An atypical hyperosmolar hyperglycemic state and diabetic ketoacidosis induced by sodium-glucose cotransporter-2 inhibitors: A case report.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have become the best choice of second-line oral antidiabetic drugs for patients with heart or chronic kidney disease. However, it is not clear how safe this treatment is for elderly patients, especially Asians, who are known to be more insulin deficient than Caucasian individuals with a similar insulin resistance. Here, we report a case concerning an elderly patient with type 2 diabetes mellitus without insulin dependence, whose antidiabetic medication had recently been changed to include an SGLT-2 inhibitor. The patient presented with an atypical hyperosmolar hyperglycemic state and diabetic ketoacidosis but recovered after insulin pump treatment and fluid supplementation. The patient was discharged with a prescription of a mixed-type insulin injection instead of oral antidiabetic medications for diabetes control. Our case demonstrates that if SGLT-2 inhibitors are administered to elderly Asian patients, their benefits and adverse effects should be carefully monitored.

The influence of disease-modifying anti-rheumatic drugs and corticosteroids on the association between rheumatoid arthritis and skin cancer: a nationwide retrospective case-control study in Taiwan.

OBJECTIVES: To investigate the influence of corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs, including conventional synthetic and biologic DMARDs) treatment on the association between rheumatoid arthritis (RA) and non-melanoma skin cancer (NMSC). METHODS: This nationwide retrospective case-control study retrieved data from Taiwan National Health Insurance Research Database during 1995-2013. Cases with newly-diagnosed NMSC (n=19,603) were matched with control without NMSC in a 1:1 ratio according to age, sex, and reference date. The aforementioned association was analysed using conditional logistic regression and adjustments for age, sex, residential regions, occupations, and co-morbidities. Causality cannot be inferred by case-control study. RESULTS: Compared to patients without RA, the patients with RA had a significantly higher association with NMSC (adjusted odds ratio (AOR)=2.23, 95% confidence interval (CI) 1.6-3.1, p<0.001), especially those using cyclosporine (AOR=5.7, 95%CI 2.2-14.86; ≥65 years: AOR=7.28, 95%CI 2.16-24.56), etanercept (AOR=5.27, 95%CI 1.15-24.27; ≥65 years: AOR=8.95, 95%CI 1.12-71.85), and d-penicillamine (AOR=4.79, 95%CI 1.63-14.12; ≥65 years: AOR=3.81, 95%CI 1.26-11.52); those using higher cumulative doses of corticosteroids and methotrexate (corticosteroids: >10g: AOR=2.96, 95%CI 1.67-5.22; >10g and ≥65years: AOR=3.5, 95%CI 1.77-6.92; methotrexate: 1-3g: AOR=2.57, 95%CI 1.13-5.82; >3g: AOR=4.64, 95%CI 1.74-12.4; >3g and ≥65 years: AOR=10.17, 95%CI 2.34-44.26); and those using more kinds of DMARDs (any 3: AOR=3.72, 95%CI 1.67-8.26; any 5: AOR=2.81, 95%CI 1.13-7.04; any 6: AOR=5.23, 95%CI 1.14-24.14; 7-8: AOR=4.06, 95%CI 1.14-14.49). CONCLUSIONS: The patients with RA had significantly increased associations with NMSC, especially those receiving cyclosporine, etanercept, and d-penicillamine; higher cumulative doses of corticosteroids and methotrexate; or more kinds of DMARDs in combination or in sequence. The aforementioned associations were much stronger in the elderly.

Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan.

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long-term urate-lowering treatment. Urate-lowering drugs should be used during the inter-critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate-lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.

Ten-eleven translocation 1 dysfunction reduces 5-hydroxymethylcytosine expression levels in gastric cancer cells.

A sixth base, 5-hydroxymethylcytosine (5hmC), is formed by the oxidation of 5-methylcytosine (5mC) via the catalysis of the ten-eleven translocation (TET) protein family in cells. Expression levels of 5hmC are frequently depleted during carcinogenesis. However, the detailed mechanisms underlying the depletion of 5hmC expression in gastric cancer cells remains unclear, and further research is required. The present study examined the expression levels of 5mC and 5hmC and the expression levels of TET1 and TET2 in gastric cancer tissues using immunohistochemistry. The results revealed that 5hmC expression levels were markedly lower in gastric cancer tissues compared with corresponding adjacent normal tissues. Furthermore, a decrease in 5hmC expression levels was associated with a decrease in TET1 protein expression levels in gastric cancer tissues. The ectopic expression level of TET1 may increase the 5hmC expression level in gastric cancer cells. In addition, the results revealed that TET1 protein expression was markedly different in regards to subcellular localization, and mislocalization was significantly associated with the depletion of 5hmC expression levels in gastric cancer. Together, the results of the present study indicated that TET1 dysfunction reduces 5hmC expression levels, and this phenomenon may serve a crucial role in gastric cancer progression.

