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In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.

Background Idiopathic (isolated) hypogonadotropic hypogonadism (IHH) is a rare disease that can be classified as Kallmann syndrome (KS) or normosmic IHH (nIHH). This study investigated the phenotype and genotype of IHH in Taiwanese patients. Methods Twenty-six unrelated IHH patients were included in this study and their clinical, hormonal, and radiological findings were analyzed retrospectively. Whole exome sequencing (WES) was performed to identify the etiology. Results The 26 patients (M:F = 19:7) were divided into a KS group (n = 11) and a nIHH group (n = 15). The diagnosis was earlier in boys than in girls. Fifteen patients were found to have pathogenic/likely pathogenic (P/LP) variants of IHH-associated genes, and the mutation detection rate was 58%. CHD7, FGFR1, and ANOS1 were the most common genetic etiologies identified in this group. Two patients with nIHH were found to have de novo SOX11 mutations and Coffin-Siris syndrome features. After treatment, the height outcomes and secondary sexual characteristics were significantly improved. There were no obvious differences between the genetically resolved (GR), variants of uncertain significance (VUS) and genetically unresolved groups (GUR). Conclusion Whole exome sequencing is useful in patients with IHH, and we identified the SOX11 gene as a causal factor in this study. We described the clinical, hormonal, and molecular characteristics, and the treatment outcomes, of Taiwanese patients with IHH, which should aid therapeutic planning and further research.

Background Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. A prolonged hyperglycemic duration of more than 48 h was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

Malignant gliomas (MGs) are the most common and devastating primary brain tumor. At present, surgical interventions, radiotherapy, and chemotherapy are only marginally effective in prolonging the life expectancy of patients with MGs. Inherent heterogeneity, aggressive invasion and infiltration, intact physical barriers, and the numerous mechanisms underlying chemotherapy and radiotherapy resistance contribute to the poor prognosis for patients with MGs. Various studies have investigated methods to overcome these obstacles in MG treatment. In this review, we address difficulties in MG treatment and focus on promising polymeric local drug delivery systems. In contrast to most local delivery systems, which are directly implanted into the residual cavity after intratumoral injection or the surgical removal of a tumor, some rapidly developing and promising nanotechnological methods—including surface-decorated nanoparticles, magnetic nanoparticles, and focused ultrasound assist transport—are administered through (systemic) intravascular injection. We also discuss further synergistic and multimodal strategies for heightening therapeutic efficacy. Finally, we outline the challenges and therapeutic potential of these polymeric drug delivery systems.

To investigate the association between progressive muscle loss and survival outcomes of patients with advanced-stage oral squamous cell carcinoma (OSCC) undergoing surgery and adjuvant (chemo)radiotherapy.We analyzed the computed tomography (CT) scans of 155 patients with stage III-IVB OSCC at baseline, at simulation CT for radiotherapy, and at 3- and 9-months post-treatment. Skeletal muscle index (SMI) was measured using CT at the C3 vertebral level. The predictors of overall survival (OS) and recurrence-free survival (RFS) were evaluated using Cox regression models.The median follow-up period was 75.0 months. Fifty-one patients (32.9%) developed recurrence, with the median time from the fourth CT to recurrence being 9.1 months. The SMI progressively decreased from baseline to simulation CT by 1.1% (p = 0.006), to 3 months post-treatment by 5.1% (p 0.001), and to 9 months post-treatment by 15.6% (p 0.001) in patients developing recurrence. Patients without recurrence lost SMI at the simulation CT by 0.7% (p = 0.001) and at 3 months post-treatment by 2.1% (p 0.001); their SMI returned to the baseline level at 9 months post-treatment. SMI changes were weakly correlated with changes in body mass index (BMI) (Spearman ρ, 0.13; p = 0.11). In multivariate analysis, SMI changes (per 5% decrease) were independently associated with significantly worse OS (hazard ratio: 1.88, 95% confidence interval: 1.58-2.23; p 0.001) and RFS (hazard ratio: 1.89, 95% confidence interval: 1.61-2.20; p 0.001).Progressive muscle loss was independently associated with worse survival outcomes in patients with stage III-IVB OSCC. Muscle loss might not be detected by changes in BMI.

Introduction In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide®) plus as-needed, short-acting β2 agonists (SABAs) in Taiwanese patients with inadequate asthma control. Methods Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4–5 and 12–16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 μg/d, n=172). Results At baseline, 72.5% and 27.5% of all patients had “partly” and “uncontrolled” asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (−0.91±1.11) than the fluticasone/salmeterol group (−0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups. Conclusion Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA. Trial Registration ClinicalTrials.gov registration number: NCT00784953.

This study investigated the impact of dental prophylaxis on 5-fluorouracil (5-FU)–related oral mucositis (OM) according to the head and neck cancer (HNC) locations and treatment times. A total of 13,969 HNC participants, including 482 5-FU–related OM subjects and 13,487 comparisons were enrolled from the Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan between 2000 and 2008. All subjects were stratified into subgroups based on the times to perform chlorhexidine use, scaling, and fluoride application before 5-FU administration. The dental prophylaxis related to 5-FU–related OM was estimated by multiple logistic regression and represented with odds ratio (OR) and 95% confidence interval (CI). Fluoride gel application and scaling significantly impacted on OM development (p

Pigmented extramammary Paget’s disease (EMPD) is a rare variant which is often confused clinically and histologically with melanoma or other pigmented lesions. Herein, we describe a rare case of pigmented EMPD involving the axilla of a 40-year-old female thought initially to represent malignant melanoma clinically. Immunohistochemically, the neoplastic cells are positive for Estrogen Receptor (ER), Progesterone Receptor (PR), and weakly positive for Human Epidermal Growth Factor Receptor 2 (Her2). A review of the literature reveals that the pigmented variant of EMPD could be easily misdiagnosed as melanoma initially and additional confirmatory studies are almost always needed to confirm the diagnosis. The expression of ER and PR in pigmented EMPD is rarely mentioned previously. We believe it should be further investigated for the understanding of pathogenesis in pigmented EMPD and the potential role of adjuvant hormonal therapy. Keywords: Extramammary Paget’s Disease; Axilla; Estrogen Receptor; Progesterone Receptor

