Up until now there have been no promising drugs for the treatment of advanced thyroid cancer, but the development of novel therapeutic agents is now anticipated as a result of the advent of molecular targeted drugs that inhibit tumor growth signals or angiogenesis. Against a background in which the development of numerous molecular targeted drugs for advanced thyroid cancer is being pursued worldwide, the development of sorafenib, vandetanib, and lenvatinib is currently also under way in Japan. All three of these compounds are undergoing phase 3 trials or have been approved abroad, and because they are in the final stage of development in Japan, they are expected to be introduced in clinical settings in the near future. After they have been introduced, it will be necessary to understand the differences between these compounds and to administer them to patients appropriately.
Complement C1q tumor necrosis factor-related protein 1 (CTRP1), an adipose tissue-derived adipokine has been shown to decrease blood glucose levels and to improve metabolism of glucose in mice. In addition, CTRP1 has exhibited significant association with BMI, adiponectin and TNF-α in diabetic animal models. However, there are no published studies addressing CTRP1 levels in type 2 diabetic patients. Therefore, it was of interest to evaluate plasma CTRP1 levels and associated clinical parameters and biomarkers in patients with type 2 diabetes. 135 subjects were recruited to this study, including 62 type 2 diabetic patients (DM group) and 73 healthy subjects (control group). We measured biochemical parameters, CTRP1, TNF-α and adiponectin using enzyme-linked immunosorbent assay (ELISA). Plasma CTRP1 levels showed a significant difference between the DM group and the control group (646.3±154.4 ng/mL vs. 442.6±165.4 ng/mL, p<0.01). In addition, CTRP1 was strongly positively associated with BMI, glucose levels, HbA1c, HOMA-IR and TNF-α in diabetic patients. CTRP1 showed negative correlation with adiponectin. In Multivariate regression analysis, CTRP1 was strongly independently associated with diabetes when CTRP1 levels were analyzed by both as a continuous variable and quartile (OR: 1.009, 95%CI: 1.004-1.015, p<0.05; OR: 2.443, 95%CI: 1.379-4.182, p<0.01, respectively). Increased plasma CTRP1 was independently associated with type 2 diabetes. Profiling of plasma adipokines such as CTRP1 is particularly important to obtain a greater understanding of their contribution to the type 2 diabetic state.
The present study set forth the reference values for penile size and determined the prevalence of buried penis in Japanese full-term newborns. The stretched penile length was measured and the presence of buried penis was assessed at 1-7 days of age in 547 Japanese full-term newborn infants born between 2008 and 2012 in Tokyo. The stretched penile lengths were compared at 1-12 hours and 1-7 days of age in 63 infants and by two observers in 73 infants to estimate postnatal changes and interobserver variation, respectively. The mean stretched penile length was 3.06 cm (SD, 0.26; 95% confidence interval [CI], 3.04-3.08) and the mean ratio of penile length to body length was 6.24×100-1 (SD, 0.55×100-1), both of which were significantly smaller than those in Caucasian newborn infants. Buried penis was identified in 20 of 547 infants (3.7%; 95% CI, 2.1-5.2%). The first measurements of penile length at 1-12 hours were significantly smaller than the next measurements at 1-7 days (95% CI of the difference, 0.22-0.34). The 95% CI for the limits of agreement in the penile lengths measured by the two observers was -0.58 to -0.40 for the lower limit and 0.33 to 0.51 for the upper limit. These findings indicate that the penile length should be assessed after 24 hours of age by the reference standard of the same ethnicity for identifying micropenis and that buried penis is not uncommon in Japanese full-term newborns.
Bartter syndrome (BS) is a disorder with normotensive hypokalemic alkalosis and hyperreninemic hyperaldosteronemia. BS affects infants or early childhood. Patients with BS type 3 harbor mutation in CLCNKB, Cl channel Kb. Gitelman syndrome (GS) is a disorder in childhood, with mutation in SLC12A3. Isolated adrenocorticotropin deficiency (IAD) causes secondary adrenal insufficiency. Neither elderly cases, nor cases with IAD were previously reported in BS. A 72-year-old man was admitted with acute adrenal crisis. He had been treated for IAD for 19 years. He had no trouble during perinatal period, delivery, and growth. After the recovery from adrenal crisis, laboratory tests revealed hypokalemia; 3.0 mEq/L (normal: 3.5-4.5), impaired renal function: eGFR; 37.6 mL/min/1.73m2, normomagnesemia; 2.1 mg/dL (1.7-2.3), hyperreninemia; 59.4 ng/mL/h (0.2-2.7), hyperaldosteronemia; 23.5 ng/dL (3.0-15.9), and normal urinary ratio of calcium/creatinine. In diuretic tests, he showed a fine response to furosemide, and a mild response to thiazide. In genetic tests, no mutation of SLC12A3 was found and homozygous mutation: c.1830 G>A in CLCNKB was shown. Thus he was diagnosed as BS type 3. Current case presented with unusual features as BS type 3, 1) his late and mild clinical manifestation suggested GS rather than BS, 2) laboratory data and diuretics tests did not show typical features as BS, and 3) IAD and chronic renal failure altered electrolyte metabolism. In conclusion, current case implies that BS type 3 should be considered even in elderly cases with normotensive hypokalemia, and highlights importance of endocrinological and genetic examinations.
