children.

Noonan syndrome is a highly variable disorder that has significant phenotypic overlap with Costello syndrome and cardio-facio-cutaneous syndrome. KRAS mutation was the second reported gene for Noonan syndrome. This study screened for mutation of the KRAS gene in 57 unrelated ethnic Chinese children suffering from Noonan syndrome without PTPN11 gene mutation in Taiwan. This work only identified two patients with different missense mutations (c.40G>A, p.Val14Ile; c.108A>G, p.Ile36Met) in the exon 1 of KRAS gene. This study also analyzed the characteristics of 34 reported cases involving KRAS mutations in the literature. All these patients presented with variable phenotypes, including Noonan syndrome (n = 19), cardio-facio-cutaneous syndrome (n = 7), Costello syndrome (n = 6), and Noonan/cardio-facio-cutaneous syndrome (n = 1). The phenotype of KRAS mutations was generally severe, including short stature, mental retardation, heart defects, etc. In conclusion, this investigation demonstrates that KRAS mutations are the cause in a minority of cases of Chinese patients with Noonan syndrome in Taiwan.

The purpose of this study was to use a phenomenological approach to explore the essential structure of mothers' life experience when helping their first- to third-grade children with Type 1 diabetes mellitus (T1DM) make life adjustments at school. Twelve mothers whose children had been diagnosed with T1DM participated in this study at a teaching hospital in Taipei, Taiwan. Study results revealed six themes and identified the presence of various dynamic relationships between T1DM symptoms, the children's development, and collaborative self-care.

Children with type 1 diabetes are usually associated with cardiovascular autonomic neuropathy. The present study explored the influence of physical activity on their autonomic nervous function by measuring the heart rate variability (HRV). A total of 93 type 1 diabetic children and 107 healthy control subjects were enrolled. The Physical Activity Questionnaire for Children (PAQ-C) was adopted to determine the physical activity level as low, moderate, or high activity. HRV was determined by frequency analysis and measured in both resting and active states. Children with type 1 diabetes had significantly lower HRV than that of healthy control subjects in resting state but not in active state. The decreased HRV in diabetic children was observed only in subjects with low physical activity. The HRV in diabetic children with moderate to high physical activity, however, was not different from that of their healthy controls. Diabetic children should be encouraged to engage in physical activity with more intensity, which can benefit their autonomic nervous function. Nevertheless, the potential risk of vigorous activity still needs our concern.

Background: Prader–Willi syndrome (PWS) is a congenital disorder caused by absent expression of paternal genes in 15q11-13 affecting multiple systems. The information concerning the clinical features of this genetic disorder is incomplete in Taiwan. Methods: A retrospective analysis was carried out of 70 PWS patients (39 male, 31 females; age range, 1 month–22 years) seen in four major medical centers in Taiwan from January 1980 through June 2005. All cases were confirmed by methylation-specific polymerase chain reaction. The molecular characteristics, birth history, clinical presentation and laboratory studies were analyzed. Results: Complete genetic analysis was performed in 52 of the 70 patients with PWS. The abnormalities found included deletions in 45 (87%), maternal uniparental disomy (UPD) in five (10%), and a probable imprinting center deletion or an imprinting defect in two (4%). The average weight of the patients at birth was 2588 ± 540 g. Bone age delay of >2 years and growth hormone (GH) deficiency were noted in 11/40 (28%) and 12/20 (60%), respectively. In the 18 in whom both bone age and GH were assessed, abnormalities of both were found in two (11%). In 2000, Taiwan instituted the Rare Diseases and Orphan Drugs Act and mandated a three-phase screening protocol for PWS. Of the 41 patients diagnosed with PWS before 2000, only four (10%) were diagnosed before the age of 3 months; in the 29 patients diagnosed after 2000, in 15 (52%) the syndrome was confirmed before 3 months of age (P < 0.001). Conclusions: The present finding is in contrast to that of most previous reports that indicated a higher incidence of UPD in PWS. It is unclear whether this discrepancy in the incidence of UPD arises from under-diagnosis or because of ethnic differences, a question worthy of further study. The three-phase screening protocol has generated notable improvement in the early diagnosis of PWS in Taiwan.

