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The cardiovascular outcomes of insulin detemir in patients with type 2 diabetes mellitus (T2DM) after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) are unclear. The aim of our real-life cohort study was to evaluate the cardiovascular outcomes of insulin detemir (IDet) versus insulin glargine (IGlar) in T2DM patients after ACS or AIS.A retrospective cohort study was conducted between June 1, 2005, and December 31, 2013, utilizing the Taiwan National Health Insurance Research Database. A total of 3,129 ACS or AIS patients were eligible for the analysis. Clinical outcomes were evaluated by comparing 1,043 subjects receiving IDet with 2,086 propensity score-matched subjects who received IGlar. The primary composite outcome included cardiovascular (CV) death, nonfatal myocardial infarction (MI) and nonfatal stroke.The primary composite outcome occurred in 322 patients (30.9%) in the IDet group and 604 patients (29.0%) in the IGlar group (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.95 to 1.32) with a mean follow-up of 2.4 years. No significant differences were observed for CV death (HR, 1.09; 95% CI, 0.86 to 1.38), nonfatal MI (HR, 0.88; 95% CI, 0.66 to 1.19), and nonfatal stroke (HR, 1.15; 95% CI, 0.97 to 1.35). There were similar risks of all-cause mortality, hospitalization for heart failure and revascularization between the IDet group and the IGlar group (P = .647, .115, and .390 respectively).Compared with IGlar, in T2DM patients after ACS or AIS, IDet was not associated with increased risks of CV death, nonfatal MI, or nonfatal stroke.ACS = acute coronary syndrome; AIS = acute ischemic stroke; ASCVD = atherosclerotic cardiovascular disease; CI = confidence interval; CV = cardiovascular; DKA = diabetic ketoacidosis; HHF = hospitalization for heart failure; HHS = hyperosmolar hyperglycemic state; HR = hazard ratio; IDet = insulin detemir; IGlar = insulin glargine; MI = myocardial infarction; NHIRD = National Health Insurance Research Database; PCI = percutaneous coronary intervention; PSM = propensity score matching; T2DM = type 2 diabetes mellitus.

The regenerative effect of Epimedium and its major bioactive flavonoid icariin (ICA) have been documented in traditional medicine, but their effect on sarcopenia has not been evaluated. The aim of this study was to investigate the effects of Epimedium extract (EE) on skeletal muscle as represented by differentiated C2C12 cells. Here we demonstrated that EE and ICA stimulated C2C12 myotube hypertrophy by activating several, including IGF-1 signal pathways. C2C12 myotube hypertrophy was demonstrated by enlarged myotube and increased myosin heavy chains (MyHCs). In similar to IGF-1, EE/ICA activated key components of the IGF-1 signal pathway, including IGF-1 receptor. Pre-treatment with IGF-1 signal pathway specific inhibitors such as picropodophyllin, LY294002, and rapamycin attenuated EE induced myotube hypertrophy and MyHC isoform overexpression. In a different way, EE induced MHyC-S overexpression can be blocked by AMPK, but not by mTOR inhibitor. On the level of transcription, EE suppressed myostatin and MRF4 expression, but did not suppress atrogenes MAFbx and MuRF1 like IGF-1 did. Differential regulation of MyHC isoform and atrogenes is probably due to inequivalent AKT and AMPK phosphorylation induced by EE and IGF-1. These findings suggest that EE/ICA stimulates pathways partially overlapping with IGF-1 signaling pathway to promote myotube hypertrophy.

This retrospective study investigated the risk factors of sodium-glucose cotransporter 2 inhibitors (SGLT2i) -related genitourinary tract infection (GUTI).We used longitudinal claims data from May 2016 to December 2017 from the Chang Gung Research Database. Diabetic patients who used SGLT2i were included. The baseline characteristics risk factors between patients who had GUTI and no GUTI were analyzed.There were 428(3.43%) patients with the first occurrence of urinary tract infection (UTI) and 5(0.04%) patients with genital tract infection (GTI). Female patients aged ≥ 65 years with HbA1c ≥ 9%, eGFR 60 ml/min/1.73 mIn diabetic patients who had underlying disease of eGRF 45 ml/min/1.73 m

