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This study investigated the effect and mechanism of electroacupuncture (EA) on the contralesional hemisphere in rats with ischemic stroke. EA of 2 Hz was applied on the contralesionally Luoque (BL8) and Tongtian (BL7) acupoints of the scalp to investigate the neurological status and mechanism in ischemia–reperfusion injury rats. The differences in the neurological deficit score and Rotarod test time between days 3 and 15 after reperfusion were significantly lower in the sham group (0.00 (−1.00, 0.00) and 3.53 (−0.39, 7.48) second, respectively) than in the EA group (−4.00 (−4.00, −3.00) and 44.80 (41.69, 54.13) second, respectively, both p < 0.001 ). The ratio of infarction volume was 0.19 ± 0.04 in the sham group greater than 0.07 ± 0.04 in the EA group ( p < 0.001 ). On day 15, in the cerebral cortex of the lesioned hemisphere, the gamma-aminobutyric acid (GABA)-A/actin ratio in the normal group (1.11 ± 0.36) was higher than that in the sham group (0.38 ± 0.07, p < 0.05 ) and similar to that in the EA group (0.69 ± 0.18, p > 0.05 ); the difference between the EA and sham groups was significant ( p < 0.05 ). EA of 2 Hz on the BL8 and BL7 acupoints on the contralesional scalp can improve motor function and also can reduce infarction volume, and this effect of EA, and that GABA-A, plays at least a partial role in ischemia–reperfusion injury rats.

Urothelial carcinoma (UC) is the ninth most prevalent malignancy worldwide. Noninvasive and efficient biomarkers with high accuracy are imperative for the surveillance and diagnosis of UC. CKD patients were enrolled as a control group in this study for the discovery of highly specific urinary protein markers of UC. An iTRAQ-labeled quantitative proteomic approach was used to discover novel potential markers. These markers were further validated with 501 samples by ELISA assay, and their diagnostic accuracies were compared to those of other reported UC markers. BRDT, CYBP, GARS, and HDGF were identified as novel urinary UC biomarkers with a high discrimination ability in a population comprising CKD and healthy subjects. The diagnostic values of the four novel UC markers were better than that of a panel of well-known or FDA-approved urinary protein markers CYFR21.1, Midkine, and NUMA1. Three of our discovered markers (BRDT, HDGF, GARS) and one well-known marker (CYFR21.1) were finally selected and combined as a marker panel having AUC values of 0.962 (95% CI, 0.94-0.98) and 0.860 (95% CI, 0.83-0.89) for the discrimination between UC and normal groups and UC and control (healthy + CKD) groups, respectively.

Epigenetics alternation of non-genetic variation and genome-wide association study proven allelic variants may associate with insulin secretion in type 2 diabetes (T2D) development. We analyzed promoter DNA methylation array to evaluate the associated with increased susceptibility to T2D (30 cases, 10 controls) and found 1,091 gene hypermethylated in promoter regions. We performed the association study of T2D and found 698 single nucleotide polymorphisms in exon and promoter sites by using 2,270 subjects (560 cases, 1,710 controls). A comparison of DNA hypermethylation and gene silencing of mouse T2D results in our T2D patients' results showed that the 5'-nucleotidase, cytosolic II (NT5C2) and fucosyltransferase 8 (FUT8) genes were strongly associated with increased susceptibility to T2D. DNA hypermethylation in promoter regions reduced NT5C2 gene expression, but not FUT8 in T2D patients. NT5C2 protein expression was decreased in pancreatic β-cells from T2D mice. Transient transfection NT5C2 into RIN-m5F cells down-regulated DNA methyltransferase I (DNMT1) expression and up-regulation of the insulin receptor. Moreover, NT5C2 knockdown induced in DNMT1 overexpression and insulin receptor inhibition. Taken together, these results showed that NT5C2 epigenetically regulated insulin receptor in patients and mice with T2D, and maybe provide for T2D therapy strategy.

Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with oestrogen receptor-positive, early-stage, and metastatic breast cancer. Although effective, the risk of falls due to AI-associated knee joint pain significantly increased. The aim of this study was to evaluate the therapeutic effects of yoga and massage on AI-associated knee joint pain. Breast cancer survivors were randomly assigned to a 6-week yoga intervention-2-week rest-6-week massage exposure (Yoga first, n = 30) or a 6-week massage intervention-2-week rest-6-week yoga exposure (Massage first, n = 30). Evaluations of the treatment efficacy were made at baseline, post-intervention, and post-exposure using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, plasma cytokine levels, and changes in meridian energy. The results showed that yoga, superior to massage intervention, significantly reduced AI-associated knee joint pain, as demonstrated by the WOMAC pain score. The yoga intervention improvements were also associated with changes in plasma cytokine levels and meridian energy changes. In conclusion, this study provides scientific evidence that yoga was more effective than massage for reducing AI-associated knee joint pain. Meridian energy changes may provide another scientific, objective, non-invasive way to monitor the therapeutic effects of yoga and investigate another alternative, complementary medicine.

Colorectal cancer is the second most common cancer and the third cancer-associated death in Taiwan. Currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy, which results in colorectal cancer being often recognized too late for successful therapy. Mitophagy is the selective autophagic degradation of damaged or excessive mitochondria. DJ-1 is an antioxidant protein that attenuates oxidative stress and maintains mitochondrial quality through activating mitophagy. Mitophagy activation contributes to anti-cancer drug resistance. However, the role of DJ-1-induced mitophagy in colorectal cancer progression remains unclear. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value and physiological function of DJ-1 in colorectal cancer. We found that DJ-1 increased in tumor tissues and serum, it was positively correlated with TNM (tumor-node-metastasis) stages of colorectal cancer patients. Through stable knockdown DJ-1 expression in metastatic colorectal adenocarcinoma cells SW620, DJ-1 knockdown inhibited cancer cell survival, migration, and colony formation. In SW620 cells, DJ-1 knockdown induced an incomplete autophagic response that did not affect ATP production, DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition. It suggests that DJ-1 knockdown inhibits mitophagy that causes metastatic colorectal adenocarcinoma cells to be unable to remove damaged mitochondria and further enhance cancer cell apoptosis. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM stage in colorectal cancer patients. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.

Background Genetic factors, dysregulation in the endocrine system, cytokine and paracrine factors are implicated in the pathogenesis of familial short stature (FSS). Nowadays, the treatment choice for FSS is limited, with only recombinant human growth hormone (rhGH) being available. Methods Herein, starting from the identification of 122 genetic loci related to FSS, we adopted a genetic-driven drug discovery bioinformatics pipeline based on functional annotation to prioritize crucial biological FSS-related genes. These genes were suggested to be potential targets for therapeutics. Results We discovered five druggable subnetworks, which contained seven FSS-related genes and 17 druggable targerts. Conclusions This study provides a valuable drug repositioning accompanied by corresponding targetable gene clusters for FSS therapy.