Objective For recurrent laryngeal cancers, trans-oral robotic surgery has been used to perform total laryngectomy, but limited cases had been reported without long-term outcome follow-up. This study aims at presenting the largest longitudinal retrospective cohort in a single tertiary referral medical center. Methods From November 2013 to August 2017, seven patients with recurrent laryngeal cancers without evidence of neck metastasis were selected to receive trans-oral robotic surgery-assisted TL without neck dissection. The para-operative details including the surgical success rates, surgical methods, resection extent, drainage tube placement, pharyngeal wound closure, console surgical time, pathologic findings and long-term complications were reviewed and described. The study end points include survival rates and preservation of swallowing function without tube feeding. Results Trans-oral robotic surgery-assisted total laryngectomy was successfully performed on all seven patients with mean surgical console time of 111 ± 66 min. Strap muscles and hyoid bone were resected like open surgery in six and five patients, respectively. For all the seven patients, there was no severe pharyngo-cutaneous fistula formation requiring repair in a second surgery, but tracheostoma stenosis was not uncommon (57%). Three patients received adjuvant chemotherapy/radiotherapy. After follow-up of 36.1 ± 15.8 months, two patients had neck recurrence, and one patient died 19 months after surgery, but the other five patients were alive without disease recurrence. The overall survival rate was 85.7% (6/7), and all patients had good swallowing function without tube feeding. Conclusions Trans-oral robotic surgery-assisted total laryngectomy is a feasible approach for selected patients with recurrent laryngeal cancers. The oncologic and functional outcomes were satisfactory. Further larger cohort study is worthwhile to further elucidate the value of trans-oral robotic surgery-assisted total laryngectomy.

Background and Objective Chronic Obstructive Pulmonary Disease (COPD) is a common chronic respiratory disease that in the long term may develop into respiratory failure or even cause death and may coexist with other diseases. Over time, it may incur huge medical expenses, resulting in a heavy socio-economy burden. The BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index is a predictor of the number and severity of acute exacerbations of COPD. This study focused on the correlation between the BODE index, comorbidity, and healthcare resource utilization in COPD. Patients and Methods This is a retrospective study of clinical outcomes of COPD patients with complete BODE index data in our hospital from January 2015 to December 2016. Based on the patients' medical records in our hospital's electronic database from January 1, 2015 to August 31, 2017, we analyzed the correlation between BODE index, Charlson comorbidity index (CCI), and medical resources. Results Of the 396 patients with COPD who met the inclusion criteria, 382 (96.5%) were male, with an average age of 71.3 ± 8.4 years. Healthcare resource utilization was positively correlated with the BODE index during the 32 months of retrospective clinical outcomes. The study found a significant association between the BODE index and the CCI of COPD patients (p < 0.001). In-hospitalization expenses were positively correlated with CCI (p < 0.001). Under the same CCI, the higher the quartile, the higher the hospitalization expenses. BODE quartiles were positively correlated with number of hospitalizations (p < 0.001), hospitalization days (p < 0.001), hospitalization expenses (p = 0.005), and total medical expenses (p = 0.024). Conclusion This study demonstrates the value of examining the BODE index and comorbidities that can predict healthcare resource utilization in COPD.

To evaluate the predictive accuracy of the %p2PSA and prostate health index (PHI) in predicting aggressive pathological outcomes in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), we enrolled 91 patients with organ-confined PCa who were treated with robot-assisted RP. p2PSA levels and the PHI were investigated for their ability to predict pathological results. The %p2PSA and PHI were both significantly higher in patients with ≥pT3 disease, high-risk disease, positive surgical margin, or seminal vesical invasion (SVI). In univariable analysis, p2PSA derivatives were significant predictors of the presence of ≥pT3 disease, high-risk disease, positive surgical margin, and SVI. To predict adverse pathological outcomes at a sensitivity of 90%, p2PSA derivatives had higher specificity than standard PSA derivatives. In multivariable analysis, additional increases in the area under the receiver operating characteristic curve (AUC) were observed with the %p2PSA and PHI for ≥pT3 disease, high-risk disease, and positive surgical margin (8.2% and 2.7%, 6.2% and 4.1%, and 8.6% and 5.4%, respectively). A PHI ≥61.26 enhanced the predictive accuracy of the model for SVI by increasing the AUC from 0.624 to 0.819 (p = 0.009). The preoperative %p2PSA and PHI accurately predict adverse pathological results and are useful for decision-making.

The optimal follow-up protocol after treatment of oral cavity cancer patients is still debatable. We aimed to investigate the impact of frequency of different imaging studies and follow-up visits on the survival of oral cavity cancer patients. The current study retrospectively reviewed oral cavity cancer patients who underwent surgical intervention in our hospital. Basic demographic data, tumor-related features, treatment modalities, imaging studies, and clinic visits were recorded. Cox proportional hazard model was used to examine the influence of variables on the survival of oral cavity cancer patients. In total, 741 patients with newly diagnosed oral cavity cancer were included in the final analysis. Overall, the frequency of imaging studies was not associated with survival in the multivariate analysis, except PET scan (hazard ratio [HR]: 5.30, 95% confidence interval [CI]: 3.57–7.86). However, in late-stage and elder patients, frequent head and neck CT/MRI scan was associated with a better prognosis (HR: 0.55, 95% CI: 0.36–0.84; HR: 0.52, 95% CI: 0.30–0.91, respectively). In conclusion, precision medicine is a global trend nowadays. Different subgroups may need different follow-up protocols. Further prospective study is warranted to clarify the relationship between frequency of image studies and survival of oral cavity cancer patients.