The efficacy of thyroxine suppressive therapy in reducing nodular growth and its effect to bone mineral density (BMD) in postmenopausal women is still debated. This study aimed to evaluate the therapeutic effect of thyroxine and its influence on BMD. Postmenopausal women with nodular or multinodular goiter during 2013-2015 at Chang Gung Memorial Hospital were enrolled and retrospectively traced back to the first date of visit or treatment. Ninety-four eligible patients were enrolled, of whom 45 were thyroxine-treated (LT-4 group) and 49 were treatment-naïve (control group). Data, including volume of nodules, were analyzed retrospectively. BMD was measured in each LT-4 group patient since the year of enrollment. Nodular volumes were reduced in both LT-4 (from 4.89 ± 4.46 to 4.10 ± 4.57 mL, p = 0.033) and control group (3.48 ± 4.36 to 3.09 ± 2.88 mL, p = 0.239) at initial 2-year follow-up. Nodular volume in LT-4 group increased insignificantly (from 4.89 ± 4.46 to 4.91 ± 5.40 mL, p = 0.711) at the end of 7-year follow-up. The best cut-off predictive nodular volume that may have responded to thyroxine is 2.6 mL (AUC, 0.740; sensitivity, 0.750; specificity, 0.733) during first 2 year. Lumbar spine, total hip and femoral neck BMD were not significantly changed during 2 year's thyroxine suppression therapy. In conclusion, thyroxine suppressive therapy in postmenopausal women had significant reduction in nodule volume at initial 2 years of treatment, especially in volume larger than 2.6 mL. Prolonged thyroxine treatment did not benefit nodular size reduction and may affect BMD minimally in postmenopausal women.

Aims/Introduction Diabetic nephropathy is one of the leading causes of end-stage renal disease. Unfortunately, reliable surrogate markers for predicting the prognostic outcome of diabetic nephropathy are as yet absent. In order to find new markers in predicting the progression of diabetic nephropathy, we carried out a prospective study by investigating the correlation between serum metabolites and the annual change of estimated glomerular filtration rate (eGFR). Materials and Methods From September 2013 to September 2015, 52 diabetes patients at various stages of chronic kidney disease were enrolled. While serum levels of 175 metabolites were measured by AbsoluteIDQ™ p180 kit, only those with a significant difference in advancing chronic kidney disease stages were selected. After then, serial renal function change of these patients was followed up for 12 months, the outcome of renal function with each selected metabolite was compared according to the occurrence of a rapid decline (sustained annual decrement rate ≥5%) of eGFR. Results A total of 26 metabolites were found to be significantly associated with the severity of chronic kidney disease. Tryptophan (Trp) showed a significant association with the event of rapid decline in eGFR (P = 0.036). Serum concentration of Trp

A retrospective review of 626 patients with multifocal papillary thyroid carcinoma (PTC) including 147 patients (23.5%) with multifocal papillary thyroid microcarcinoma (PTMC) from a total of 2,536 patients with PTC who visited the Chang Gung Medical Center in Linkou, Taiwan, was performed. A comparison of the clinical features between 626 multifocal and 1,910 solitary PTC cases showed that patients in the multifocal PTC group were older and had a smaller mean tumor size, a more advanced tumor-node-metastasis (TNM) stage, and a higher percentage of nonremission status compared to patients in the solitary PTC group. Of the 626 patients with multifocal PTC, the group with larger tumors showed a more advanced TNM stage, a higher percentage of lymph node metastasis and soft tissue invasion, and a higher nonremission rate compared to the multifocal PTMC group. Of the 626 patients with multifocal PTC, 25 patients (4%) died during a mean follow-up period of 7.1 ± 5.3 years. Kaplan-Meier survival curves showed a significantly lower survival rate associated with multifocal PTMC compared to that with solitary PTMC.

Objective: The objective of this study was to investigate the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on renal function in different stages of chronic kidney disease (CKD). Design and Methods: We conducted a retrospective cohort study using longitudinal claims data from May 2016–December 2017 from the Chang Gung Research Database. Patients who used one of the three types of SGLT2 inhibitor available at Chang Gung Memorial Hospital, namely empagliflozin 10 mg/tab (Empa10), empagliflozin 25 mg/tab (Empa25), and dapagliflozin 10 mg/tab (Dapa), were included, with the same number of matched non-users. Analysis of variance was used for continuous variables and the chi-square test was applied for categorical variables. Differences in data between two groups were analyzed using an independent t-test, and the basic data before and after treatment were analyzed using generalized estimating equation (GEE). The association among renal function changes was analyzed using a Cox proportional hazards model, with the results presented as unadjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results: Among the 7,624 SGLT2 inhibitor users, 1,696 patients used Empa10, 2,654 used Empa25, and 3,274 used Dapa. Compared with non-users, dapagliflozin had the lowest risk of estimated glomerular filtration rate (eGFR) decrease over 40% from baseline within 1 year (HR 0.36, 95% CI 0.25–0.51). By using the ICD-10-CM code N179, the acute kidney injury (AKI)-related hospitalization rate was lower in Empa10 and Dapa users than in non-users (HR 0.65, 95% CI 0.49–0.86). Conclusion: Lower risk of eGFR decrease over 40% and AKI-related hospitalization was found in all SGLT2 inhibitor users across the different CKD stages.