Background/Aim: C-Reactive protein (CRP) is a common marker of inflammation. Elevated CRP levels have been associated with increased risk of development of type 2 diabetes mellitus (T2DM). This study aimed to evaluate the association of CRP gene polymorphisms with early-onset T2DM and the effect of genetic variants on CRP level. Materials and Methods: In total, 948 individuals with early-onset (n=271) or late-onset (n=677) T2DM were enrolled in the study. Five single-nucleotide polymorphisms (SNPs) in the CRP gene, namely rs3093077, rs2808630, rs1800947, rs11265263, and rs11265265, were selected for genotyping, and CRP levels were measured. Results: Genotypic, allelic, and haplotype frequencies of these five SNPs were not significantly different between patients with early- and those with late-onset. T2DM Higher serum CRP levels were independently associated with the C-allele of rs3093077 and T-allele of rs11265265 (p

Background and Objectives: To regain the ability of community ambulation is a meaningful goal for stroke patients. Recent research recommended that the distance accomplished during the six-minute walk test (≥205 m in 6MWT) is the fittest for defining community ambulation. Until now, there are few studies that have used the updated definition to investigate the related predictors. The aim of this study was to investigate the association between the admission clinical parameters and community ambulation measured by the 6MWT at discharge. The other aim was to find the admission Berg Balance Scale (BBS) cut-off score to discriminate between household or community ambulators. Materials and Methods: This cohort study collected the data of patients who entered the post-acute Care Cerebrovascular Diseases program. Multivariate logistic regression was used to identify significant predictors measured at admission that are associated with community ambulation, and a receiver operating characteristic was adopted to calculate the cut-off value for admission status. There were 120 participants included in this study, and 25% (n = 30) of them regained the ability of community ambulation at discharge. The BBS on admission was identified as the only significant predictor for community ambulation (odds ratio 1.06). Results: The optimal cut-off score for the BBS at admission was 29, and the area under the curve for BBS scores on admission when discriminating between household and community ambulators at discharge was 0.74. Conclusions: The admission BBS scores could be used to predict household and community ambulators at discharge in stroke patients. The results of this study could help clinical physicians set appropriate discharge goals early.

Taking advantage of isomeric form of vitamin E in the supplement, adherence to supplement could be evaluated by changes in circulating α- and γ-tocopherol concentrations. Accordingly, effects of supplementation on postoperative nutrition and bone metabolism were studied in terms of adherence. Thirty-eight SG patients were all prescribed a postoperative nutritional supplement containing a low dose of vitamin D (600 IU) and calcium (200 mg). Blood samples were collected prior to (M0) and 6 months after (M6) surgery and concentrations of nutrients and C-terminal telopeptide of type I collage (CTX), a marker of bone resorption, were measured. Adherence and non-adherence were stratified according to change (△, M6-M0) in serum α-tocopherol concentrations (> 0 vs. ≤ 0, respectively). When M0 and M6 were compared, there were significant increases in serum concentrations of 25(OH)D, α-tocopherol and selenium, whereas there were reductions in parathyroid hormone, ferritin, and γ-tocopherol. At M6, the prevalence of vitamin D insufficiency (25(OH)D < 30 ng/mL) and high CTX were 72 and 26%, respectively. When comparison was made between adherence and non-adherence, only △25(OH)D concentrations, but no other nutrients nor postoperative CTX differed. Multiple linear regression demonstrated that postoperative vitamin D status was independently associated with its preoperative concentrations (β = 0.85, p < 0.001) and adherence (β = 0.52, p < 0.05). SG patients’ adherence to supplementation, even with a low dose of vitamin D and calcium, determined vitamin D status but not bone resorption marker concentrations, at least within 6 months after surgery.

Background This study aims to identify the age trajectories of disability in instrumental activities of daily life (IADLs) over 11 years and their correlates, and to estimate disability-free life expectancy for identified trajectory groups in middle-aged and older adults. Methods We included 3118 participants aged 50 and over without IADL limitations at baseline from the Taiwan Longitudinal Study in Aging, followed across 1996–2007. We used group-based trajectory models to identify age trajectories of IADL disability, and multiple logistic regressions to examine their correlates. Sullivan method was used to compute IADL disability-free life expectancy for trajectory groups at different ages. Results We identified two trajectories groups: 67.7% of participants classified as the late-onset group and 32.3% as the early-onset group. Female (adjusted odds ratio [aOR]: 1.93, 95% confidence interval [95% CI]: 1.54, 2.41), not being employed (aOR: 1.30, 95% CI: 1,08, 1,56), poor/fair self-rated health (aOR: 1.31, 95% CI:1.09, 1.58), hypertension (aOR: 1.32, 95% CI: 1.07, 1.63), diabetes mellitus (aOR: 2.29, 95% CI: 1.72, 3.07), arthritis (aOR: 1.42, 95% CI: 1.11, 1.81), stroke (aOR: 2.21, 95% CI: 1.04, 4.70), and one-point increase in a 10-item depression scale (aOR: 1.04, 95% CI: 1.02, 1.06) were associated with early-onset of disability, whereas higher education (aOR: 0.59, 95% CI: 0.42, 0.81), regular exercise (aOR: 0.76, 95% CI: 0.62, 0.93), and participating voluntary or club activities (aOR: 0.78, 95% CI: 0.65, 0.93) related to the late-onset. IADL disability-free life expectancies at 65 years old in the late-onset group were 15.6 years for women and 14.4 for men, respectively, comprising 56.6 and 64.2% of their remaining life, whereas those of the early-onset group were 4.8 and 4.6 years for women and men respectively, comprising 22.5 and 27.2% of remaining life. Conclusions Early-onset of IADLs disability may correlate to chronic conditions, and engagement in employment, exercise, and social participation were associated with a reduced risk of early disability in IADLs.

Adiponectin (APN) is suggested to be a potential biomarker for predicting diabetic retinopathy (DR) risk, but the association between APN and DR has been inconsistent in observational studies. We used a Mendelian randomization (MR) analysis to evaluate if circulating APN levels result in DR. We applied three different genetic risk scores (GRS): GRSAll combined all 47 single nucleotide polymorphisms (SNPs), which from a genome-wide association study (GWAS) database-catalog reach significance level, GRSLimited comprised 16 GRSAll-SNPs with a rigorous threshold (p &lt, 5.0 &times, 10&minus, 8 for GWAS), and GRSAPN combined 5 SNPs significantly associated with APN level. The MR-inverse-variance weighted method analysis showed that for each 1-SD increase in genetically induced increase in plasma APN, the OR of having DR was &beta, = 0.20 (95% CI: &minus, 0.46&ndash, 0.85, p = 0.553) for GRSAPN, 0.61 (95% CI: 0.10&ndash, 1.13, p = 0.020) for GRSAll, and 0.57 (95% CI: &minus, 0.06 to 1.20, p = 0.078) for GRSLimited. Sensitivity analysis, including MR-egger regression and the weighted-median approach, did not provide evidence of the pleiotropic effect of IVs. Limited evidence for the causal role of APN in DR risk among Taiwanese diabetic patients was shown based on MR analysis in the present study.