MicroRNA-324 in Human Cancer: miR-324-5p and miR-324-3p Have Distinct Biological Functions in Human Cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that have crucial regulatory functions in carcinogenesis. miR-324-5p and miR-324-3p are generated from the same hairpin RNA structure, however, both are diverse in their direct target genes and expression levels. We report that expression of miR-324-5p and -3p was frequently observed to be either up-regulated or down-regulated, and the selection preference of miR-324 for 5p and 3p arms significantly varied in various types or human cancer. Overexpression of miR-324-5p or -3p suppressed growth and invasion of breast cancer cells. Overexpression of miR-324-5p reduced the growth and invasive abilities of colorectal cancer cells, whereas miR-324-3p suppressed colorectal cancer cell invasion but did not influence cell growth. We conclude that miR-324-5p and miR-324-3p might have distinct biological functions, further complicating the regulatory network in human cancer. Therefore, the arm selection preference of miR-324 may be a method for modulating its function.

Risk of skin cancer in patients with diabetes mellitus: A nationwide retrospective cohort study in Taiwan.

Increasing evidence suggests that certain types of cancers are more common in people with diabetes mellitus (DM). This study aimed to investigate the risk of skin cancer in patients with DM in Taiwan. In this retrospective cohort study using data from the Taiwan Longitudinal Health Insurance Research Database, the risk of developing overall skin cancer, including nonmelanoma skin cancer (NMSC) and melanoma, was compared by Poisson regression analysis and Cox regression analysis between the DM and non-DM cohorts. The DM cohort with newly diagnosed DM (n = 41,898) and a non-DM cohort were one-to-one matched by age, sex, index date, and comorbidities (coronary artery disease, hyperlipidemia, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and obesity). Compared with non-DM cohort statistically, for the people with DM aged ≥60 years, the incidence rates of overall skin cancer and NMSC were significantly higher (overall: DM/non-DM: number [n] = 99/76, incidence rate ratio [IRR] = 1.44, P = 0.02; NMSC: DM/non-DM: n = 94/66, IRR = 1.57, P = 0.005). By Cox regression analysis, the risk of developing overall skin cancer or NMSC was significantly higher after adjusting for sex, comorbidities, and overall diseases with immunosuppression status (overall: adjusted hazard ratio [AHR] = 1.46, P = 0.01; NMSC: AHR = 1.6, P = 0.003). Other significant risk factors were older males for skin cancer (overall: AHR = 1.68, P = 0.001; NMSC: AHR = 1.59, P = 0.004; melanoma: AHR = 3.25, P = 0.04), chronic obstructive pulmonary disease for NMSC (AHR = 1.44, P = 0.04), and coronary artery disease for melanoma (AHR = 4.22, P = 0.01). The risk of developing melanoma was lower in the DM cohort than in the non-DM cohort, but without significance (AHR = 0.56, P = 0.28; DM/non-DM: n = 5/10). The incidence rate and risk of developing overall skin cancer, including NMSC, was significantly higher in older adults with DM. Other significant risk factors for older adults with DM were males for NMSC and melanoma, chronic obstructive pulmonary disease for NMSC, and coronary artery disease for melanoma.

Isocitrate Dehydrogenase 2 Dysfunction Contributes to 5-hydroxymethylcytosine Depletion in Gastric Cancer Cells.

The isocitrate dehydrogenase (IDH) family of enzymes comprises of the key functional metabolic enzymes in the Krebs cycle that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). α-KG acts as a cofactor in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). However, the relationship between 5hmC and IDH in gastric cancer remains unclear. Our study revealed that the 5hmC level was substantially lower and 5mC level was slightly higher in gastric cancer tissues; however, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) levels did not change significantly in these tissues. We further examined the expression levels of IDH1 and IDH2 in gastric cancer tissues and observed that IDH2 levels were significantly lower in gastric cancer tissues than in the adjacent normal tissues. The ectopic expression of IDH2 can increase 5hmC levels in gastric cancer cells. In conclusion, our results suggested that IDH2 dysfunction is involved in 5hmC depletion during gastric cancer progression.