Plasmodium vivax is the dominant Plasmodium spp. causing the disease malaria in low-transmission regions outside of Africa. These regions often feature high proportions of asymptomatic patients with sub-microscopic parasitaemia and relapses. Naturally acquired antibody responses are induced after Plasmodium infection, providing partial protection against high parasitaemia and clinical episodes. However, previous work has failed to address the presence and maintenance of such antibody responses to P. vivax particularly in low-transmission regions. We followed 34 patients in western Thailand after symptomatic P. vivax infections to monitor antibody kinetics over 9 months, during which no recurrent infections occurred. We assessed total IgG, IgG subclass and IgM levels to up to 52 P. vivax proteins every 2-4 weeks using a multiplexed Luminex® assay, and identified protein-specific variation in antibody longevity. Generally, an increase in antibody level was observed within 1-week post symptomatic infection, followed by an exponential decay of different rates. We observed mostly IgG1 dominance and IgG3 sub-dominance in this population. IgM responses followed similar kinetic patterns to IgG, with some proteins unexpectedly inducing long-lived IgM responses. We also monitored antibody responses against 27 IgG-immunogenic antigens in 30 asymptomatic individuals from a similar region. Our results demonstrate that most antigens induced robust and long-lived total IgG responses following asymptomatic infections in the absence of (detected) boosting infections. Our work provides new insights into the development and maintenance of naturally acquired immunity to P. vivax and will guide the potential use of serology to indicate immune status and/or identify populations at risk.

Stent implantation impairs local endothelial function and may be associated with subsequent adverse cardiovascular events. Telmisartan, an angiotensin II receptor blocker that has unique peroxisome proliferator-activated-receptor-gamma-mediated effects on cardiovascular disease, has been shown to enhance endothelial function and limit neointimal hyperplasia. This study utilized hybrid biodegradable/stent nanofibers to facilitate sustained and local delivery of telmisartan to injured arterial vessels. Telmisartan and poly(d,l)-lactide-co-glycolide (PLGA) (75:25) were dissolved in hexafluoroisopropyl alcohol and electrospun into biodegradable nanofibrous tubes which were coated onto metal stents. By releasing 20% of the loaded telmisartan in 30 days, these hybrid biodegradable/stent telmisartan-loaded nanofibers increased the migration of endothelial progenitor cells in vitro, promoted endothelialization, and reduced intimal hyperplasia. As such, this work provides insights into the use of PLGA nanofibers for treating patients with an increased risk of stent restenosis.

Background and objectives: Exertional desaturation (ED) is often overlooked in chronic obstructive pulmonary disease (COPD). We aim to investigate the impact of ED on mortality and the predictors of ED in COPD. Materials andmethods: A cohort of COPD patients with clinically stable, widely ranging severities were enrolled. ED is defined as oxyhemoglobin saturation by pulse oximetry (SpO2) &lt, 90% or a drop of ΔSpO2 ≥ 4% during a six-minute walk test (6MWT). Cox regression analysis is used to estimate the hazard ratio (HR) for three-year mortality. Results: A total of 113 patients were studied, including ED (N = 34) and non-ED (N = 79) groups. FVC (% of predicted value), FEV1/FVC (%), FEV1 (% of predicted value), DLCO (%), maximal inspiratory pressure, SpO2 during the 6MWT, GOLD stage, and COPD severity were significantly different between the ED and non-ED groups in univariate analysis. Low minimal SpO2 (p &lt, 0.001) and high maximal heart rate (p = 0.04) during the 6MWT were significantly related to ED in multivariate analysis. After adjusting for age, gender, body mass index, 6MWD, FEV1, mMRC, GOLD staging, exacerbation, hs-CRP, and fibrinogen, the mortality rate of the ED group was higher than that of the non-ED group (p = 0.012, HR = 4.12, 95% CI 1.37–12.39). For deaths, the average survival time of ED was shorter than that of the non-ED group (856.4 days vs. 933.8 days, p = 0.033). Conclusions: ED has higher mortality than non-ED in COPD. COPD should be assessed for ED, especially in patients with low minimal SpO2 and high maximal HR during the 6MWT.

Chondrosarcoma is a malignant bone tumor with high metastatic potential. Lymphangiogenesis is a critical biological step in cancer metastasis. WNT1-inducible signaling pathway protein 3 (WISP-3) regulates angiogenesis and facilitates chondrosarcoma metastasis, but the role of WISP-3 in chondrosarcoma lymphangiogenesis is unclear. In this study, incubation of chondrosarcoma cells with WISP-3 increased the production of VEGF-C, an important lymphangiogenic factor. Conditioned medium from WISP-3-treated chondrosarcoma cells significantly enhanced lymphatic endothelial cell tube formation. WISP-3-induced stimulation of VEGF-C-dependent lymphangiogenesis inhibited miR-196a-3p synthesis in the ERK, JNK, and p38 signaling pathways. This evidence suggests that the WISP-3/VEGF-C axis is worth targeting in the treatment of lymphangiogenesis in human chondrosarcoma.

This retrospective study included COPD patients who attended our medical center between January and October 2018, and analyzed the outcomes of their influenza vaccination, including medical visits, hospitalization, medical expenses, and the incidence of respiratory failure. Airflow limitation was stratified according to GOLD guidelines. Overall, 543 COPD patients were enrolled, including 197, 113, 126, and 107 mild, moderate, severe, and very severe patients, respectively. Of all the participants, 238 received an influenza vaccination (43.8%), which significantly reduced hospital utilization for moderate (odds ratio [OR] 0.22, 95%CI 0.09–0.51), severe (OR 0.19, 95%CI 0.08–0.44), and very severe patients (OR 0.15, 95%CI 0.05–0.5) compared to mild patients (OR 0.51, 95%CI 0.2–1.26), reduced emergency department utilization for moderate (OR 0.33, 95%CI 0.14–0.77), severe (OR 0.22, 95%CI 0.10–0.52), and very severe patients (OR 0.30, 95%CI 0.10–0.88) compared to mild patients (OR 0.64, 95%CI 0.30–1.37), and reduced the occurrence of respiratory failure for moderate (OR 0.20, 95%CI 0.06–0.68), severe (OR 0.40, 95%CI 0.16–0.98), and very severe patients (OR 0.36, 95%CI 0.15–0.82) compared to mild patients (OR 0% CI 0.14–3.20). Influenza vaccination is more effective in COPD patients with moderate, severe, and very severe airflow obstruction than in those with mild obstruction with respect to hospital utilization, emergency department utilization, and respiratory failure.

INTRODUCTION AND OBJECTIVE:The dynamic duplex sonography (DUS) measures the blood flow velocity but not the volumetric flow rate of blood, which is the blood volume infused per unit of time. In our...