We systematically investigated the association between single nucleotide polymorphisms (SNPs) in the natriuretic peptide system (NPPA, NPPB, NPPC, NPRA, NPRC, and Corin genes) and blood pressure in a Chinese population. The study population was recruited from a mountainous area 500 km south of Shanghai from 2003 to 2009. Using the ABI SNapShot method, we first genotyped 951 subjects enrolled in 2005 for 16 SNPs and then the remaining 1355 subjects as validation for 5 SNPs selected from the primary study. Overall, the association of the studied genetic polymorphisms with blood pressure and urinary excretion of cations was weak or non-significant. However, in the primary study, there was significant (Pint=0.003) interaction between the rs198358 polymorphism and age in relation to diastolic blood pressure. After adjustment for covariates, diastolic blood pressure was significantly higher in the G allele carriers than AA homozygotes in 176 subjects aged 60 years or older (77.8±1.72 vs 73.9±1.54 mmHg, P=0.001). In the primary combined with validation studies, this interaction remained statistically significant (Pint=0.02). The odds ratio of hypertension for carrying the G allele versus AA homozygotes was 1.25 (95% CI: 1.03-1.52; P=0.03) in all subjects, and 0.85 (0.51-1.41; P=0.53), 1.30 (0.98-1.73; P=0.06), and 1.45 (0.95-2.22; P=0.08) in the subjects younger than 40 years, 40-59 years, and 60 years or older, respectively. Some of the genetic polymorphisms in the natriuretic peptide system might be associated with blood pressure. However, not only the size, but also the direction of the association may change with age.
Following the accident at the Fukushima Daiichi Nuclear Power Station which occurred on March 11, 2011 due to the Eastern Japan Great Earthquake (the Accident), there have been concerns over elevation of the risk of thyroid cancer among children due to internal exposure to radioactive iodine. In Fukushima Prefecture, screening of children with thyroid ultrasonography has been carried out, yielding numerous findings, suggesting a possible influence from the Accident. We report thyroid ultrasonographic findings, used by similar device at Fukushima Prefecture’s study, at Ito-hospital. Of the 2721 children aged 15 or less who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age, 12; range of age, 4-15) were covered by evaluation of thyroid ultrasonographic findings, excluding children known in advance to have thyroid disease on the basis of disease history, palpation and blood tests. Among these 1214 children, 709 children (58.4%) were found cysts (≤5 mm in 665 cases) by ultrasonography, 43 children (3.5%) were found nodules (≤5 mm in 18 cases) and 9 children (5.2%) were found an intrathyroid ectopic thymus. Analysis of the data before and after the Accident using the same device, involving age adjustment on the basis of the standard population in 2010, showed no difference in the incidence rate of cysts or nodules. In children examined, the incidence rate of cyst formation (particularly ≤5 mm) was higher, and there was no difference in the incidence rate of cysts or nodules between the pre- and post-accident period.
Type 1 diabetes, one of two major forms of diabetes, results from the complete destruction of pancreatic beta cells. Viral infection has been suggested to be a trigger of beta cell destruction, the pathogenesis of type 1 diabetes. The aim of this study was to clarify the role of the protein encoded by intherferon stimulated gene (ISG) 15, an antiviral effector, in the development of this clinical entity. We used the mouse beta cell line MIN6 to investigate the role of ISG15 and paid special attention to apoptosis. Although not detected in native MIN6 cells, free ISG15 and ISG15 conjugated proteins were both present in dose-dependently increased amounts following stimulation with interferon alpha. As assessed both by caspase 3/7 activity and an annexin V assay, the percentage of apoptotic MIN6 cells (after exposure to the inflammatory cytokines of interleukin-1beta plus interferon gamma or tumor necrosis factor alpha) was decreased by pretreatment with adenovirus-expressing ISG15 and increased by expressing a short hairpin RNA directed against ISG15. In conclusion, ISG15 has an anti-apoptotic effect on MIN6 cells. Thus, promoting ISG15 expression in the pancreatic beta cells could be a potential therapeutic approach for patients with type 1 diabetes.