Arm Selection Preference of MicroRNA-193a Varies in Breast Cancer.

MicroRNAs (miRNAs) are short noncoding RNAs derived from the 3' and 5' ends of the same precursor. However, the biological function and mechanism of miRNA arm expression preference remain unclear in breast cancer. We found significant decreases in the expression levels of miR-193a-5p but no significant differences in those of miR-193a-3p in breast cancer. MiR-193a-3p suppressed breast cancer cell growth and migration and invasion abilities, whereas miR-193a-5p suppressed cell growth but did not influence cell motility. Furthermore, NLN and CCND1, PLAU, and SEPN1 were directly targeted by miR-193a-5p and miR-193a-3p, respectively, in breast cancer cells. The endogenous levels of miR-193a-5p and miR-193a-3p were significantly increased by transfecting breast cancer cells with the 3'UTR of their direct targets. Comprehensive analysis of The Cancer Genome Atlas database revealed significant differences in the arm expression preferences of several miRNAs between breast cancer and adjacent normal tissues. Our results collectively indicate that the arm expression preference phenomenon may be attributable to the target gene amount during breast cancer progression. The miRNA arm expression preference may be a means of modulating miRNA function, further complicating the mRNA regulatory network. Our findings provide a new insight into miRNA regulation and an application for breast cancer therapy.

Developing a Prediction Model for Post-Operative Delirium and Long-Term Outcomes Among Older Patients Receiving Elective Orthopedic Surgery: A Prospective Cohort Study in Taiwan.

This study aimed to develop a prediction model for post-operative delirium among older patients receiving elective orthopedic surgery and to evaluate its effectiveness in predicting long-term health outcomes. This prospective cohort study screened all subjects aged over 60 years who were admitted for elective orthopedic surgery in a tertiary medical center in Taiwan from April, 2011, to December, 2013. Demographic characteristics, surgery-related factors, and results of comprehensive geriatric assessment (CGA) were all used to develop the prediction model. Long-term health outcomes, including mortality, nursing home admission, and functional status in the first year after surgery, were used to further evaluate the effectiveness of the prediction model. Overall, 461 patients (median age, 73 years; interquartile range [IQR], 67-80 years; 42.3% males) were enrolled, and 37 patients (8.0%) developed post-operative delirium. Prediction models were developed on the basis of demographic characteristics and surgery-related factors (model 1) and of demographic characteristics, surgery-related factors, and geriatric assessment variables (model 2). Although both models effectively predicted the occurrence of post-operative delirium, duration of post-operative delirium, total hospital days, nursing home admission, and mortality, model 2 was more likely to differentiate cases with functional decline during the first year after surgery. In conclusion, a prediction model developed by using demographic characteristics, surgery-related factors, and results of CGA was highly predictive for post-operative delirium, as well as long-term health and functional outcomes.

A novel hemoglobin variant found on the α1 chain: Hb KSVGH (HBA1: p.Lys57_Gly58insSerHisGlySerAlaGlnValLys).

Glycosylated hemoglobin (Hb A1C) is a crucial indicator for the long-term control and the diagnosis of diabetes. However, the presence of hemoglobin (Hb) variants may affect the measured value of Hb A1C and result in an abnormal graph trend and inconsistency between the clinical blood sugar test and Hb A1C values. In this study, laboratory data of 41,267 patients with diabetes were collected. The Hb A1C levels and the graph results were examined. We identified 74 cases containing abnormal Hb A1C graph trends. The conducted blood cell counts and capillary Hb electrophoresis were used to analyze Hb variants. We also determined gene variation for the Hb variants by a sequence approach. Fifteen different types of Hb variants were identified in this study. Among these, we found a novel variant in which the α1 subunit of Hb showed an insertion of 24 nucleotides (nts) between the 56th and 57th residues. We named this novel variant Hb Kaohsiung Veterans General Hospital (Hb KSVGH) (HBA1: p.Lys57_Gly58insSerHisGlySerAlaGlnValLys).

Emerging role of microRNAs in modulating endothelin-1 expression in gastric cancer.