Objectives: To investigate factors associated with major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA). Methods: We conducted a nationwide, population-based, case-control study using Taiwan’s National Health Insurance Research Database for 2003–2013. From 2004 to 2012, we identified 108,319 newly diagnosed RA patients without previous MACEs, of whom 7,580 patients (7.0%) developed MACEs during follow-up. From these incident RA patients, we included 5,994 MACE cases and 1:4 matched 23,976 non-MACE controls for analysis. The associations of MACEs with comorbidities and use of anti-rheumatic medications within 1 year before the index date were examined using conditional logistic regression analyses. Results: Using multivariable conditional logistic regression analysis, the risk of MACE in RA patients was associated with use of golimumab [odd’s ratio (OR), 0.09; 95% confidence interval (CI), 0.01-0.67], abatacept (OR, 0.13; 95% CI, 0.02–0.93), hydroxychloroquine (OR, 0.90; 95% CI, 0.82-0.99), methotrexate (OR, 0.72; 95% CI, 0.64–0.81), cyclosporin (OR, 1.43; 95% CI, 1.07–1.91), nonsteroidal anti-inflammation drugs (NSAIDs) (OR, 1.36; 95% CI, 1.27–1.46), antiplatelet agent (OR, 2.47; 95% CI, 2.31-2.63), hypertension (without anti-hypertensive agents: OR, 1.04; 95% CI, 0.96-1.12; with anti-hypertensive agents: OR, 1.47; 95% CI, 1.36-1.59), diabetes (OR, 1.27; 95% CI, 1.18-1.37), hyperlipidemia without lipid-lowering agents (OR, 1.09; 95% CI, 1.01-1.17), ischemic heart disease (OR, 1.20; 95% CI, 1.10-1.31), and chronic obstructive pulmonary disease (COPD) (OR, 1.12; 95% CI, 1.03-1.23) in the parsimonious model. The risk of MACE in RA patients also increased markedly in participants younger than 65 years with some comorbidities. Conclusions: This population-based case-control study revealed that the use of golimumab, abatacept, hydroxychloroquine, and methotrexate were associated with a decreased risk of MACE development in newly diagnosed RA patients, while the use of cyclosporin, NSAIDs, and antiplatelet agents, and comorbidities, including hypertension, diabetes, hyperlipidemia without lipid-lowering agent therapy, ischemic heart disease, and COPD, were associated with an increased risk of MACE development in RA patients.

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.

Background The high lifetime risk of vascular disease is one of the important issues that plague patients with diabetes mellitus. Systemic oral vildagliptin administration favors endothelial recovery and inhibits smooth muscle cell (SMC) proliferation. However, the localized release of vildagliptin in the diabetic vessel damage has seldom been investigated. Research design and methods In this work, nanofiber-eluting stents that loaded with vildagliptin, a dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor, was fabricated to treat diabetic vascular disease. To prepare nanofibers, the poly (D,L)-lactide-co-glycolide (PLGA) and vildagliptin were mixed using hexafluoroisopropanol and electrospinning process. In vitro and in vivo release rates of the vildagliptin were characterized using high-performance liquid chromatography. Results Effective vildagliptin concentrations were delivered for more than 28 days from the nanofibrous membranes coating on the surface of the stents in vitro and in vivo. The vildagliptin-eluting PLGA membranes greatly accelerated the recovery of diabetic endothelia and reduced SMC hyperplasia. The type I collagen content of the diabetic vascular intimal area that was treated by vildagliptin-eluting stents was lower than that of the non-vildagliptin-eluting group. Conclusion The experimental results revealed that stenting with vildagliptin-eluting PLGA membranes could potentially promote healing for diabetic arterial diseases.

The impact of sialadenitis on osteoradionecrosis (ORN) is controversial. The aim of this study was to determine the association between sialadenitis and ORN.Participants were derived from the Taiwanese Longitudinal Health Insurance Database. From January 1, 2000 to December 31, 2008, cases of sialadenitis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 527.2, 527.3, 527.5 to 527.7, 527.9, and 710.2) and ORN (ICD-9-CM codes 526.89, 526.5, 730.0, and 730.1) were identified. Different treatment modalities, including surgery versus medicine, were used to distinguish the severity of sialadenitis. The primary predictor variable was sialadenitis. The secondary predictor variable was severity of sialadenitis. The primary outcome variable was time to developing ORN. Other study variables were grouped for age, gender, risk factor, and medical treatment. Cox proportional hazard regression was used to investigate the associations between sialadenitis and ORN after adjusting for statistical confounders.The sample was composed of 47,385 patients with a mean age of 46.6 years (standard deviation, 19.9 yr) and 37.2% were men. Twenty percent had a diagnosis of sialadenitis and 1.13% had a diagnosis of ORN. Sialadenitis was associated with an increased risk of ORN (hazard ratio [HR] = 1.93; 95% confidence interval [CI], 1.61-2.31; P .0001). After adjustment for confounders, sialadenitis was associated with ORN (multivariable HR = 1.83; 95% CI, 1.52-2.19; P .0001). Severity of sialadenitis was associated with an increased risk of ORN; risks for ORN were 1.79 (95% CI, 1.49-2.16; P .0001) and 3.52 (95% CI, 1.67-7.44; P .001) in patients with mild and serious sialadenitis, respectively, compared with the no-sialadenitis cohort. For the joint effect of ORN between sialadenitis and malignancy type, patients with sialadenitis had 11.6-fold risk for ORN (95% CI, 5.58-23.9) compared with patients without malignancy.Sialadenitis markedly increased the risk to develop ORN. The severity of sialadenitis was positively correlated with the incidence of ORN.

Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.

Background Kawasaki disease (KD) is the most common acute coronary vasculitis disease to occur in children. Its incidence has been attributed to the combined effects of infection, genetics, and immunity. Although the etiopathogenesis of KD remains unknown, we have performed a survey of global genetic DNA methylation status and transcripts expression in KD patients in order to determine their contribution to the pathogenesis of KD. Methods We recruited 148 participants for this case-control study. The chip studies consisted of 18 KD patients that were analyzed both before undergoing intravenous immunoglobulin (IVIG) treatment and at least 3 weeks afterward, as well as 36 non-KD control subjects, using Illumina HumanMethylation450 BeadChip and Affymetrix GeneChip® Human Transcriptome Array 2.0. We then carried out real-time quantitative PCR on a separate cohort of 94 subjects for validation. Results According to our microarray study, CD177, a neutrophil surface molecule, appeared to be significantly upregulated in KD patients when compared to controls with epigenetic hypomethylation. After patients received IVIG treatment, CD177 mRNA levels decreased significantly. PCR validation indicated that the CD177 expression is consistent with the Transcriptome Array 2.0 results. Furthermore, the area under the curve values of CD177 between KD patients and controls is 0.937. We also observed significantly higher CD177 levels in typical KD than in incomplete presentation or KD with IVIG resistance. Conclusion In this study, we have demonstrated the epigenetic hypomethylation and increased expression of CD177 during the acute stage of KD. Furthermore, a higher expression of CD177 in KD patients with typical presentation was associated with IVIG resistance.