Betel nut is the second largest economic food product in Taiwan. In Southeast Asia, the habit of chewing betel nut seems to be highly correlated with oral submucous fibrosis and oral squamous cell carcinoma. Oral submucous fibrosis is characterized by abnormal accumulation of oral submucous collagen fibers and limitation of mouth opening. Although the mechanism responsible for tissue damage is still unknown, prolonged irritation caused by betel nut and tobacco is considered to be a major factor contributing to the pathogenesis of oral submucous fibrosis. The effect of betel nut chewing on immune system remains unknown. Present study aims to investigate the change of plasma hormones including cortisol, testosterone, and inflammatory cytokine concentrations in male chewing betel nut compared with normal subjects. Heparinized blood was obtained from control group (normal young+mid-aged individuals), betel nut-chewing, and oral cancer male subjects. The study was approved by the Ethics Committee of the Chang-Gung Memorial Hospital. Written informed consent was granted by the patients. Plasma cortisol and testosterone concentrations were detected by commercial enzyme-linked immunosorbent assay (ELISA). The inflammatory cytokines, including interleukin-1β (IL-1β), IL-15, tumor necrosis factor-α (TNF-α), were analyzed by ELISA with commercial monoclonal capture antibodies and polyclonal detection antibodies. The median concentrations of plasma IL-1β, IL-15, and TNF-α were 3.14pg/ml, 3.14pg/ml, and 6.85pg/ml, respectively, in patients with oral cancer, compared with median plasma IL-1β, IL-15, and TNF-α concentration of 2.64pg/ml, 5.86pg/ml, and 5.38pg/ml, respectively, in patients with betel nut-chewing habit. In contrast, the median concentrations of plasma IL-1β, IL-15, and TNF-α in mid-aged males (aged 30-50) were 7.00pg/ml, 10.64pg/ml, and 31.73pg/ml, respectively, compared with median plasma concentration of IL-1β, IL-15, and TNF-α of 4.48pg/ml, 33.36pg/ml, and 97.77pg/ml in young males (aged 20-22), respectively. Also, significantly elevated plasma cortisol concentration was noted in betel nut-chewing (median 727.2ng/ml) and oral cancer patients (561.9ng/ml) compared to the mid-aged (176.8ng/ml) and young males (173.4ng/ml), respectively. In addition, lower plasma testosterone concentrations were found in betel nut-chewing subjects compared with young males (2.6±3.3ng/ml vs 6.2±2.9ng/ml). To summarize, the inflammatory cytokines and steroid hormones may reflect the degree of inflammation in betel nut-chewing males and the oral cancer subjects. The above findings suggest that betel nut-chewing or oral cancer inhibits plasma cytokines and regulates steroid hormones concentrations compared to mid-aged or young normal subjects. It is also indicated that betel nut-chewing causes decreased inflammatory cytokines as the same levels as in oral cancer subjects.

BackgroundIn Asian countries, many patients with type 2 diabetes fail to achieve controlled glycated hemoglobin (HbA1c) levels while taking several classes of oral hypoglycemic agents (OHAs). Traditional Chinese medicine could be an alternative therapeutic option for poorly controlled type 2 diabetes. YH1 is a concentrated Chinese herbal extract formula that combines Rhizoma Coptidis and Shen-Ling-Bai-Zhu-San. This randomized, double-blind, placebo-controlled pilot study evaluated YH1 as an add-on medication for poorly controlled type 2 diabetes.MethodsForty-six patients with poorly controlled type 2 diabetes were randomly assigned 1:1 to the YH1 or placebo group. Before the trial, all subjects had received three or more classes of OHAs with HbA1c > 7.0% (53 mmol/mol) and a body mass index ≥ 23 kg/m2. During the 12-week trial, participants continued to take OHAs without any dose or medication changes. The primary endpoint was the percentage change in HbA1c level. Per-protocol analysis was applied to the final evaluation.ResultsAt week 12, there was an 11.1% reduction in HbA1c from baseline and a 68.9% increase in homeostatic model assessment (HOMA) of β cell function in the YH1 group, which also exhibited significant reductions in two-hour postprandial glucose (-26.2%), triglycerides (-29.5%), total cholesterol (-21.6%), low-density lipoprotein cholesterol (-17.4%), body weight (-0.5%), and waist circumference (-1.1%). The changes in fasting plasma glucose, HOMA insulin resistance and symptom scores were not significantly different between the YH1 and placebo groups. No serious adverse events occurred during this clinical trial.ConclusionsThis pilot study indicates that YH1 together with OHAs can improve hypoglycemic action and β-cell function in overweight/obese patients with poorly controlled type 2 diabetes. YH1 is a safe add-on medication for OHAs and has beneficial effects on weight control and lipid metabolism. A larger study population with longer treatment and follow-up periods is required for further verification.

To investigate the correlation between gender and the clinical presentation of papillary thyroid cancer and the long-term followup results, 435 patients who underwent total or near-total thyroidectomy were enrolled in this study. Among these papillary thyroid cancer patients, 12.2% showed lymph node metastases and a higher incidence of male patients in the N1b group. There were 65 from 316 female (20.6%) and 49 from 120 male (40.8%) patients who had a postoperative disease progression. A total of 55 (12.6%) patients died of thyroid cancer. Male patients showed a higher thyroid cancer mortality than the females. Multiple regression analysis showed that male gender was an independent risk factor for cancer recurrence and mortality. Male patients with TNM stages II to IV of papillary thyroid cancer need to adopt aggressive surgical and postoperative131I therapy.