Glaucoma is characterized by the degeneration of retinal ganglion cells that cause progressive optic neuropathy, finally resulting in changes to the optic nerve head. Lowering intraocular pressure (IOP) is the only method proven for treating glaucoma. Several studies have discovered that acupuncture can reduce IOP and also increase ocular perfusion and ocular blood flow. Therefore, the present study investigated the effect of acupuncture on IOP in glaucoma patients. We conducted a single-blinded, randomized, controlled trial involving 45 glaucoma patients. The results indicated that the difference between the IOP 60 min after the intervention and IOP immediately before the intervention was greater in the acupuncture group (AG) and electroacupuncture group (EG) than in the sham group (SG) for all four of the interventions performed and in both eyes (all p<0.05). The IOP difference between immediately before the first intervention and after finishing the final intervention was also greater in the AG and EG than in the SG in both eyes (all p<0.05). In conclusion, IOP was reduced at 60 min after acupuncture or electroacupuncture was performed at BL1 and EX-HN7. Additionally, IOP was reduced after finishing four acupuncture or electroacupuncture sessions. Therefore, our results suggest that acupuncture and electroacupuncture are beneficial for lowering IOP in glaucoma patients. This trial is registered with NCT04157530.

// Yu-Chuen Huang 1, 8, * , Wen-Ling Liao 2, 9, * , Jane-Ming Lin 3, 8 , Ching-Chu Chen 4, 8 , Shih-Ping Liu 5, 10, 14 , Shih-Yin Chen 1, 8 , Yu-Ning Lin 1 , Yu-Jie Lei 1 , Huan-Ting Liu 1 , Yu-Jen Chen 1, 11, 12, 13 and Fuu-Jen Tsai 1, 6, 7, 15 1 Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan 2 Center for Personalized Medicine, China Medical University Hospital, Taichung 404, Taiwan 3 Department of Ophthalmology, China Medical University Hospital, Taichung 404, Taiwan 4 Division of Endocrinology and Metabolism, China Medical University Hospital, Taichung 404, Taiwan 5 Center for Translational Medicine, China Medical University Hospital, Taichung 404, Taiwan 6 Children's Hospital of China Medical University, Taichung 404, Taiwan 7 Department of Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan 8 School of Chinese Medicine, China Medical University, Taichung 404, Taiwan 9 Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan 10 Graduate Institute of Biomedical Science, China Medical University, Taichung 404, Taiwan 11 Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan 12 Department of Medical Research, Mackay Memorial Hospital, New Taipei City 251, Taiwan 13 Institute of Traditional Medicine, National Yang-Ming University, Taipei 112, Taiwan 14 Department of Social Work, Asia University, Taichung 413, Taiwan 15 Department of Biotechnology, Asia University, Taichung 413, Taiwan * These authors contributed equally to this work Correspondence to: Fuu-Jen Tsai, email: d0704@mail.cmuh.org.tw Yu-Jen Chen, email: chenmdphd@gmail.com Keywords: type 2 diabetes; diabetic retinopathy; circulating endothelial progenitor cells; ARHGAP22 Received: July 03, 2017 Accepted: September 21, 2017 Published: April 03, 2018 ABSTRACT Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 ( ARHGAP22 ) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR. Fifty T2D patients with DR were recruited. Circulating EPCs were characterized as CD31 + /vascular endothelial growth factor-2 + /CD45 dim /CD133 + and were quantified using triple staining flow cytometry. Real-time polymerase chain reaction tests were used to quantify ARHGAP22 expression. We found that T2D patients with proliferative DR had significantly lower EPC levels than those with non-proliferative DR ( P = 0.028). T2D patients with EPC levels above the median value (> 4 cells/10 5 events) had higher levels of ARHGAP22 expression ( P = 0.002). EPC levels were positively correlated with ARHGAP22 expression ( r = 0.364, P = 0.009). Among T2D patients with DR, a higher expression of ARHGAP22 was associated with higher levels of EPCs. ARHGAP22 may be involved in the mobilization or active circulation of EPCs, thus contributing to neovascularization during DR development.

Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. Methods: The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. Results: We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). Conclusion: Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

PURPOSE: Type-2 diabetes mellitus (T2D) is a metabolic disorder that can progress to a serious chronic disease and frequently develops in obese individuals in association with various pathogenic complications that shorten the lifespan of these patients. The liver is an important organ regulating lipid metabolism, which is damaged in both obesity and T2D; however, the specific pathways involved in these pathogenic effects remain unclear. Establishing a suitable animal model that effectively mimics the human biological condition is a critical factor to allow for precise identification of T2D-related genes. METHODS: The KK.Cg-A(y) mouse strain is one such model that has offered insight into obesity-related T2D pathogenesis. To comprehensively assess the association between obesity and T2D, in the present study, we performed microarray analysis on liver tissue samples of KK.Cg-A(y) and KK-α/α wild-type mice to examine differences in gene expression and methylation patterns and their related biological processes and pathways. RESULTS: We found that inflammation accompanied by abnormal lipid metabolism led to the spontaneous mechanism of obesity-induced diabetes, resulting in differential expression of some genes related to the terms of insulin resistance and glucose tolerance. Surprisingly, disruption of steroid biosynthesis strongly facilitated the diabetic pathogenesis. To support these findings, we highlighted some candidate genes and determined their relationships in biological networks of obesity-induced T2D. CONCLUSION: These findings provide valuable reference data that can facilitate further detailed investigations to elucidate the pathogenic mechanism of obesity-induced diabetes in mice, which can be associated with the human condition to inform new prevention and treatment strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-019-00453-8) contains supplementary material, which is available to authorized users.

Background/Aim: Diabetic retinopathy (DR) is a type of retinal damage caused by a complication of diabetes and is a major cause of blindness in working-age adults. Ecto-NOX disulfide-thiol exchanger 1 (ENOX1) is a member of the ecto-NOX family involved in the plasma membrane electron transport pathway. This study aimed to investigate the role of ENOX1 in the development of DR. Materials and Methods: Human retinal endothelial cells (HRECs) and human retinal pigment epithelial cells (HREpiCs) exposed to a high concentration (25 mM) of D-glucose and type 2 diabetes (T2D) mice (+Lepr(db)/+Lepr(db), db/db) with retinopathy were used as models to determine the ENOX1 expression levels there. Results: Our results showed that ENOX1 expression levels did not significantly change in both HRECs and HREpiCs under hyperglycemic conditions for 48 h. Nevertheless, ENOX1 expression increased significantly in T2D mouse retinas, particularly in the photoreceptor layer, compared to the control mouse retinas. Conclusion: Different retinal ENOX1 expression in T2D mice and control mice suggested that ENOX1 may be involved in DR development.