The aim of this study is to determine whether there is a significant relationship between certain insomnia symptoms and drinking water shortly before bedtime as seen anecdotally in a clinical setting. A survey was done of 1223 patients receiving standard physical exams at a large hospital in Taiwan. Every patient was asked whether they were willing to answer a series of questions; if they agreed, they were given the questionnaire. Information in questionnaire form was gathered concerning demographic information and about pre-bedtime lifestyle habits of the respondents, including whether they drank specified beverages. Analysis of the data revealed three discrete classes based on the degree of their insomnia symptoms: Group 1, Group 2, and Group 3. From the multivariate logistic regression mode, Group 2 and Group 3 show a higher proportion of beverage-drinking behavior of study participants before going to bed than Group 1. Group 3 and Group 2 have ORs of 1.59 (P

Background/Purpose: 45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. Patients and Methods: We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. Results: Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from −3.4 ± 1.1 to −1.4 ± 0.9 in adulthood (P

Yi-Pin Chen,1,2 Yen-Wei Liu,3 Demei Lee,3 Jiantai Timothy Qiu,4,5 Tzung-Yan Lee,6,7 Shih-Jung Liu3,8 1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 2Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 3Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan; 4Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Tao-Yuan, Taiwan; 5Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 6Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 7Department of Traditional Chinese Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 8Department of Orthopedic Surgery, Linkou Chang Gung Memorial Hospital, Tao-Yuan, Taiwan Background: In this study, we developed biodegradable andrographolide (AG)-eluting nanofibrous mats and evaluated their efficacy in treating cervical cancer. Materials and methods: Membranes of two different poly[(D,L)-lactide-co-glycolide] (PLGA)-to-AG ratios (6:1 and 3:1) were prepared via electrospinning technology. The liberation behavior of AG was evaluated. A cervical cancer model with C57BL/6J mice was created and employed for an invivo efficacy assessment of the drug-eluting nanofibers. Twelve mice with cervical cancer were stochastically divided into three different groups (four animals per group): group A received no treatment as the control, group B was treated with pure PLGA mats, and group C was treated with AG-loaded nanofibrous membranes. The changes in tumor sizes were recorded. Results: All membranes eluted high concentrations of AG at the target area for three weeks, while the systemic drug concentration in the blood remained low. Histological analysis showed no obvious tissue inflammation. Compared with the mice in groups A and B, the tumor size of the mice in group C decreased with time until day 25, when the daily drug concentration reduced to 3 µg/mL. Conclusion: Biodegradable nanofibers with a sustainable release of AG exhibit adequate efficacy and durability for the treatment of mice with cervical cancer. Keywords: andrographolide, cervical cancer, biodegradable nanofiber, sustainable release

Yi-Hsun Yu,1 Yu-Ting Lin,2 Yung-Heng Hsu,1 Ying-Chao Chou,1 Steve WN Ueng,1 Shih-Jung Liu1,2 1Department of Orthopedic Surgery, Bone and Joint Research Center, Chang Gung Memorial Hospital, Tao-Yuan, 33305, Taiwan; 2Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, 33302, TaiwanCorrespondence: Shih-Jung LiuDepartment of Mechanical Engineering, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, TaiwanTel +886-3-2118166Fax +886-3-2118558Email shihjung@mail.cgu.edu.twPurpose: Postoperative infection and pain management are of great concern to orthopedic surgeons. Although there are several protocols available to deal with these aspects, they are fraught with complications, such as cartilage damage, cardiovascular and neurological intoxication, and systemic adverse responses. Therefore, it is necessary to develop safe and effective perioperative protocols. In the current study, antimicrobial agents/analgesics/growth factor-embedded biodegradable hybrid fixators (polycaprolactone fixator + poly[lactide-co-glycolide] sheath-core structured nanofibers) for bone fracture repair were designed.Methods: The biodegradable hybrid fixators were fabricated using solution-extrusion three-dimensional printing and electrospinning. In vitro, the characteristics of the hybrid fixators were examined. Additionally, the release of the incorporated vancomycin, ceftazidime, lidocaine, and bone morphogenetic protein-2 (BMP-2) was evaluated. The in vivo efficacy including drug-eluting properties, fracture repair, and pain management of the biomolecule-loaded nanofibrous fixators was investigated in rabbit rib-fracture models.Results: The nanofibrous fixators released vancomycin, ceftazidime, and lidocaine in a sustained manner under both in vitro and in vivo conditions and protected BMP-2 from burst release. The implantation of these hybrid fixators around the fractured rib significantly improved animal activities and bone union, indicating that the inclusion of analgesic in the fixator effectively reduced postsurgical pain and thereby helped in recovery.Conclusion: The novel biomolecule-loaded nanofibrous hybrid fixators resulted in excellent therapeutic outcomes. These fixators may be effective in the repair of rib fractures in clinical settings and may help mitigate surgical complications, such as infection, nonunion, and intolerable postoperative pain.Keywords: sheath-core structured nanofiber, bone union, biodegradable fixator, antimicrobial, analgesics, growth factor

Laparoscopic bariatric surgery is increasingly performed in morbidly obese patients. However, post-surgical pain is common and is usually managed with classical opioids such as morphine and fentanyl. Further, morbidly obese patients are predisposed to opioid-related side effects, especially post-operative nausea and vomiting (PONV) and respiratory depression. Obstructive sleep apnea in morbidly obese patients even predisposes them to respiratory depression. Thus, reducing opioid consumption is important. Multimodal analgesia (MMA) provides optimal perioperative analgesia while minimizing opioid consumption. Studies showed that MMA strategy provides satisfying pain relief in bariatric surgery with enhanced recovery. There are very few reports on the use of dinalbuphine sebacate (DS), a newly introduced non-controlled distinguishing opioid medication with long-lasting analgesic effects. DS has a different mechanism of action from that of morphine or fentanyl and is non-addictive, with minimal side effects. It has been successfully used in laparoscopic cholecystectomy in our previous study. We, in this case report, conducted a new MMA protocol with DS on a 46-year-old morbidly obese female patient who underwent laparoscopic sleeve gastrectomy. The MMA protocol included ultrasound-guided intramuscular DS injection plus transversus abdominis plane (TAP) block and other analgesics; it achieved good perioperative analgesia with opioid-sparing effect and enhanced patient’s recovery with no pain in the following 4 months.