Endothelin-1 (ET-1) is a small 21-amino acid peptide that is known to exert diverse biological effects on a wide variety of tissues and cell types through its own receptors. The ET-1-ETRA axis is frequently dysfunctional in numerous types of carcinomas, and contributes to the promotion of cell growth and migration. microRNAs (miRNAs) are small non-coding RNAs that play a critical role in carcinogenesis through mRNA degradation or the translational inhibition of cancer-associated protein-coding genes. However, the role of ET-1 and the relationship between ET-1 and miRNAs in gastric cancer remain unknown. Results of the analysis of the database of The Cancer Genome Atlas (TCGA) revealed that ET-1 is significantly overexpressed in gastric cancer cells when compared with its expression in adjacent normal cells. Exogenous ET-1 significantly enhanced gastric cancer cell proliferation, implying that ET-1 plays an oncogenic role in gastric cancer carcinogenesis. Using a luciferase reporter assay we showed that 18 miRNA candidates had a significant silencing effect on ET-1 expression by up to 20% in HEK293T cells. Among them, 5 miRNAs (miR-1, miR-101, miR-125A, miR-144 and let-7c) were shown to be involved in ET-1 silencing through post-transcriptional modulation in gastric cancer. Our data also revealed that DNA hypermethylation contributes to the silenced miR-1 expression in gastric cancer cells. The ectopic expression of miR-1 significantly inhibited AGS cell proliferation by suppressing ET-1 expression. Overall, our study revealed that ET-1 overexpression may be due to DNA hypermethylation resulting in the silencing of miR-1 expression in gastric cancer cells. In addition, we identified several miRNAs as potential modulators for ET-1 in gastric cancer, which may be used as targets for gastric cancer therapy.

A survey of dermatological diseases among older male adults of a Veterans Home in Southern Taiwan.

BACKGROUNDS: The dermatologic diseases of the dependent elderly require special attention. METHODS: This screening and treatment service of dermatological diseases was conducted in a Veterans Home in Southern Taiwan. RESULTS: A total of 337 male residents were screened with mean age 83 years (range 46-99). 271 (80.4 %) residents were in dependent status. Their skin diseases were recorded and the distribution pattern was compared with those in the other studies. Comparing by Chi-square test, scabies, bacterial infection, chronic ulcers, pruritus, and brown spots on the legs were present significantly in certain major systemic diseases, respectively. Higher prevalence of certain skin diseases was related to the severity of disability or major systemic diseases of the residents. Actinic keratosis and non-melanoma skin cancers were early detected and managed. CONCLUSIONS: The distribution patterns of skin diseases in a Veterans Home were unique. It provides the evidences on appropriate management and key nursing points for dependent elderly.

Downregulation of hepatoma-derived growth factor contributes to retarded lung metastasis via inhibition of epithelial-mesenchymal transition by systemic POMC gene delivery in melanoma.

The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial-mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma.

High HbA1c level was the most important factor associated with prevalence of diabetic retinopathy in Taiwanese type II diabetic patients with a fixed duration.

BACKGROUND: To identify the prevalence and related risk factors for diabetic retinopathy (DR) in non-insulin dependent diabetes in Taiwan. METHODS: A retrospective review of type II diabetic patients in the Diabetes Shared Care System database of our Hospital enrolled from 2002 to 2009. A retinopathy severity score was assigned according to fundus examination by indirect ophthalmoscopy or binocular biomicroscopy. RESULTS: Data was collected on 901 subjects, 497 males and 404 females. Of these, 230 (25.53 %) had DR at enrolment. Compared with patients without DR, those with DR were more likely to be female (p = 0.03) or have higher HbA1c (p < 0.001), longer duration of diabetes (p < 0.001), hypertension (p < 0.001), higher systolic blood pressure (p < 0.001), higher diastolic blood pressure (p = 0.05), as well as impaired renal function (p = 0.001). In subgroup analysis stratified by diabetes duration, HbA1c was the most consistent independent risk factor associated to the prevalence of DR. Higher systolic blood pressure and female sex were significantly independent risk factors only in patients with a duration of diabetes < 4 years. On the contrary, old onset age showed a protective effect against DR only in those with a disease duration > 8 years. CONCLUSIONS: High HbA1c level was the most important factor associated with prevalence of DR in Taiwanese type II DM patients with a fixed duration.

Inertia on hypoglycemia: highlight from a Taiwan subgroup analysis of Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study.