It is well known that muscle strength and power are important factors in exercise. Plyometrics is designed to gain muscle strength and power in a shock method. The passive repetitive isokinetic (PRI) machine is developed for plyometrics. The present study aims to understand the effect of ten-week PRI training in different intensities on human plasma concentration cytokines as well as hormonal changes. Thirty young male subjects were enrolled into the ten-week PRI training program and were divided randomly into traditional, low- and high-intensity PRI training groups. Blood samples were obtained before, during, after and 1-, 2-, 3-, 5- and 7-day (D) post-training. The plasma concentrations of cytokines and hormones were measured by an enzyme-linked immunosorbent assay (ELISA). Elevated plasma IL-2 was found in the subjects in all the training programs. Significant increases of proinflammatory cytokines IL-1beta and TNF-alpha were observed at post 7 D in the high-intensity PRI training (29.5 +/- 4.4 and 515.8 +/- 127.1 pg/ml, respectively). No significance in differences in the plasma concentration of IL-6 was observed in the traditional and low-intensity PRI training. Significant elevation of IL-6 was found at post 5 D in high-intensity PRI training. Higher plasma IL-6 concentration was observed at post 3 and 5 D in high-intensity PRI training compared to low-intensity PRI training (P0.05). Significant elevation of plasma IL-15 during (week 6) and after (post 0 D) was observed in low-intensity PRI training. Also, there were differences between low-intensity PRI training and traditional training at post 0, 2, 3, and 5 D. The plasma concentration of cortisol was decreased to the lowest value (118.0 +/- 17.3 ng/ml) at post 0 D in traditional training, then returned to the baseline (220.5 +/- 19.1 ng/ml). In the high-intensity PRI training, but not in the low-intensity PRI training, the cortisol level dropped from 224.9 +/- 25.8 ng/ml at post 0 D down to the 123.2 +/- 22.6 ng/ml at post 1 D. Significant differences were found at post 1 and 5 D between low- and high-intensity PRI training, and post 0, 1, 2, and 3 D between traditional and high-intensity PRI training. Significant increased testosterone was found post 0, 1, 2, and 3 D in traditional training. Higher plasma testosterone was observed during and the recovery period in low-intensity, but not in high-intensity, PRI training. In conclusion, high-intensity PRI training could induce the proinflammatory cytokines, i.e., IL-1beta and TNF-alpha, and decrease plasma cortisol in the recovery period.

Primary nonfunction (PNF) adversely impacts islet transplantation. In addition to determining whether sodium 4-phenylbutyrate (4-SPB), an anti-inflammatory agent, reduces PNF, this study investigates how 4-SPB affects PNF. Streptozotocin-induced diabetic C57BL/6 mice, that received 75 syngeneic islets underneath left subrenal space, were fed twice daily of either 4-SPB at 500 mg/kg body weight or isotonic saline (NaCl) from 2 days before through 7 days after transplantation. The graft was removed at days 3, 10 and 84 following transplantation. At 68 h following transplantation, serum levels of interleukin-1beta (IL-1beta) were 2.2+/-0.4 and 0.4+/-0.2 pmol/L (n=6, p0.005) for NaCl and 4-SPB groups, respectively. Graft genetic expression of IL-1beta was significantly suppressed in 4-SPB group (p0.01). At day 10, the blood glucose levels were 22.7+/-1.0 and 17.1+/-1.7 mmol/L (n=12, p0.05) and graft insulin contents (IC) were 35.0+/-8.3 and 107.6+/-29.7 pmol (n=12, p0.05) for NaCl and 4-SPB groups, respectively. Moreover, the 4-SPB group had a shorter temporary hyperglycemia (15+/-2, n=21 vs. 25+/-2 days, n=19, p=0.001) and a higher cumulative cure rate of diabetes (p0.001) than the NaCl group. In-vitro studies indicated that 4-SPB did not impact the islets function. These experimental results demonstrated that perioperative administration of 4-SPB decreased serum level and graft genetic expression of IL-1beta and attenuated PNF, which enhanced islet engraftment in a syngeneic transplantation mouse model.

The expression of TSH receptor (TSHR) gene is frequently lost in thyroid cancers during the process of dedifferentiation that involves perturbation of several nuclear transcription factors. We have established that thyroid hormone receptor beta1 (TRbeta1) is associated with the loss of TSHR gene expression in an anaplastic human thyroid cancer cell line, ARO. To demonstrate that TRbeta1 regulates TSHR gene expression, we performed electrophoresis mobility shift and 3,5,3'-triiodothyronine (T3) transactivation assays. As expected, TRbeta1 bound the synthesized oligomer containing TSHR promoter sequence by heterodimerizing with retinoid X receptor. When a chimeric reporter pTRCAT5'-146 enclosing the minimal TSHR promoter was applied for T3 transactivation assay, two TRbeta1-overexpressing transfectants of ARO cells (ARO1 and ARO2) demonstrated higher basal activity than their parental cells. Consequentially, T3 suppressed the reporter gene activity only in ARO1 and ARO2, but not in ARO cells. A point mutation creating a cAMP response element (CRE) in the reporter pTRCAT5'-146 CRE led to T3-induced suppression of the reporter gene in ARO cells without changing the basal or T3-induced activities in ARO1 and ARO2 cells. We conclude that the regulatory effect of T3 on TSHR gene expression is TR- and promoter DNA sequence-determined.