Background: The 2019 coronavirus disease (COVID-19) has been an emerging, rapidly evolving situation in China since late 2019 and has even become a worldwide pandemic. The first case of severe childhood novel coronavirus pneumonia in China was reported in March 2020 in Wuhan. The severity differs between adults and children, with lower death rates and decreased severity for individuals under the age of 20 years old. Increased cases of Kawasaki disease (KD) have been reported from New York City and some areas of Italy and the U.K., with almost a 6-10 times increase when compared with previous years. We conducted this article to compare characters and laboratory data between KD and COVID-19 in children. Methods: We obtained a total of 24 COVID-19 children from the literature review and 234 KD cases from our hospital via retrospective chart review. Results: We found that patients with KD had higher levels of white blood cell (WBC), platelet, neutrophil percentage, C-reactive protein (CRP), procalcitonin, Aspartate Aminotransferase (AST), and body temperature, while patients with COVID-19 had higher age, hemoglobin levels, and lymphocyte percentage. After performing multiple logistic regression analysis, we found that age, WBC, platelet, procalcitonin, and AST provide identical markers for distinguishing COVID-19 from KD in children. Conclusion: In this COVID-19 pandemic period, clinicians should pay attention to children with COVID-19 infection when high WBC, platelet, procalcitonin, and AST values are present in order to provide precision treatment with intravenous immunoglobulin (IVIG) for KD or multisystem inflammatory syndrome in children (MIS-C).

Thermogenesis (non-exercise activity) in brown adipose tissue (BAT) promotes energy expenditure because of its higher number of mitochondria than white adipose tissue (WAT). The main function of thermogenesis in BAT can counteract obesity through the dissipation of calories as heat. N-butylidenephthalide (BP) is a natural derivative from Angelica sinensis, a Chinese herb that has been used for thousands of years. In this report, we demonstrated that BP improved the metabolic profiles of mice with high fat diet-induced obesity (DIO) by preventing weight gain, improving serum blood parameters, enhancing energy expenditure, stimulating white fat browning, and reversing hepatic steatosis. Further investigations demonstrated that BP administration upregulated the mRNA expression of beige (CD137, TMEM26) and brown fat selected genes (UCP1, PRDM16, PGC-1α, PPARγ) in white adipose tissues. In vitro studies, BP treatment increased multilocular lipid droplet levels, induced β-adrenergic receptor (cAMP/PKA) and AMP-activated protein kinase (AMPK) signaling (AMPK/acetyl-CoA carboxylase/SIRT1), and increased oxygen consumption in murine differentiated beige adipocytes, and the effects of BP were blocked by an AMPK inhibitor. BP promoted the interaction of AMPK with PGC-1α in beige adipocytes. Our findings provide novel insights into the application of BP in regulating energy metabolism and suggest its utility for clinical use in the treatment of obesity and related diseases.

Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Background:Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation:We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. Sustained hyperglycemic duration lasting longer than 48 hours was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions:This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

This study aimed to determine the relation between temporomandibular disorder (TMD) and ankylosing spondylitis (AS) bidirectionally and ascertain the important comorbidities for AS occurrence in TMD patients. We conducted this population-based cohort study through Longitudinal Health Insurance Database, Taiwan. Study 1 investigated the risk of TMD in AS patients. Study 2 assessed the risk of AS in TMD patients. In total, 3204 AS patients and 12,816 age-matched and gender-matched comparisons were enrolled in study 1. The TMD incidence in the AS cohort was 2.88-fold higher when compared with the comparisons (1.54 vs. 0.53 per 10,000 person-years). After adjusting for age, gender, and comorbidity, the AS cohort had a 2.66-fold (95% CI = 1.79–3.97) increased risk of TMD occurrence (P < 0.0001). The second study recruited 4998 TMD patients and 19,991 age-matched and gender-matched comparisons. Both TMD and comparison cohorts showed similar AS risk (HR = 1.49, 95% CI = 0.91–2.43, P = 0.1108) in the adjusted model. Study 2 identified a 3.66-fold increased risk of AS occurrence in TMD patients with comorbidity, including parapsoriasis, rheumatoid arthritis, osteoporosis, Cushing’s syndrome, and climacteric arthritis (P < 0.012). AS appears to significantly impact the occurrence of TMD. TMD might play a synergic role in AS development. Clinicians have to be vigilant about the increased risk of TMD in AS patients and take care of AS disease activity and prognosis. The symptoms and signs of TMD could be a predictor of AS in patients with the aforementioned comorbidities.

OBJECTIVES Sarcopenia and systemic inflammation can affect survival of advanced-stage oral squamous cell carcinoma (OSCC) patients; however, their reciprocal associations with survival outcomes are yet to be investigated. STUDY DESIGN Retrospective review at a tertiary cancer center. METHODS Patients with stage III-IVB OSCC that underwent surgery and (chemo)radiotherapy at our institution between 2010 and 2015 were reviewed. Skeletal muscle index (SMI) was assessed using computed tomography scans at the C3 vertebra. Sarcopenia was defined at the lowest sex-specific tertile for SMI. Systemic inflammation was estimated using the modified Glasgow prognostic score (mGPS), which ranges from 0 to 2 based on serum C-reactive protein and albumin levels. The predictors of overall survival (OS) were evaluated using Cox regression models. RESULTS A total of 174 patients were included in the study. The cut-off values for sarcopenia were set at SMI

Background: Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and susceptibility for fractures. Only few studies have compared the management for femoral fractures in children with OI. Nevertheless, no cohort studies have described the treatment for femoral fractures in adults with OI in Taiwan. This study aimed to investigate and compare the incidence of union and non-union femoral fractures and the best treatment options to avoid non-union fractures. Methods: We enrolled 72 patients with OI who were older than 18 years at MacKay Memorial Hospital between January 2010 and December 2018. Femoral fracture incidence, non-union rate, and treatment modality were analyzed. Results: Of 72 patients with OI, 11 patients had femoral fractures and 4 patients of them had >1 femoral fracture. The incidence for all types of femoral fractures was 651 fractures per 100,000 person-years annually. In 15 total fractures, 4 fractures resulted in non-union, and patients with type 4 OI mostly had shaft fractures. The best outcomes for non-union shaft fracture is achieved by surgical treatment. Conclusion: Adults with OI tended to develop femoral fractures and non-unions. Adults with type 4 OI were particularly at high risk for non-unions in shaft fractures with conservative treatment.