Type 2 diabetes mellitus is a global health issue. Patients with poor glycemic control often suffer from cardiovascular, cerebrovascular, neuropathic, and nephropathic complications as well as other chronic conditions. Therapeutic guidelines recommend that diabetic patients should maintain their HbA(1c) level below a certain target in order to minimize the risk of developing complications. However, hypoglycemia is recognized as a major impediment to the adequate control of type 2 diabetes. Hypoglycemia can manifest symptoms of varying degrees of severity. Moreover, an association between hypoglycemia and cardiovascular morbidity and mortality has been reported. Here, we present a post hoc Taiwan subgroup analysis of these data collected in the RECAP-DM study to indicate probably more emphasis and concern on hypoglycemia in type 2 diabetic patients in Taiwan. In this analysis, we found no significant difference was observed in treatment-related satisfaction between Taiwanese patients with or without hypoglycemia. Another finding of our study further shows that varying order of hypoglycemic symptoms or severity has no effect on patients' assessment of health-related quality of life scores. We need to pay more attention to this issue because of its enduring impact on compliance and concerns about hypoglycemia in type 2 diabetic patients. Nevertheless, socio-demographic characteristics are also important factors influencing glycemic control and patients' health-related quality of life. Future interventions and therapeutic algorithms should emphasize the probable patients' unawareness or neglect on hypoglycemia in diabetic patients.

PTEN overexpression attenuates angiogenic processes of endothelial cells by blockade of endothelin-1/endothelin B receptor signaling.

Arteriovenous (AV) graft is frequently used as vascular access in hemodialysis patients. However, clotting or thrombosis of AV grafts often occurs and requires surgical removal. At present, the molecular pathogenesis underlying thrombosis of AV graft is not clear. The PTEN/Akt signaling has been implicated in the pathogenesis of vascular diseases. In this study, elevated PTEN expression and concomitant Akt inactivation was observed in endothelium of atherosclerotic brachial arteries from hemodialysis patients. To investigate whether PTEN upregulation affects endothelial function, adenovirus-mediated PTEN (Ad-PTEN) overexpression was performed in aorta rings and cultured endothelial cells. It was found that PTEN overexpression potently inhibited the microvessel sprouting in aorta rings and the angiogenic activities of endothelial cells including migration and tube formation. On the contrary, PTEN knockdown by RNA interference promoted the endothelial migration and reversed the Ad-PTEN-induced inhibition of endothelial migration. Expression analysis showed that PTEN overexpression attenuated the expression of endothelin-1 (ET-1) and endothelin B receptor (ETBR) in endothelial cells at transcriptional levels. However, exogenous ET-1 supply only partially reversed the PTEN-induced inhibition of migration and tube formation. This was delineated due to that PTEN overexpression also perturbed endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) release. In summary, PTEN upregulation induces endothelial dysfunction by attenuating the availability and signaling of multiple angiogenic pathways in endothelial cells, thereby may contribute to thrombosis of AV graft.

Elevated serum retinol-binding protein 4 concentrations are associated with chronic kidney disease but not with the higher carotid intima-media thickness in type 2 diabetic subjects.

To examine the association of serum retinol-binding protein 4 (RBP4) concentrations with carotid intima-media thickness (CIMT) in type 2 diabetic subjects with chronic kidney disease (CKD). A total of 239 type 2 diabetic patients (64 ± 13 years, 154 males) were divided into two groups: one with CKD, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m(2) (n = 86), and one without (n = 153). We recorded clinical and biochemical data as well as CIMT. The patients with CKD were older, had had diabetes mellitus longer, and had higher incidence of hypertension, dyslipidemia and microalbuminuria than those without. They also had higher serum concentrations of RBP4 (44.8 ± 6.4 vs 39.5 ± 4.9 µg/mL, p < 0.001), higher mean CIMT (0.75 ± 0.16 vs 0.69 ± 0.14 mm, p = 0.0070), and higher incidence of carotid plaques (27.9 vs 11.8 %, p = 0.002). The RBP4 were negatively correlated with eGFR (r = -0.514, p < 0.001). However, the RBP4 were not correlated with mean CIMT (r = 0.065, p = 0.318). Moreover, when dividing the patients into two groups by the mean CIMT, those with mean CIMT above 0.71 mm did not have different RBP4 concentrations compared with those below (41.5 ± 5.7 vs 41.3 ± 6.3 µg/mL, p = 0.856). In conclusion, we observed an elevation of serum RBP4 concentrations and CIMT levels in type 2 diabetic subjects with CKD. However, the elevated RBP4 were not associated with the higher CIMT among these patients.

Hyperthyroidism-associated insulin resistance is not mediated by adiponectin levels.