ObjectiveDiabetic nephropathy (DN) and diabetic retinopathy (DR) comprise major microvascular complications of diabetes that occur with a high concordance rate in patients and are considered to potentially share pathogeneses. In this case-control study, we sought to investigate whether DR-related single nucleotide polymorphisms (SNPs) exert pleiotropic effects on renal function outcomes among patients with diabetes.Research design and methodsA total of 33 DR-related SNPs were identified by replicating published SNPs and via a genome-wide association study. Furthermore, we assessed the cumulative effects by creating a weighted genetic risk score and evaluated the discriminatory and prediction ability of these genetic variants using DN cases according to estimated glomerular filtration rate (eGFR) status along with a cohort with early renal functional decline (ERFD).ResultsMultivariate logistic regression models revealed that the DR-related SNPs afforded no individual or cumulative genetic effect on the nephropathy risk, eGFR status or ERFD outcome among patients with type two diabetes in Taiwan.ConclusionOur findings indicate that larger studies would be necessary to clearly ascertain the effects of individual genetic variants and further investigation is also required to identify other genetic pathways underlying DN.

Background: Functional impairment is frequently seen in patients with stroke. Although the progression of functional recovery after stroke has been proposed, the recovery profile after acute stroke is not well described. The objective of this study is to investigate functional recovery in stroke patients entering post-acute rehabilitation care. Methods: A retrospective cohort study collected the data of patients who entered the stroke Post-acute Care (PAC) programs. Ninety-five patients after stroke with a modified Ranking Scale (mRS) score of 3–4 who were referred to a post-acute care unit for intensive rehabilitation were recruited. The patients underwent functional, quality of life, and neuropsychological evaluation tests at admission and before discharge. The test scores before discharge were used as outcome variables and were compared with the test scores at admission to show functional recovery. Results: The average length of stay was 58.15 days. After an intensive rehabilitation intervention, significant improvements were observed in all test scores. Additionally, a significant removal rate for nasogastric tubes (p = 0.000) and Foley catheters (p = 0.003) was found at discharge. Conclusion: This study showed that the PAC rehabilitation unit was beneficial for patients with acute stroke who had functional impairments. The study results may call for further investigation to identify and develop better models for the delivery of rehabilitation in the stroke PAC unit. Keywords: Post-acute care, Rehabilitation, Stroke, Modified ranking scale

Our objective was to determine how docosahexaenoic acid (DHA) proportions in human milk are modulated by maternal FADS gene variants and dietary intake in Taiwanese women. Inclusion criteria included being healthy, 20–40 y old, having had a full-term baby that they intended to breast feed for at least 1 month, and willingness to participate in this study. Intake of DHA was assessed by food frequency questionnaire and fatty acids were analyzed in human milk samples collected 3–4 weeks postpartum. Based on multiple linear regression of data from 164 mothers that completed this study, there was 0.28% (FA%) reduction in milk DHA in high versus low genetic risk (stratified by whether minor allele numbers were ≥ 3 in rs1535 and rs174448) and 0.45% reduction in low versus high intake (stratified by whether DHA intake reached 200 mg/d). There was a significant gene–diet interaction, mothers with low genetic risk only had high milk DHA proportions with high DHA intake, whereas for mothers with high genetic risk, dietary effects were quite limited. Therefore, for FADS single nucleotide polymorphism in Taiwanese women, increasing DHA intake did not correct low milk DHA proportions in those with a high-risk genotype. Diet only conferred benefits to those with a low-risk genotype. Trial registration: This trial was retrospectively registered (Feb 12, 2019) in ClinicalTrials.gov (No. NCT03842891, https://clinicaltrials.gov/ct2/show/NCT03842891).

Diabetic nephropathy (DN) is a major complication in diabetic patients. Microalbuminuria testing is used to identify renal disease, however, its predictive value is questionable. We aimed to identify urinary biomarkers to early diagnosis nephropathy before identifiable alternations in kidney function or urine albumin excretion occurs. Proteomic approaches were used to identify potential urinary biomarkers and enzyme-linked immunosorbent assay was performed to verify the results. The data identified haptoglobin (HPT) and &alpha, 1-microglobulin/bikunin precursor (AMBP) as two biomarkers with the highest ability to distinguish between healthy individuals and patients with nephropathy, and between diabetic patients with and without DN. Further, the HPT-to-creatinine ratio (HCR) was evaluated as an independent predictor of early renal functional decline (ERFD) in a cohort with an average follow-up of 4.2 years. The area under the curve (AUC) value for ERFD prediction was significantly improved when the HCR biomarker was included in the model with albumin to creatinine ratio (ACR) and baseline characteristics (AUC values were 0.803 and 0.759 for HCR and ACR, respectively, p value was 0.0423 for difference between models). In conclusion, our results suggest that HCR represents an early indicator of nephropathy, and a marker related to ERFD among diabetic patients in Taiwan.

Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Leprdb/ + Leprdb, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). To discover early stage biomarkers of DN, untargeted liquid chromatography-mass spectrometry-based metabolomic analysis was performed in urine samples from healthy subjects and patients with micro- or macroalbuminuria due to nondiabetic disease (macro), type 2 DM without microalbuminuria (T2DM), and type 2 DM with microalbuminuria (T2DM+micro). Levels of four metabolites were significantly different among groups, and they were quantified in a larger group of 267 urine samples. Two metabolites were also discovered and validated in targeted metabolic study of amino acids. For diagnosis of nephropathy, N1-methylguanosine had the highest area-under-the-curve (AUC) value of 0.75 when compared to those of valine (0.68), xanthosine (0.67), and 7-methyluric acid (0.69). After combining fasting blood glucose and diastolic blood pressure (DBP) with N1-methylguanosine, the AUC increased to 0.987. To distinguish between T2DM and T2DM+micro conditions, xanthosine and N1-methylguanosine have AUC value of 0.612 and 0.624, respectively. After adjustment of HbA1c and DBP, AUC values of xanthosine and N1-methylguanosine increased to 0.716 and 0.723, respectively, and could be used to predict the development of nephropathy in T2DM patients.

The aim of this study is to explore the effect of genetic variation on diabetic retinopathy (DR) risk in a Taiwanese population. The logistic regression model was used to evaluate the relationship between DR status and risk factors, including the conventional parameters and genetic risk score (GRS). Candidate single nucleotide polymorphisms (SNPs) in GRS were selected based on previous reports with a combined P −4 (genome-wide association) and P P P = 0.0024) and improving the sensitivity of the model such that 40 more subjects were reclassified into DR status. The developed multivariate logistic regression model combining conventional risk factors and the multilocus GRS can predict DR, thus enabling timely treatment to reduce blindness in T2D patients.