Complementary DNAs for two mutant thyroid hormone alpha1 receptors (TR alpha1) were isolated from hepatocellular carcinomas of two patients. Sequence analyses of the complementary DNAs showed a single Val390Ala and double Pro398Ser/Glu350Lys mutations in mutants H and L, respectively. We characterized their hormone-binding, DNA-binding, and dominant negative activities. Mutants H and L did not bind the hormone T3. Their DNA-binding activities were analyzed using three types of thyroid hormone response elements (TREs) in which the half-site binding motifs are arranged in an everted repeat (Lys), an inverted repeat (Pal), or a direct repeat separated by four nucleotides (DR4). Compared with wild-type TR alpha1 (w-TR alpha1), which bound these TREs with different homodimer/monomer ratios, binding of mutant L to the three TREs as homodimers was reduced by approximately 90%. However, binding of mutant H to these TREs was more complex. Although it bound normally to DR4 as homodimers, its binding to Lys as homodimers was reduced by approximately 80%. Surprisingly, its binding to Pal was markedly enhanced compared with w-TR alpha1. The binding of these two mutants to the three TREs as heterodimers with retinoid X receptors (RXR alpha and -beta) was not significantly affected. Consistent with the lack of T3-binding activity, both mutants had lost their trans-activation capacity. Mutants H and L exhibited dominant negative activity, but differed in their TRE dependency. The dominant negative potency of mutant H was in the rank order of PalDR4Lys, whereas no TRE dependency was observed for mutant L. The present study indicates that mutations of the TR alpha gene do occur in patients and that these novel TR alpha1 mutants provide a valuable tool to further understand the molecular basis of the dominant negative action of mutant TRs.

To study the role of a peroxisome proliferator-activated receptor agonist, rosiglitazone, on islet engraftment, streptozotocin-induced diabetic C57BL/6 mice were fed daily rosiglitazone (2.4 mg/kg) for 9 and 31 days starting 2 days before transplantation with 75 and 150 syngeneic islets, respectively. After receiving 75 islets and 9 days of rosiglitazone, half of the treated diabetic mice became normoglycemic at 4 weeks, while none were normoglycemic among those mice that did not receive treatment. After transplanting 150 islets and receiving 31 days of rosiglitazone, 80% of the treated diabetic mice became normoglycemic while the incidence was only 25% for the controls. The insulin content of the islet grafts in the rosiglitazone groups was 0.8 times (75-islet group) and 1.3 times (150-islet group) higher than that of control mice. The insulin content of pancreatic remnants did not differ significantly among all groups. An in vitro study revealed that the glucose-stimulated insulin secretion and insulin content of cultured islets was not different in the presence versus absence of 4.5 or 22.5 micromol/L rosiglitazone. In vitro study revealed that rosiglitazone inhibited the lipopolysaccharide-induced secretion of interleukin-1 beta and interferon-gamma from peritoneal exudate cells. In conclusion, our data suggest that short-term administration of rosiglitazone enhances islet engraftment.

BACKGROUND: Increased body mass index is related to the incidence of thyroid cancer. However, the presentation and therapeutic outcomes of different thyroid cancers and type 2 diabetes mellitus (DM) have not been studied. This study investigated the effect of type 2 DM on the clinical presentations and therapeutic outcome of well-differentiated thyroid cancer. METHODS AND FINDINGS: A retrospective analysis of adult thyroid cancer patients with or without type 2 DM admitted between January 2001 and December 2010 was performed at an institution. A total of 1,687 well-differentiated thyroid cancer patients with different histological patterns were enrolled. Among these subjects, 122 were type 2 DM patients. Patients with thyroid cancer and type 2 DM were significantly older than non-DM patients. After a mean follow-up period of 5.6±0.1 years, patients with thyroid cancer and type 2 DM showed a higher percentage of disease progression than non-DM patients (24.6% vs. 17.4%). In addition, disease-specific mortality was higher in the type 2 DM group (10.7% vs. 3.8%). Thyroid cancer patients with type 2 DM showed a higher percentage of secondary primary cancers than those without DM (10.7% vs. 4.9%). Thyroid cancer-specific survival rates in the type 2 DM and non-DM groups were 82.2% and 94.9% at 5 years, 72.9% and 91.4% at 10 years, and 36.5% and 61.3% at 20 years, respectively. Multivariate analysis showed that type 2 DM was independent of thyroid cancer-specific mortality. CONCLUSION: Patients with type 2 DM and well-differentiated thyroid cancer had an advanced tumor-node-metastasis stage at the time of diagnosis and an increased disease-specific mortality. Aggressive surgical procedures and close follow-up for well-differentiated thyroid cancer patients with type 2 DM are therefore necessary.