Pelvic congestion syndrome (PCS) typically causes chronic non-cyclical abdominal pain with a considerable negative effect on the quality of life of women. However, pediatric cases with PCS are limited and non-invasive therapy for adolescent patients has not been reported. We report here a 13-year-old girl who presented with intermittent abdominal pain since the age of 2 years and her symptoms further deteriorated after breast development at 6 years and 9 months old. PCS and coexistent idiopathic central precocious puberty were finally diagnosed on the basis of tortuous ovarian and pelvic veins, and a pubertal response to a gonadotropin-releasing hormone (GnRH) test without hypothalamic–pituitary lesions. After treatment with the GnRH agonist, the pain score was greatly reduced and there was increased prediction of adult height. This case highlights the occurrence of PCS in adolescents and also indicates the role of non-invasive GnRH agonists in young patients with PCS before surgical intervention.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that binds to binary FGFR/α-Klotho receptor complexes in the kidney tubules to inhibit phosphate reabsorption and 1,25(OH)2D production. Excess FGF23 causes X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). Recently, Burosumab, an FGF23 blocking antibody, was approved for treating these hypophosphatemic disorders. A small molecule inhibitor that specifically binds to FGF23 to prevent activation of FGFR/α-Klotho complexes has potential advantages over a systemically administered FGF23 blocking antibody. We previously identified the small molecule ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a therapeutic lead FGF23 antagonist. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinicalHypmouse homologue of XLH a direct connect analogue (8n) [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] that exhibited the greatest stability in microsomal assays, and13a[(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increasedin vitropotency. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and significantly increased serum phosphate and 1,25(OH)2D concentrations inHypmice. Long-term parenteral treatment with8nor13aalso enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate inHypmice. The more potent13acompound showed greater therapeutic efficacy inHypmice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat FGF23-mediated disorders.

Introduction: Patient support groups (PSGs) should be designed according to the backgrounds of participants and the nature of their diseases. Using health literacy as an outcome indicator for PSGs is rare. Methods: All questionnaires (Mandarin Multidimensional Health Literacy Questionnaire, MMHLQ) were collected from eight PSGs to evaluate the health literacy of participants. Background data of participants were also collected, including patient or family, age, and first-time participation or not. Results: A total of 458 questionnaires were collected from eight PSGs. The diseases were: autoimmune disease (systemic lupus nephritis (SLE), malignancy (head and neck cancer (HNC), chronic disease (diabetes mellitus or DM), chronic kidney disease (CKD), hemodialysis and chronic obstructive pulmonary disease (COPD), genetic disease (autosomal dominant polycystic kidney disease (ADPKD), and degenerative disease (osteoporosis). For vasculitis (42.21 &plusmn, 16.49 years old for SLE) and genetic disease (48.95 &plusmn, 17.58 years old for ADPKD), participants were younger. More significant differences between first-time participation and MMHLQ scores were found in disease of osteoporosis, CKD, COPD, and hemodialysis. More significant differences between role of participation (patients themselves or family) and MMHLQ scores were found in SLE, ADPKD, hemodialysis, and CKD. More significant differences between age (elderly or not) and MMHLQ score were found in HNC, DM, CKD, COPD, and osteoporosis. Conclusion: Background data of participants varied across different diseases. Different disease natures and patient background statuses should therefore demand different designs in PSG. MMHLQ before PSGs can be used to help to improve the PSG curriculum on the health literacy of patients.

The movement disorder Parkinson&rsquo, s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of &alpha, synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of &alpha, synuclein was diminished by 27% (p &lt, 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

Since the first case of coronavirus disease 2019 (COVID‐19) was identified in Taiwan 2020.01.21. Several family cluster infections were found later. This study aimed to report family cluster infections and observe subsequent development. We collected domestic family cluster infections among COVID‐19 confirmed cases from 21 January 2020 to 16 March 2020. There were three domestic family clusters infections in this period. The first cluster was cases 19 to 23. The infectious source was a Taiwanese passenger from Zhejiang. The second cluster was cases 24 to 26 and the third cluster was cases 27 to 32. The infectious sources of the latter clusters are currently uncertain. All contacts of three clusters have been isolated and no new confirmed cases have been identified to date. Some measures which have reduced the spread of these three clusters included: First, high suspicion of COVID‐19 for unexplained pneumonia is very important for early detection. Second, immediate epidemic investigation is taken especially COVID‐19 is infectious during the incubation period. Third, when the second and third clusters could not find infectious sources, CECC's press conference let the public know immediately the epidemic situation, so that people could raise their awareness and seek medical treatment or quarantine.

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups&mdash, group A (n = 13, stereotactically injected pure PLGA microparticles), group B (n = 12, stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13, stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.