A nationwide, population-based, retrospective cohort study.To investigate whether benign paroxysmal positional vertigo (BPPV) is associated with an increased risk of fracture.Benign paroxysmal positional vertigo is a brief rotational vertigo induced by head position change that may increase the risk of falls and, therefore, fracture.Data from the Taiwan National Health Insurance Research Database were used for this study. We selected a case cohort comprising 3796 patients aged over 20 years who were newly diagnosed with BPPV between 2000 and 2006. In addition, we randomly selected a control cohort of 15 184 individuals without BPPV. Patients with BPPV were matched to individuals in the control group according to sex, age, and index year. A Cox proportional hazard regression was performed to compute the hazard ratio of fracture, after adjusting for demographic characteristics and comorbidities.The prevalence of comorbidities was higher among patients with BPPV. After adjusting for age, sex, and comorbidities, patients with BPPV exhibited a 1.14-fold (95% confidence interval [CI]: 1.04, 1.25; P.01) higher risk of fracture than those without BPPV. Trunk fracture (vertebra, rib, and pelvis) was the fracture type with the highest adjusted hazard ratio (1.24; 95% CI: 1.06, 1.45; P.01) in patients with BPPV relative to those without BPPV. An analysis stratified according to demographic factors revealed that men with BPPV exhibited a 1.43-fold (95% CI: 1.22, 1.66; P.001) higher risk of fracture. Patients with BPPV aged over 65 years exhibited a significantly higher risk of fracture (adjusted hazard ratio = 1.17; 95% CI: 1.03, 1.33; P.05) than did those without BPPV.Patients with BPPV exhibited a higher risk of fracture than did those without BPPV.Prognosis, level 2b.

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of type 2 diabetes (T2D). This study investigated CETP gene variants to assess the risk of T2D and specific complications of diabetic kidney disease (DKD) and diabetic retinopathy. Towards this, a total of 3023 Taiwanese individuals (1383 without T2D, 1640 with T2D) were enrolled in this study. T2D mice (+Leprdb/+Leprdb, db/db) were used to determine CETP expression in tissues. The A-alleles of rs3764261, rs4783961, and rs1800775 variants were found to be independently associated with 2.86, 1.71, and 0.91 mg/dL increase in HDL-C per allele, respectively. In addition, the A-allele of rs4783961 was significantly associated with a reduced T2D risk (odds ratio (OR), 0.82, 95% confidence interval (CI), 0.71‒0.96)), and the A-allele of rs1800775 was significantly related to a lowered DKD risk (OR, 0.78, 95% CI, 0.64‒0.96). CETP expression was significantly decreased in the T2D mice kidney compared to that in the control mice (T2D mice, 0.16 0.01 vs. control mice, 0.21 0.02, p = 0.02). These collective findings indicate that CETP variants in the promoter region may affect HDL-C levels. Taiwanese individuals possessing an allele associated with higher HDL-C levels had a lower risk of T2D and DKD.

Background Irritable bowel syndrome (IBS) is characterized by chronic, recurrent abdominal pain or abdominal discomfort and changes in defecation habits. Xiang-Sha-Liu-Jun-Zi tang (XSLJZT) is a traditional Chinese medical formula that can modulate gastrointestinal disturbance. Purpose To investigate the therapeutic effect of XSLJZT on IBS. Materials and methods This study was designed as a double-blind, randomized, controlled preliminary study. Eighty patients with IBS were assigned to a control group (CG, 40 patients) that received oral administration of an XSLJZT 10% comparator (3.0 g three times daily) for 28 days or to a treatment group (TG, 40 patients) that received XSLJZT. The primary outcome measure was changes in scores on the Gastrointestinal System Rating Scale-IBS. The secondary outcome measures were changes in scores on the irritable bowel syndrome-quality of life (IBS-QOL) and World Health Organization-quality of life-brief. Results A total of 63 patients completed the study (n = 31 for the CG; n = 32 for the TG). The TG were discovered to have significantly lower diarrhea scores than the CG at V2 (second assessment) compared with V1 (first assessment, baseline) (mean change ± SD: CG: 0.19 ± 1.33 vs. TG: −0.38 ± 0.91, p = 0.05). The scores for Item 28 on the IBS–quality of life (QOL) scale (“I feel frustrated that I cannot eat when I want because of my bowel problems”) were lower in the CG at V3 (third assessment) compared with V1 but slightly higher in the TG (CG: −0.48 ± 0.89 vs. TG: 0.03 ± 0.65, p = 0.01). Conclusion Oral administration of XSLJZT (3.0 g) for 28 days lowered the mean diarrhea score in patients with IBS, indicating that the patients in the TG had greater diarrhea improvement than those in the CG. The present study used 10% XSLJZT as a comparator, and the different items of the Gastrointestinal System Rating Scale–IBS, IBS-QOL, and World Health Organization Quality of Life–Brief were scored separately. Therefore, the selection of an appropriate comparator or placebo and score assessment are crucial issues for future study.

Adiponectin (APN) and its receptors have been reported to be associated with metabolic phenotypes. To better understand the effects of APN levels and its receptors on diabetic retinopathy (DR), we investigated the association of the plasma APN level and variations in APN-related genes with DR, individually and in combination.Patients with type 2 diabetes (T2D; N = 1604), above 20 years of age from the Taiwanese population participated in the study. Demographic information, blood pressure, and serological markers were recorded at enrollment. Genomic DNA was isolated and genotyped. The plasma APN levels were measured by enzyme-linked immunosorbent assay.T2D patients with DR (N = 632) had diabetes for a longer duration, and had higher HbA1c, and systolic and diastolic blood pressure compared to those without DR (N = 972) (P < .001, for all the parameters). Overall, 10 single nucleotide polymorphisms (SNPs) in ADIPOQ and CDH13 susceptibility loci were associated with DR. Gene risk score (GRS) was calculated based on 10 SNPs for each subject and the cumulative effect of genes was observed. Among the subjects with plasma APN level (N = 518), natural logarithm (LN) of APN (LN [APN]; odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.19-2.25) and GRS (OR = 1.90, 95% CI = 1.11-3.26 for middle range of GRS, and OR = 2.61, 95% CI = 1.48-4.59 for high range of GRS) were independent risk factors for DR after adjustment for other parameters.In conclusion, the plasma APN level and the genetic variations in adiponectin receptors were associated with DR.

Personalized medicine is based on the established principle that each individual is born with unique biological characteristics. Genomics, the science of studying the genes in a genome and their interactions with each other, forms the foundation of personalized medicine. Several genomic methods are currently used to identify susceptibility loci for diseases or phenotypic traits, namely, linkage analysis, candidate gene association studies, and genome-wide association studies. The success of personalized medicine depends on having accurate diagnostic tests capable of identifying patients who can benefit from targeted therapy. Larger cohort studies plus the application of genome-wide association studies offer great potential for identifying the genetic factors that influence the pharmacology of specific drugs. By combining these approaches, physicians can predict health risks, determine and quantify the dynamics of disease development, and tailor therapeutic protocols to the needs of the individual. In this review, we focus on the effect of genetic profiling on disease outcomes as well as the potential of genomic methods to predict disease and drug response.