The complementary role of hyperglycemia and suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-termex vivobeneficial effect of silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent suppression have a synergistic effect on islet beta cell replication in adult mice.

Aim: Although percutaneous transluminal angioplasty (PTA) is an effective therapeutic procedure for critical limb ischemia, several clinical factors can influence the outcome of PTA for peripheral arterial disease (PAD). The aim of this study is to identify the outcome predictors of PTA in infected diabetic foot patients with PAD. Methods: Eighty-five diabetic patients with a total of 90 infected limbs treated by PTA participated in this study. Patients were initially admitted for infected foot ulcers and were later diagnosed with PAD. Even though all patients underwent successful PTA within 15 days of admission, limb salvage was successful in 66 cases while 24 underwent subsequent amputation. The clinical characteristics and laboratory variables of both groups before PTA were compared and analyzed. Results: Significantly higher level of C-reactive protein (CRP) was observed in the major amputation group before PTA. The cutoff value via receiver operating characteristic curve was 50 mg/L (81.8% specificity, 70.7% sensitivity). Multivariate logistic regression analysis revealed that CRP levels may serve as valuable marker in determining a successful outcome. Conclusion: Reduced CRP levels (

The aim of this study was to explore the effect and action mechanisms of intermittent hypoxia on the production of testosterone both in vivo and in vitro. Male rats were housed in a hypoxic chamber (12% O2+ 88% N2, 1.5 l/ml) 8 h/day for 4 days. Normoxic rats were used as control. In an in vivo experiment, hypoxic and normoxic rats were euthanized and the blood samples collected. In the in vitro experiment, the enzymatically dispersed rat Leydig cells were prepared and challenged with forskolin (an adenylyl cyclase activator, 10−4M), 8-Br-cAMP (a membrane-permeable analog of cAMP, 10−4M), hCG (0.05 IU), the precursors of the biosynthesis testosterone, including 25-OH-C (10−5M), pregnenolone (10−7M), progesterone (10−7M), 17-OH-progesterone (10−7M), and androstendione (10−7-10−5M), nifedipine (L-type Ca2+channel blocker, 10−6-10−4M), nimodipine (L-type Ca2+channel blocker, 10−5M), tetrandrine (L-type Ca2+channel blocker, 10−5M), and NAADP (calcium-signaling messenger causing release of calcium from intracellular stores, 10−6-10−4M). The concentrations of testosterone in plasma and medium were measured by radioimmunoassay. The level of plasma testosterone in hypoxic rats was higher than that in normoxic rats. Enhanced testosterone production was observed in rat Leydig cells treated with hCG, 8-Br-cAMP, or forskolin in both normoxic and hypoxic conditions. Intermittent hypoxia resulted in a further increase of testosterone production in response to the testosterone precursors. The activity of 17β-hydroxysteroid dehydrogenase was stimulated by the treatment of intermittent hypoxia in vitro. The intermittent hypoxia-induced higher production of testosterone was accompanied with the influx of calcium via L-type calcium channel and the increase of intracellular calcium via the mechanism of calcium mobilization. These results suggested that the intermittent hypoxia stimulated the secretion of testosterone at least in part via stimulatory actions on the activities of adenylyl cyclase, cAMP, L-type calcium channel, and steroidogenic enzymes.

The goal of this study was to determine whether conservative surgical therapy had been adequate for low-risk patients with papillary thyroid cancer.1,931 patients were categorized as either low risk or high risk, using tumor-node-metastasis (TNM) staging from the sixth edition of International Union Against Cancer (UICC); TNM stage I was designated low risk during this retrospective review.After an average follow-up period of 8.7 years, 58 of 1,931 patients (3.0%) died from thyroid cancer. Ten-year survival rates of papillary thyroid carcinoma from sixth edition TNM stages I to IV are 99.7%, 95.6%, 90.7%, and 84.0%, respectively. Age, tumor size, (131)I therapeutic dose, and follow-up status were statistically significant when comparing high- and low-risk groups. Of the 1,432 patients in stage I, 338 underwent conservative surgical procedures. Among 338, 4 patients died of thyroid carcinomas (1.2%) and 15 (4.4%) had persistent or recurrent disease. In contrast, 2 of the 1,094 (0.2%) patients who received near-total thyroidectomy or limited lymph node dissection died from thyroid cancer, and 32 (2.9%) had persistent or recurrent disease.TNM stage I papillary thyroid carcinomas were with low cancer-specific mortality rate; otherwise, patients aged 45 years or younger should not be considered a homogeneous low-risk group. Initial extent of disease was an important predictor among these patients. In particular, local invasion with airway compression predicts outcomes.