Background: Uremic vascular calcification (UVC) is reminiscent of osteogenesis and apoptosis in vascular smooth muscle cell (VSMC). We aimed to identify how circulating procalcific particles dramatically leak into VSMC layer in human tissue models of vascular rings. Methods: According to baseline estimated glomerular filtration rate (eGFR), patients following lower extremity amputation were divided into three groups: normal renal function (eGFR ≧ 60 ml/min), mild-to-moderate (15 ml/min < eGFR ≧ 60 ml/min) and severe chronic kidney disease (CKD) (eGFR ≦ 15 ml/min). Arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, internal elastic lamina (EL) disruption, α-SMA, osteogenesis, apoptosis, and oxidative injury. Correlations among UVC severity, eGFR, EL disruption, osteogenesis, and oxidative injury were investigated. Results: CKD arteries were associated with eGFR-dependent EL disruption corresponding to UVC severity. CKD arteries exhibited lower α-SMA, higher expressions of caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), indicative of contractile VSMC loss, and apoptosis. Enhanced expressions of alkaline phosphatase and Runx2 were presented in VSMCs of CKD arteries, indicative of osteogenic differentiation. Above eGFR-dependent UVC and EL disruption correlated expressions of 8-hydroxy-2'-deoxyguanosine (8-OHdG), indicating oxidative EL injury promoted procalcific processes. Conclusions: Circulating uremic milieu triggers vascular oxidative stress, leading to progressive internal EL disruption as a key event in disabling VSMC defense mechanisms and catastrophic mineral ion influx into VSMC layer. Oxidative EL injury begins in early CKD, corresponding with active VSMC re-programming, apoptosis, and ultimately irremediable UVC. In light of this, therapeutic strategies targeting oxidative tissue injury might be of vital importance to hinder the progression of UVC related cardiovascular events.

Background Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis. Methods The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression. Results The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition. Conclusion The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.

Brain abscesses are emergent and life-threating despite advances in modern neurosurgical techniques and antibiotics. The present study explores the efficacy of vancomycin embedded to 50:50 poly(lactic-co-glycolide acid) (PLGA) microparticles in the treatment of brain abscess. The vancomycin embedded microparticles (VMPs) were stereotactically introduced into the cerebral parenchyma in Staphylococcus aureus bacteria- induced brain abscess-bearing rats. Experimental rats were divided into three groups: group A (n = 13, no treatment), group B (n = 14, daily vancomycin injection (5 mg intraperitoneally), and group C (n = 12, stereotactic introduction of VMPs into the abscess cavity). Group C exhibited no inflammatory response and significantly increased survival and reduced mean abscess volumes (p &lt, 0.001) at the eighth week, compared with other groups. Vancomycin delivery via a biodegradable PLGA vehicle can easily attain Area Under the Curve (AUC)/minimum inhibitory concentration (MIC) ratios of &ge, 400, and strengthens the therapeutic efficacy of antibiotics without provoking any potential toxicity. Biodegradable VMPs are a safe and sustainable drug delivery vehicle for the treatment of brain abscess.

ObjectiveTo examine the relative risk of end-stage renal disease (ESRD) requiring dialysis among treated ankylosing spondylitis (AS) patients compared with non-AS individuals.MethodsWe used claims data from Taiwan's National Health Insurance Research Database obtained between 2003 and 2012, and enrolled 37,070 newly treated AS patients and randomly selected 370,700 non-AS individuals matched (1:10) for age, sex and year of index date. Those with a history of chronic renal failure or dialysis were excluded. After adjusting for age, sex, diabetes mellitus, hypertension, IgA nephropathy, frequency of serum creatinine examinations, use of methotrexate, sulfasalazine, ciclosporis, corticosteroid, aminoglycoside, amphotericin B, cisplatin, contrast agents and annual cumulative defined daily dose (cDDD) of traditional NSAIDs, selective cyclooxygenase-2 inhibitors (COX-2i) and preferential COX-2i, we calculated the adjusted hazard ratios (aHRs) with 95% confidence intervals using the Cox proportional hazard model to quantify the risk of ESRD in AS patients. We re-selected 6621 AS patients and 6621 non-AS subjects by further matching (1:1) for cDDDs of three groups of NSAIDs to re-estimate the aHRs for ESRD.ResultsFifty-one (0.14%) of the 37,070 AS patients and 1417 (0.38%) of the non-AS individuals developed ESRD after a follow-up of 158,846 and 1,707,757 person-years, respectively. The aHR for ESRD was 0.59 (0.42-0.81) in AS patients compared with non-AS individuals. However, after further matching for cDDD of NSAIDs, the aHR of ESRD was 1.02 (0.41-2.53). Significant risk factors included hypertension, IgA nephropathy and use of COX-2i.ConclusionsThe risk of ESRD was not significantly different between treated AS patients and non-AS individuals matched for age, sex, year of index date and dose of NSAID.

Purpose Male urinary incontinence (UI) is a global health issue associated with bothersome symptoms which affect daily life. This study aims to evaluate the prevalence of male UI in China, Taiwan, and South Korea and to determine if UI is an independent risk factor affecting the health-related quality of life (HRQoL), mental health, work limitations, and healthcare seeking behavior. Materials and Methods A post-hoc analysis was conducted on the LUTS Asia database which was collated from a cross-sectional, population-based internet survey in China, Taiwan, and South Korea. Prevalence of male UI was assessed, and the effect on HRQoL, Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores, work performance, and healthcare seeking behaviors was determined using univariate and multivariate analyses. Results A total of 4,076 male participants were surveyed. Prevalence of male UI was 17.3%. UI adversely affected the HRQoL in both physical and mental domains. Both multivariate and univariate analyses showed that male UI could be correlated with a negative effect on the HADS anxiety and depression scores. Multivariate analysis suggested that work difficulties were correlated to the presence of UI. Up to 28% of participants who reported urge UI only did not adopt any management measures. Conclusions UI is common in men over 40 years and adversely impacts HRQoL. It is an independent risk factor for anxiety and depression and may cause significant work limitations. Despite these negative effects, many men still do not seek any intervention., Graphical Abstract

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP-binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR-519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR-519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

Background: SHOX deficiency is a common cause of idiopathic short stature. The aim of this study was to describe the clinical characteristics and molecular findings of patients with SHOX deficiency in Taiwan. Methods: A phenotype scoring system was used to evaluate several anthropometric measures in patients with idiopathic short stature. Twenty-three patients with a phenotype score >7 were enrolled for SHOX gene analysis by MLPA and sequencing. Another patient with a deletion/insertion of the short arm of the X chromosome containing the SHOX gene was enrolled for the assessment. Results: SHOX deficiency was detected in 26% of short children with a phenotype score >7. The arm-span-to-height ratio was significantly lower in SHOX-D patients than in non-SHOX-D patients. In patients with SHOX deficiency, an arm-span-to-height ratio