This study aimed to evaluate whether geneticpolymorphisms of the inducible nitric oxidesynthase (iNOS) gene NOS2A could be associat-ed with a sustained virological response (SVR)among patients infected with hepatitis C virusgenotypes 1 and 2 (HCV-1 and HCV-2) who weretreated with peginterferon plus ribavirin (PEG-IFNa-RBV). We analyzed the associations be-tween SVR to PEG-IFNa-RBV therapy and twosingle nucleotide polymorphisms (SNPs) inNOS2A. This study included Taiwanese Chinesepatients infected with either HCV-1 (n ¼ 265) orHCV-2 (n ¼ 195) with or without a SVR. Amongthe NOS2A SNPs examined, the combination ofgenotypes A/A and A/G of rs2248814 was in-versely correlated with SVR in patients infectedwith HCV-1 (P ¼ 0.0048), particularly in males(P ¼ 0.0281). This effect was not observed inpatients infected with HCV-2. The AC NOS2Ahaplotype comprising two SNPs (rs2248814 andrs2072324) was found to be associated withSVR, and its presence may decrease the chancesfor a successful outcome of treatment of patientsinfected with HCV-1 (P ¼ 0.0053). HCV-1 infectedpatients who carried the A-C diplotype willhave a lower success rate of achieving a SVR(P ¼ 0.0117). In addition, a multivariate logisticregression model for predicting a SVR revealedthat the presence of the A-C diplotype interac-tively affected the outcome of PEG-IFNa-RBVtreatment. The presence of NOS2A SNPs andthe association with SVR showed that NOS2Apolymorphisms may influence the therapeuticoutcomes of patients infected with HCV-1 understandard of care treatment. J. Med. Virol. 85:1206–1214, 2013.

// Wen-Ling Liao 1, 2, * , Wen-Jane Lee 3, * , Ching-Chu Chen 4, 5, * , Chieh Hsiang Lu 6, 7, 8, * , Chien-Hsiun Chen 5, 9 , Yi-Chun Chou 9 , I-Te Lee 10, 11, 12 , Wayne H-H Sheu 10, 12, 13, 14 , Jer-Yuarn Wu 5, 9 , Chi-Fan Yang 9 , Chung-Hsing Wang 15, 16 , Fuu-Jen Tsai 5, 17, 18 1 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan 2 Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan 3 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan 4 Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan 5 School of Chinese Medicine, China Medical University, Taichung, Taiwan 6 Department of Internal Medicine, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi City, Taiwan 7 Department of Nursing, College of Nursing and Health Sciences, DAYEH University, Changhua, Taiwan 8 Department of Business management, College of Management, National Chung Cheng University, Chia-yi, Taiwan 9 National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 10 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans Hospital, Taichung, Taiwan 11 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 12 School of Medicine, National Yang-Ming University, Taipei, Taiwan 13 School of Medicine, National Defense Medical Center, Taipei, Taiwan 14 Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan 15 Department of Genetics and Metabolism, Children’s Hospital of China Medical University, Taichung, Taiwan 16 School of Medicine, China Medical University, Taichung, Taiwan 17 Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan 18 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Fuu-Jen Tsai, email: d0704@www.cmuh.org.tw Keywords: DPP-4 inhibitors, pharmacogenetics, Taiwanese, type 2 diabetes Received: January 29, 2016 Accepted: January 03, 2017 Published: February 01, 2017 ABSTRACT Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes ( T2D ). Despite DPP-4 inhibitors’ advantages, the patients’ therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors ( P < 1 × 10 -4 ) were identified at or near PRKD1 , CNTN3 , ASK, and LOC10537792. A SNP located within the fourth intron of PRKD1 (rs57803087) was strongly associated with DPP-4 inhibitor response ( P = 3.2 × 10 -6 ). This is the first pharmacogenomics study on DPP-4 inhibitor treatment for diabetes in a Taiwanese population. Our data suggest that genes associated with β-cell function and apoptosis are involved in the therapeutic effect of DPP-4 inhibitors, even in the presence of additional oral anti-diabetic drugs. Our findings provide information on how genetic variants influence drug response and may benefit the development of personalized medicine.

Background Benign paroxysmal positional vertigo (BPPV), the most common type of vertigo in the general population, is thought to be caused by dislodgement of otoliths from otolithic organs into the semicircular canals. In most cases, however, the cause behind the otolith dislodgement is unknown. Dental procedures, one of the most common medical treatments, are considered to be a possible cause of BPPV, although this has yet to be proven. This study is the first nationwide population-based case-control study conducted to investigate the correlation between BPPV and dental manipulation. Methods Patients diagnosed with BPPV between January 1, 2007 and December 31, 2012 were recruited from the National Health Insurance Research Database in Taiwan. We further identified those who had undergone dental procedures within 1 month and within 3 months before the first diagnosis date of BPPV. We also identified the comorbidities of the patients with BPPV, including head trauma, osteoporosis, migraine, hypertension, diabetes, hyperlipidemia and stroke. These variables were then compared to those in age- and gender-matched controls. Results In total, 768 patients with BPPV and 1536 age- and gender-matched controls were recruited. In the BPPV group, 9.2% of the patients had undergone dental procedures within 1 month before the diagnosis of BPPV. In contrast, only 5.5% of the controls had undergone dental treatment within 1 month before the date at which they were identified (P = 0.001). After adjustments for demographic factors and comorbidities, recent exposure to dental procedures was positively associated with BPPV (adjusted odds ratio 1.77; 95% confidence interval 1.27–2.47). This association was still significant if we expanded the time period from 1 month to 3 months (adjusted odds ratio 1.77; 95% confidence interval 1.39–2.26). Conclusions Our results demonstrated a correlation between dental procedures and BPPV. The specialists who treat patients with BPPV should consider dental procedures to be a risk factor, and dentists should recognize BPPV as a possible complication of dental treatment.

Diabetic nephropathy (DN) is one of the most common complications in diabetic patients. New noninvasive markers are still needed for the early detection of DN before identifiable alternations in kidney function or urine albumin excretion occurs. A C18 plate and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were used to compare the urinary protein profiles of 238 subjects from the following 4 groups: patients with type 2 diabetic (T2D) with microalbuminuria, patients with DM without micro- or macroalbuminuria, patients with micro- or macroalbuminuria due to nondiabetic disease, and healthy controls. β2-microglobulin (B2M) and Clara-cell protein (CC16) were found to be highly released in the urine of patients with proteinuria due to nondiabetic or diabetic diseases. In differentiating nephropathy from healthy subject, the B2M and CC16 markers have a combined sensitivity and specificity of 77.3% and 91.8%, respectively. In distinguishing T2D with microalbuminuria from T2D patients, the combined markers have sensitivity and specificity of 66% and 73%, respectively. The predictive ability of B2M and CC16 for early renal functional decline (ERFD) was validated in 125 T2D patients with a follow-up times. The odds ratio (OR) of combined B2M and CC16 markers for developing ERFD was 7.59 (95% CI: 1.97-29.24). The detection of B2M and CC16 with the C18 plate-MALDI-TOF MS approach could be an attractive and practical assay for rapid diagnosis of nephropathy in nondiabetic/diabetic patients and as a predictor of ERFD among T2D patients who had not manifested significant kidney disease at baseline.