To evaluate the relationship between circulating adiponectin and insulin sensitivity in patients with hyperthyroid Graves' disease, we studied 19 adult patients with this disease and 19 age- and sex-matched euthyroid controls. All hyperthyroid patients were treated with antithyroid drugs and were re-evaluated after thyroid function normalized. Before antithyroid treatment, the adiponectin plasma concentrations were not different comparing with those in control group. The adiponectin levels remained unchanged after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) in hyperthyroid group was higher before treatment than after treatment. There was no significant difference in serum glucose and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. BMI-adjusted adiponectin levels were not different among three groups. On the other hand, BMI-adjusted insulin levels and HOMA-IR values were significantly decreased after management of hyperthyroidism. Pearson's correlation revealed that insulin and HOMA-IR values positively correlated with triiodothyronine (T3) and free thyroxine (FT4) levels. However, adiponectin did not correlate with T3, FT4, insulin, HOMA-IR and thyrotropin receptor autoantibody (TRAb) levels. In conclusion, insulin resistance associated with hyperthyroidism is not mediated by the levels of plasma adiponectin.

Systemic pro-opiomelanocortin expression induces melanogenic differentiation and inhibits tumor angiogenesis in established mouse melanoma.

Malignant melanoma is one of the leading causes of cancer mortality worldwide, underlining the need for effective novel therapies. In this study, the therapeutic efficacy and mechanism of systemic pro-opiomelanocortin (POMC) therapy were evaluated in mice bearing established melanoma. Injection of adenovirus encoding POMC (Ad-POMC) led to hepatic POMC overexpression and elevated adrenocorticotropin (ACTH) levels in the circulation. Systemic POMC therapy significantly attenuated the growth of established melanoma and prolonged the survival of tumor-bearing mice. Histological analysis revealed that systemic POMC therapy induced melanogenic differentiation while reducing melanoma growth. In addition, POMC therapy also elicited a significant reduction in the neovascular network of melanoma. Last, we demonstrated that POMC-derived peptides, including ACTH, α-melanocyte-stimulating hormone (α-MSH), and ß-MSH, are involved in POMC-mediated melanogenic differentiation and angiogenesis inhibition. In summary, systemic POMC therapy suppresses melanoma growth via induction of melanogenic differentiation and angiogenesis blockade, thereby demonstrating its potential as a novel treatment modality for melanoma.

Common hemoglobin variants in southern Taiwan and their effect on the determination of HbA1c by ion-exchange high-performance liquid chromatography.

BACKGROUND: Patients with hemoglobin (Hb) variants may produce false HbA1c measurement. This study aimed to detect the common Hb variants in southern Taiwan and to evaluate their effect on the determination of HbA1c. METHODS: A total of 1,434 samples collected for HbA1c measurement at Kaohsiung Veterans General Hospital in southern Taiwan in March 2008 were submitted for Hb variant analysis by Primus CLC-385. HbA1c measurements were obtained using ion-exchange high-performance liquid chromatography (HPLC) (Tosoh HLC-723 G7) for routine analysis. Patients identified with Hb variants were recalled for boronate-affinity HPLC analysis. The values of estimated average glucose (eAG) were converted from HbA1c. Values of eAG-FPG, calculated by eAG minus fasting plasma glucose (FPG), were compared to estimate the accuracy of HbA1c measurement in patients with Hb variants. RESULTS: Among the 1,434 patients, the mean standard deviation of FPG was 162.8 +/- 60.5 mg/dL, HbA1c was 8.28 +/- 1.97%, and eAG was 190.9 +/- 56.6 mg/dL. Five Hb variants were detected in 11 patients, the incidence being 0.76%. Hb J was identified in 4 patients, Hb G in 2 patients, Hb E in 1 patient, Hb owari in 3 patients, and high fetal hemoglobin (HbF) in 1 patient. Abnormal HPLC chromatograms were seen among the patients with Hb J, E, G and HbF, but not in the patients with Hb owari. In patients with Hb variants, FPG was 149.5 +/- 39.9 mg/dL, HbA1c was 7.29 +/- 2.01%, and eAG was 162.5 +/- 57.7 mg/dL. Lower values of eAG-FPG may have occurred in the patients with Hb J and E, and in those with high HbF. On scattergrams of the relationship between HbA1c and FPG, the plots of Hb J, E and high HbF lay below the regression line of non-Hb variants. Inconsistent Hb values between both methods were only observed among some samples of patients with Hb variants. CONCLUSION: The existence of Hb variants may result in false HbA1c measurement. The possible presence of spuriously low HbA1c levels or abnormal HPLC chromatograms by using ion-exchange methods should be kept in mind.