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have a potent antiatherosclerotic effect. The aim of this study is to investigate whether PTU has a beneficial effect on endothelial function.Ninety patients with a history of hyperthyroidism receiving either PTU (n=45) or methimazole (MMI) (n=45) during the euthyroid status were enrolled in this study. Brachial artery endothelium-dependent (flow-mediated dilatation [FMD]) and endothelium-independent (nitroglycerin-mediated dilatation) responses were assessed by high-resolution ultrasound image. Data for these two groups were compared with those of 41 healthy control subjects. The FMD values were significantly increased in patients maintained on PTU versus those in the MMI and control groups (9.3+/-4.4%, 3.4+/-2.5%, and 3.6+/-3.4%, respectively; P0.01). Nitroglycerin-mediated dilatation had no significant difference between the PTU, MMI, and control groups (17.4+/-7.5%, 15.9+/-6.1%, and 17.5+/-6.8%, respectively; P=0.455). On multivariate analysis, no significant relationship was found between the FMD and thyroid hormone index levels. To further elucidate whether PTU has a direct effect on endothelial function, the effect of PTU on isolated segments of Sprague-Dawley rat aorta was studied. Vasodilatation induced by PTU was endothelium-dependent and could be blocked by pretreatment with nitric oxide (NO) inhibitors. PTU also increased NO formation in aortic segments.This study demonstrated that PTU produced endothelium-dependent vasodilatation through thyroid-independent and NO-mediated mechanisms that may contribute to its beneficial effect on atherosclerosis.

Thyroid nodule is common disorder in endocrine clinics. In Taiwan, thyroid ultrasonography with fine-needle aspiration cytology (FNAC) is the first-line examination procedure. Data in large series on the incidence of thyroid malignancy presenting with thyroid nodules are lacking in this area. To determine the incidence of malignancy in thyroid nodules and compare the results with other populations, this investigation retrospectively reviewed 21,748 subjects who were examined in one medical center from January 1986 to December 1999. All patients underwent thyroid ultrasonography studies using a real-time ultrasonographic machine and a 10-MHz transducer. Fine-needle aspirations were made in the suspected thyroid nodule and stained using the Romanowsky- based method developed by Liu. By the end of 2002, some 3629 patients (16.7%) had thyroid nodules after surgical treatment. This group comprised 3011 women with a mean age of 41.5 +/- 13.9 years, and 618 men with a mean age of 45.7 +/- 14.9 years. Of patients undergoing surgical treatment, 2761 (76.1%) patients were diagnosed with benign nodules, 858 (23.6%) with malignant nodules, and 10 (0.3%) with atypical adenoma (7 follicular and 3 Hurthle cells). The percentages of thyroid malignancy in each age group revealed two peaks in both genders, namely in patients aged 20 to 29 years and in elderly patients (aged over 65 years). The peak age for thyroid malignancy in both genders was 41 to 60 years (male) and 21 to 40 years (female). The highest ratio of malignancy occurred in the elderly group (37.2%) receiving surgical treatment. In young patients (below 19 years) the percentage of malignancy was no greater than for the whole age group (20.2% versus 25.6%). Anaplastic and metastatic cancers affecting the thyroid were the main subjects in the age group. The present results demonstrated a younger distribution for well-differentiated thyroid cancer, particularly papillary thyroid carcinoma, compared to previous studies. This outcome may have resulted from the routine application of ultrasonography with FNAC in assessing the thyroid nodules, possibly helping to achieve more timely detection. The incidence of thyroid malignancy in young patients was no higher than in adults. Early detection of thyroid malignancy may be the main reason for this phenomenon. Male subjects with thyroid nodules displayed a higher incidence of this malignancy than females. Aging subjects with thyroid nodules suffered a higher rate of malignancy and were poorly differentiated. In conclusion, this retrospective large-series study demonstrated that 3.9% (858/21,748 cases) of patients with thyroid nodules showed histopathologically proven malignancy. Thyroid cancer detected by ultrasonography with FNAC occurred an average of 10 years younger than in prior studies.

Sodium 4-phenylbutyrate (4-SPB), an aromatic derivative of butyric acid, was examined to elucidate its effect on islet engraftment in a syngeneic transplantation model using C57BL/6 mice. Diabetic mice that received subrenal implantation of 150 islets on day 0 and oral administration of twice daily 4-SPB (500 mg/kg body weight) on days -2 through 28 displayed a significantly shorter duration of posttransplantation temporary hyperglycemia than diabetic mice that received islets in isotonic sodium chloride solution (NaCl), namely 16 +/- 2 (n = 12) vs 23 +/- 2 days (n = 7; P.05). Four weeks after transplantation, the insulin content (IC) of grafts from mice treated with islets and 4-SPB was substantially higher than that of grafts from mice treated with islets and NaCl, namely 2.59 +/- 0.37 (n = 8) vs 1.36 +/- 0.36 mug (n = 13; P.01). The IC of pancreatic remnants showed no significant difference between groups after 2 and 4 weeks of incubation. In vitro studies demonstrated that the net glucose-stimulated insulin secretion (GSIS) and the ratio of net GSIS to the IC of islets cultured with 4-SPB (1 mM) did not differ significantly from those cultured with NaCl. The lipopolysaccharide-stimulated secretions of IL-1beta, IL-10, and IFNgamma from peritoneal exudate monocytes were significantly reduced by co-incubation with 4-SPB (1 mM). In conclusion, our data suggest that daily administration of 4-SPB reduces primary nonfunction and enhances islet engraftment in a syngeneic mouse transplantation model.