A serosurvey targeting Hepatitis B virus (HBV)-vaccinated children born between 1986 and 1998 was conducted in 2001 in remote Taiwanese villages where a 1993 serosurvey indicated high vaccine failure. The HBV S antigen (HBsAg) seropositive rate among vaccinees of 3-6-year-old children in 2001 was significantly lower than that of 1993 and was higher among children who had a delayed vaccination schedule and received the plasma-derived vaccine. Vaccine escape variants were more prevalent among recipients of recombinant HBV vaccine residing in Hualien. Our study highlights the importance of continued monitoring of vaccinees for incidence of HBV infection in order to refine future vaccination policy.

Transcutaneous electrical nerve stimulation (TENS) has been widely used for pain relief; however, the effect remains controversial. The authors hypothesized that TENS can relieve acute pain. Therefore, a single-blinded, randomized, controlled preliminary study was designed on postoperative pain in patients with Colles' fracture.In total, 36 patients were assigned to a real TENS or sham TENS group (18 patients in each group). TENS (50 Hz, 15 min/day) was applied near the Quchi (LI11) and Waiguan (TE5) surfaces of the operative side continuously for 5 days after surgical treatment.The visual analog scale (VAS) scores did not differ significantly between the real and sham TENS groups before the TENS period, from the first to fifth day after surgical treatment (all p 0.05), whereas the VAS scores were lower for the real TENS group than for the sham TENS group in the post-TENS period, on the first, third, fourth, and fifth days after surgical treatment (all p ≤ 0.01).TENS might be valuable as a treatment of postoperative pain, but clinicians and researchers should know that it is no different than a treatment with placebo. Especially, since this form of treatment and sham treatment has a great chance of working under the mechanism of the placebo effect due to its single-blindedness.

Background Graves’ disease (GD) and Graves’ ophthalmopathy (GO) are autoimmune disorders, which might be influenced by genetic factors. Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. This study investigated the association between CNV in the TSHR and TLR7 genes and the development of GD and GO in a Chinese population in Taiwan. Methods For this case-control study, sample from 196 healthy controls and 484 GD patients, including 203 patients with GO were studied. CNV was detected by real-time polymerase chain reaction (PCR) using TaqMan™ probes and the relative copy number (CN) was estimated by using the comparative Ct method. Results The differences in the distribution of TSHR CNV in healthy controls and GD patients were statistically significant (p value = 0.01). However, the difference in the distribution of TSHR CNV in the control group and the GO group was not statistically significant (p value = 0.06). For TLR7 CNV, the results were not significantly different when we compared the distribution in healthy controls and GD patients and in healthy controls and GO patients (p values for Fisher’s exact test were 0.13 and 0.09, respectively). However, a lower than normal CNV for TLR7 (CNV Conclusions These results suggested that TSHR and TLR7 CNV might be associated with susceptibility to GD.

Aim To investigate whether chimerin 2 ( CHN2) genetic polymorphisms were associated with the susceptibility to diabetic retinopathy (DR) in Taiwanese individuals with type 2 diabetes. Methods This case-control study comprised of 171 individuals with DR and 548 without DR. Four rs39059, rs2023908, rs1002630 and rs1362363 polymorphism of CHN2 were genotyped for each subjects. All subjects underwent a complete ophthalmologic examination, and basic information (age, gender, age at diagnosis of diabetes, and ocular history of the patient) was record. Several clinical parameters (systolic and diastolic blood pressure, waist and hip circumferences, body mass index levels, fasting glucose and HbA1c) were measured. Results Logistic regressions were used to analyze odds ratios between SNPs and DR after controlling for gender, systolic blood pressure, waist and hip ratio, duration of diabetes, serum HbA1c levels and nephropathy classification. A protective effect of rs1002630 (GA+AA) and rs1362363 (AG+GG) [odds ratio (OR) (95% confidence interval)=0.45 (0.22–0.88), 0.66 (0.44–0.99), respectively) was observed. Furthermore, the protective effect of rs1002630 was observed when compared subjects with non-proliferative DR with subjects without DR [OR=0.25 (95%C.I. = 0.09–0.73)]. Conclusions This study showed that the rs1002630 of CHN2 were associated with DR risk and non-proliferative DR risk in Taiwanese individuals with type 2 diabetes. Variations at this locus may contribute to the pathogenesis of DR.

Background The aim of this study was to evaluate whether polymorphisms in the guanine nucleotide binding (G protein), beta polypeptide 1 (GNB1) gene are associated with a rapid virological response (RVR) among HCV genotype 1 (HCV-1) and 2 (HCV-2) infected patients receiving peginterferon plus ribavirin treatment (PEG-IFNα-RBV). Methods We analyzed the association between RVR to PEG-IFNα-RBV therapy and 4 tagging single nucleotide polymorphisms (SNPs) of the GNB1 gene. This study included 265 HCV-1 and 195 HCV-2 infected patients in a Chinese population in Taiwan. Results Among the GNB1 SNPs examined, the combination of genotypes G/G and G/T populations of rs12126768 was significant inversely correlated with RVR in HCV-1 infected patients (P = 0.0330), whereas HCV-2 infected patients, combination of A/A and A/C genotypes populations at rs4648727 responded better to the PEG-IFNα-RBV treatment (P = 0.0089). However, there were no significant differences in the allele frequencies of those SNPs between RVR responders and non-responders. Several RVR susceptibility GNB1 haplotypes were identified, and the ACAT haplotype of the 4 SNPs may increase the successful outcomes of HCV-1 and HCV-2 infected patients (P = 0.0261 and P = 0.0253, respectively). Conclusion The data for GNB1 SNPs and the association of RVR showed that GNB1 polymorphisms might be associated with the therapeutic outcomes of HCV-1 and HCV-2 infected patients under standard of care (SOC) treatment.