Aim: Several different genetic defects have been found to result in the characteristic phenotypic expression of Prader–Willi syndrome (PWS). Methods: We performed a retrospective analysis of 67 cases of molecularly confirmed PWS diagnosed from January 1980 through July 2006 in five medical centres in Taiwan. Clinical manifestations were compared between patients with deletion and those with maternal uniparental disomy (UPD). Results: Deletion was present in 56 (84%), UPD in 10 (15%), and a probable imprinting centre deletion or imprinting defect in 1 (1%). PWS with deletion was more likely than that with UPD to be characterized by hypogonadism (p < 0.001), small hands and feet (p < 0.001), and hypopigmentation (p < 0.002). Both maternal (p = 0.015) and paternal age (p = 0.021) were higher in the UPD group. No other clinical features differed significantly different between the two groups. Conclusion: In contrast to most Western populations with a higher incidence of UPD, this study of PWS in Taiwan shows a higher incidence of deletion. There may be subtle phenotypic differences between the UPD and deletion genotypes, but its not clear that these are important clinically.

Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer. The host immunogenetic background plays an important role in the persistence of HPV infection and subsequent development of cervical cancer. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a molecule expressed mainly on activated T cells and is important in the down-regulation of T-cell activation. The aim of this study was to determine if polymorphisms of the CTLA-4 gene are associated with HPV-induced cervical cancer in Taiwanese women. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype -318 C/T, +49 A/G and CT60 A/G polymorphisms in 144 women with cervical squamous cell carcinoma (CSCC) and 378 ethnicity-matched healthy control women. The presence and genotypes of HPV in CSCC were determined by E6-, E7-based nested polymerase chain reaction. The frequency of C/T genotype of -318 C/T polymorphism was significantly higher in patients with HPV-16-positive CSCC compared with controls (odds ratio = 1.99, 95% confidence interval = 1.16-3.42, P(c) = 0.03). No significant associations were found for +49 A/G and CT60 A/G polymorphisms. Analysis of haplotypes, computationally inferred from genotype data, also revealed no significant differences in distribution among all subjects with CSCC, those with HPV-16-positive CSCC and controls. Our results suggest that the -318 C/T variant in the promoter region of the CTLA-4 gene is associated with HPV-16-associated CSCC in Taiwanese women.

Noonan syndrome (NS) is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 ( PTPN11 ), encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38%) patients, including a novel missense mutation (855T > G, F285L). These mutations were clustered in exon 3 ( n = 6) encoding the N-SH2 domain, exon 4 ( n = 2) encoding the C-SH2 domain, and in exons 8 ( n = 2) and 13 ( n = 3) encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients. [ J Formos Med Assoc 2007;106(2):169-172]

Background: Understanding the predictors of glycemic control in adolescents of various age groups with type 1 diabetes (T1D) is crucial for nurses to cultivate developmental-specific interventions to improve glycemic control in this age group. However, research has rarely addressed this issue, particularly in the context of Asian populations. Purpose: We explored the predictive influence of demographic characteristics, self-care behaviors, family conflict, and parental involvement on glycosylated hemoglobin (HbA1C) levels 6months after the baseline measurement in adolescents of various age groups with T1D in Taiwan. Methods: A prospective survey design was applied. At baseline, adolescents with T1D completed a self-care behavior scale. Parents or guardians finished scales of parental involvement and family conflict. The HbA1C levels 6 months after baseline measurement were collected from medical records. Two hundred ten adolescent-parent/guardian pairs were enrolled as participants. Multiple stepwise regressions examined the significant predictors of HbA1C levels 6 months after the baseline measurement in the three adolescent age groups: 10-12, 13-15, and 16-18 years. Results: Family conflict was a significant predictor ofHbA1C level within the 10-12 years of age group 6 months after the baseline measurement. Self-care behaviors were a significant predictor of HbA1C level within the 13-15 years of age group 6 months after the baseline measurement. Being female and self-care behaviors were each significant predictors of HbA1C level in the 16-18 years of age group 6months after the baseline measurement. Conclusions/Implications for Practice: Nurses should design specific interventions to improve glycemic control in adolescents of various age groups with T1D that are tailored to their developmental needs. For adolescents with T1D aged 10-12 years, nurses should actively assess family conflict and provide necessary interventions. For adolescents with T1D aged 13-18 years, nurses should exert special efforts to improve their self-care behaviors. In addition, female adolescents aged 16-18 years should be considered an at-risk group.