This study examined whether treating donor mice with a single-dose of cobalt protoporphyrin (CoPP) could induce heme oxygenase-1 (HO-1) and thus protect islet cells from suppression by high-dose glucocorticoid. Islets were isolated from mice receiving either a single dose of CoPP (20 mg/kg body weight) (CoPP-islets) or isotonic sodium chloride solution (control islets) at 24 hours before isolation. Following incubation in the absence or presence of methylprednisolone (100 and 1000 ng/mL) for 24 hours, glucose-stimulated insulin secretion and insulin content of cultured islets were determined. Data were expressed as the mean ± standard error. HO-1 protein level of CoPP-islets was significantly higher than that of normal islets at 12 hours (P

To study the effect of treatment with cobalt-protoporphyrin (CoPP) for the induction of the heme oxygenase-1 (HO-1) enzyme on islet engraftment donor mice received either a single intraperitoneal injection of CoPP (20 mg/kg body weight) 1 day prior to islet isolation or this injection plus a 9 day posttransplantation course of Copp. After a single injection of CoPP, the CoPP-induced islets contained higher HO-1 proteins than did the normal islets both at 12 (5.3 +/- 1.5 vs 0.1 +/- 0.1 ng/mg protein, P.01) and at 30 hours (6.8 +/- 2.1 vs 0.4 +/- 0.3 ng/mg protein, P.05), but not at 56 hours (1.9 +/- 0.8 vs 1.6 +/- 0.8 ng/mg protein, P.05). In contrast, diabetic mice that received 75 CoPP-induced islets and a 9-day CoPP injection course posttransplantation showed better improvement in blood glucose levels and body weights than did the mice that only received CoPP-induced islets. Mice of both CoPP-treated groups displayed better improvement in glycemic control than mice that received control islets. At 8 weeks after transplantation, the insulin content of grafts from both CoPP groups was significantly higher than that in the control group. In conclusion, CoPP treatment for the induction of HO-1 enhances engraftment of islets in a syngeneic murine transplantation model.

This study examined whether treating donor mice with a single dose of cobalt protoporphyrin (CoPP) induced heme oxygenase-1 (HO-1) and protected islet cells from interleukin-1 beta (IL-1 beta) suppression. Islets were isolated from mice receiving a single dose of either CoPP (20 mg/kg of body weight, CoPP islets) or isotonic NaCl solution vehicle (control islets), 24 hours before isolation. Glucose-stimulated insulin secretion (GSIS) and insulin content (IC) of the islets were determined following incubation in the presence versus absence of murine IL-1 beta for 21 or 65 hours. The HO-1 protein level of CoPP-induced islets, as determined by an enzyme immunoassay, was significantly higher than that of control islets at 12 hours (P.01) and 30 hours (P.05), and returned to basal levels at 56 hours (P = NS). Following a 21-hour incubation with IL-1 beta, CoPP islets secreted significantly more insulin upon glucose stimulation and preserved significantly more IC than control islets. After 65-hour incubation with IL-1 beta, CoPP islets secreted significantly less insulin upon glucose stimulation than control islets and preserved significantly less IC compared to islets incubated without IL-1 beta. In conclusion, treatment with cobalt-protoporphyrin to induce heme oxygenase-1 protects islets against the suppressive effects of IL-1 beta.

Background Clozapine, an atypical antipsychotic drug, induces derangements in glucose homeostasis in certain patients. This study investigated the mechanisms of clozapine-induced beta-cell toxicity. Methods Fifty-two healthy C57BL/6 male mice were randomized into 4 groups to study the effects of clozapine (group C, D) and a high-fat diet (group B, D). Three mice from each group were randomly selected to determine the amount of food intake on days 8-10, and their pancreases were removed for histological examination on day 11. The remaining 10 mice in each group were sacrificed at the 8th week to measure pancreatic insulin content (PIC). Results Mice given clozapine for 8 weeks demonstrated trends of lower PIC. The histological examination of the pancreases retrieved on day 11 already revealed apoptotic changes and suppression of cell proliferation. Although mice fed high-fat chow gained weight, mice given both clozapine and a high-fat diet showed less weight gain and more severe histological deterioration, and had the lowest PIC levels of the 4 groups. Conclusion Pancreatic beta-cell apoptosis, suppression of cell proliferation, and trends of reduction in pancreatic insulin content were observed in mice taking clozapine. The findings of clozapine induced beta-cell toxicity were further aggravated when mice were concomitantly fed a high-fat diet.