Adipocytokine genes encoding adiponectin (ADIPOQ) and the leptin receptor (LEPR) affect glucose and fatty acid metabolism. The purpose of this study was to examine the association between early-onset type 2 diabetes mellitus (T2DM) and variability within these two genes in the Han Chinese population of Taiwan.A cross-sectional study of 999 patients from the Han Chinese population of Taiwan with early-onset T2DM (n=264; age at diagnosis, 20 to45 years) and late-onset T2DM (n=735; age at diagnosis, ~45 years) was performed. Blood samples from T2DM patients were taken for DNA extraction, and levels of serological markers were measured at enrollment. Seven single-nucleotide polymorphisms (SNPs) were selected for genotyping (three SNPs in AIDPOQ and four SNPs in LEPR) by polymerase chain reaction in each patient.Polymorphisms at the position rs10937273 in ADIPOQ and at the positions rs1892534 and rs2211651 in LEPR were statistically associated with early-onset T2DM (P=0.0246, 0.0014 and 0.0012, respectively). C-reactive protein levels were significantly different among the early-onset T2DM patients with different genotypes at the SNPs rs1892534 and rs2211651 in LEPR (P=0.003 and P=0.004, respectively). In addition, fasting glucose levels were also significantly different among different genotypes at the SNP rs1892534 in LEPR (P=0.038).We conclude that the polymorphisms in the adipocytokine genes ADIPOQ and LEPR are significantly associated with the age at diagnosis of T2DM in the Han Chinese population of Taiwan.

A 60-yr-old man presented with chronic vestibulopathy induced by Ramsay Hunt syndrome for 1 yr. Prolonged dizziness and postural imbalance affected his quality-of-life. He was treated using a 2-mo protocol of customized vestibular rehabilitation therapy consisting of 16 treatment sessions in a rehabilitation clinic and daily home exercises. Significant improvements in the subjective perception of dizziness and objective balance function were found. The results suggest that vestibular rehabilitation therapy may be an effective therapeutic method for chronic vestibulopathy of Ramsay Hunt syndrome.

Background and objective Hyperglycaemia is a common result of stress signals caused by pain and surgical procedure. Volatile anaesthetics also directly manipulate glucose homeostasis by affecting pancreatic insulin release and induce hyperglycaemia without surgical stress. We determined the preoperative application of transcutaneous electrical nerve stimulation (TENS) to the Chinese acupoints ST36 (Zusanli) and SP6 (Sanyinjiao) as a complementary therapy for controlling plasma glucose and improving insulin resistance during anaesthesia. Methods We designed a single-blind, randomised controlled clinical study of female patients, scheduled for elective hysterectomy. The 52 patients consented to enrolment and were assigned to receive either TENS (n = 26) on bilateral ST36 and SP6 acupoints with continuous mode at a frequency of 15 Hz and the intensity of 10 mA synchronously for 30 min or non-stimulation (placebo group, n = 26) preoperatively. Haemodynamics, blood glucose and plasma insulin were measured during general anaesthesia. Results At baseline, there was no significant difference between the TENS group and the placebo group in plasma glucose and insulin levels as well as homeostasis model assessment (HOMA) index. In the placebo group, plasma glucose, insulin and HOMA index increased during induction of general anaesthesia, surgical incision, and throughout the operation. Plasma glucose and insulin levels as well as HOMA index were significantly lower in the TENS group as compared to the placebo group at different time points after discontinuation of TENS application. These results indicate the positive effect of prevention of hyperglycaemia and the increased sensitivity of plasma insulin in the TENS group. Conclusion We found TENS at bilateral ST36 and SP6 acupoints to be an alternative means of managing the plasma glucose level and improving insulin resistance perioperatively.

Objective This study evaluates whether B7 molecules (CD80 and CD86) could be used as genetic markers for the development of Graves' ophthalmopathy (GO). Design Cross-sectional study. Participants We included 471 patients with Graves' disease (GD; 200 patients with GO and 271 patients without GO) in a Chinese population in Taiwan. Methods An endocrinologist with substantial experience in thyroid diseases identified GO. Blood samples were taken for DNA extraction from GD subjects. The gene polymorphism of CD80 and CD86 was genotyped by polymerase chain reaction in each patient. Main Outcome Measures Genotypes of CD80 and CD86 polymorphism. Results We found that the frequency of C allele at position rs_9831894 of the CD86 gene is different in patients with GD (with and without GO; chi-square test, P = 0.0017). In addition, the multifactor dimensionality reduction method was used to identify the best gene–gene interaction to predict the risk of GO. We identified an interaction between CD80_rs9289131 and CD86_rs9872483 (sign test, P = 0.0010). Moreover, the G-A haplotype was shown to have a protective effect in the development of ophthalmopathy among patients with GD (odds ratio, 0.63; 95% confidence interval, 0.44–0.90). Moreover, among patients with GO, the patients carrying the G-A haplotype had a lower level of free thyroxine T 4 than those not carrying the G-A haplotype ( P = 0.0001). Conclusions These results suggest that the polymorphisms of the CD86 gene may be used as genetic markers for making the diagnosis and prognosis of GO. Therefore, GO could be a disease with complex genetic factors, resulting from the existing gene–gene interaction found in the present study. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

The functional polymorphism that explains the established association of Fc gamma receptor IIIb (FCGR3B) with Graves' disease (GD) and Graves' ophthalmopathy (GO) remains unidentified, but copy number variation (CNV) might be relevant. The aim of this study was to determine whether CNV for FCGR3B is associated with GD and GO. Genotype analysis involved 624 GD patients, including 397 without GO (GDnonGO) and 227 with GO (GDGO), and 227 healthy controls. The relative copy number (CN) ofFCGR3B was determined using a relative real-time quantitative polymerase chain reaction. Our findings indicated the distribution of the relative CN of FCGR3B significantly differed between the GDGO patients and the healthy controls (p = 0.02) but not between the total GD patients and the healthy control groups (p = 0.06). Individuals with less than 2 CN or more than 2 CN of FCGR3B were at significantly decreased risk of developing GDGO. In addition, GD patients with less than 2 copies of FCGR3B were at reduced risk for developing nodular hyperplasia and vitiligo, but at increased risk for myxedema. Our results suggest that CNV of FCGR3B is associated with the development or progression of GD in Taiwan Chinese population.

PURPOSE To evaluate whether variations in the IL1B gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease (GD). METHOD This case-control study included 471 Taiwan Chinese patients with GD (200 with GO and 271 without GO) and 160 healthy volunteers. Eight single-nucleotide polymorphisms (SNPs) in IL1B were genotyped with an allele-specific extension and ligation assay. RESULTS In the IL1B SNPs examined, the C allele of rs1143634 was associated with GD, whereas the T/T genotype of the SNPs rs1143634 and rs16944 were less associated with the disease. The A/A genotype of the SNPs rs3917368 and rs1143643, which had the strongest interaction, may increase the risk of GO (P = 0.024 and P = 0.017, respectively). Several GD susceptibility and insusceptibility IL1B haplotypes have been identified, and the Ht4-GCGCCTCC haplotype, composed of eight SNPs and associated with low circulating IL1β levels, may be protective against the development of GO (P = 0.025). Moreover, that the GO-susceptible genotype was associated with lower plasma IL1β concentrations implies that the origin of GO may go beyond the IL1B polymorphism-associated elevation of circulating IL1β. CONCLUSIONS The data for IL1B polymorphisms and the association of GD and GO with plasma IL1β levels show that IL1B polymorphisms may be associated with the development of GD and GO.