Adiponectin (APN), secreted by white adipose tissue (WAT), acts as a protective factor against inflammatory conditions. However, the changes in the expression levels of endogenous APN and the two types of APN receptor (AdipoR1 and AdipoR2) induced by acute inflammatory conditions have not been fully elucidated. In this study, the changes in peripheral and/or central APN and AdipoR expression caused by lipopolysaccharide (LPS)-induced sepsis were examined in gonadal-intact (Sham) and ovariectomized (OVX) female rats. As it has been reported that APN and AdipoR suppress the production of inflammatory cytokines to prevent excessive inflammation, the mRNAs of these molecules were also examined. LPS injection induced increases in visceral WAT APN mRNA without affecting the serum APN level in both the Sham and OVX rats. OVX rats exhibited higher serum APN levels than Sham rats. LPS injection increased the subcutaneous WAT APN mRNA in OVX rats. In both Sham and OVX rats, LPS injection led to a decrease in hepatic AdipoR2 mRNA and an increase in hypothalamic AdipoR2 mRNA. Hypothalamic AdipoR2 mRNA was upregulated 24 h after LPS injection in OVX but not Sham rats. Serum TNF-α level at 6 h after LPS injection and hypothalamic and hepatic IL-6 and TNF-α mRNA at 24 h after LPS injection were significantly higher in Sham than OVX rats. These results suggest that APN and AdipoR play roles in modulating inflammation under septic conditions in female rats.
We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 α (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.
Some type 2 diabetic patients can maintain optimal glycemic control by oral hypoglycemic agents (OHA) after their uncontrolled hyperglycemia is corrected by a temporary introduction of insulin therapy. The objective of this study was to investigate the clinical predictors for the efficacy of OHA after intensive insulin therapy was temporarily introduced. We analyzed a retrospective database of 108 Japanese type 2 diabetic patients who underwent a 75-g oral glucose tolerance test (OGTT) after the temporary introduction of intensive insulin therapy, and tried the switch to OHA. The multivariate logistic regression analysis revealed that shorter diabetic duration, higher body mass index, and lower 2-h post meal glucose levels were independently associated with the efficacy of OHA (all p < 0.001). The C statistic of the multivariate model was calculated to be 0.86. The addition of 120-min insulinogenic index, calculated from 0-, 30-, 60-, and 120-min data during an OGTT, to the model significantly increased the C statistic to 0.91 (p = 0.025). Interestingly, omitting 30- and 60-min data from the calculation of the index did not reduce the predictive performance. Furthermore, the ratio of 120-min insulin levels to 120-min glucose levels also provided a comparable predictive performance. In conclusion, 0- and 120-min data during an OGTT, or even 120-min data alone, in combination with diabetic duration, body mass index, and 2-h post meal glucose levels were useful in predicting the efficacy of OHA after intensive insulin therapy in Japanese type 2 diabetic patients.
The aim of this study was to evaluate the effect of a six-month lifestyle intervention on adiponectin, resistin, and two soluble forms of tumor necrosis factor-α receptor (sTNFR) in obese adolescents. A total of 54 obese adolescents aged 10 to 16 years completed the program. Twenty-four adolescents with normal weight at baseline were used as a control group. Our results demonstrated that obese adolescents had abnormal lipid profile, homeostasis model assessment (HOMA) index, adiponectin level (5.6±2.7 vs. 7.6±2.9 μg/mL, p=0.005) as well as resistin level (31.0±9.0 vs. 24.3±8.5 ng/mL, p=0.003), whereas levels of both sTNFRs were similar to those in normal weight subjects. After the six-month lifestyle intervention, obese adolescents had a slight but significant drop in standard deviation score-body mass index (SDS-BMI), a significant decrease in waist circumference, total cholesterol, triglycerides, HOMA index, as well as resistin, and a significant increase in adiponectin and high-density lipoprotein-cholesterol. In adolescents without decreased SDS-BMI, no change was observed in adipokines. Changes in adiponectin correlated negatively with changes in waist circumference (r=-0.275, p=0.044). Changes in resistin correlated positively with changes in triglycerides (r=0.302, p=0.027). The study demonstrated the increase of resistin and the decrease of adiponectin in obese adolescents. Lifestyle intervention improved adipokine abnormalities in obese subjects.
The physiology of insulin signaling under normal and disease conditions is well studied in classical insulin target tissues, but not in podocytes. To examine insulin stimulation of podocyte GLUT4 translocation, we established a protocol involving treatment with the PPARα agonist fenofibrate to induce E11 podocyte differentiation within 48 hours rather than 7-10 days, which is required for differentiation under the reported protocol. This allowed us to transiently introduce GLUT4 reporter cDNA and RNAi and thereby to examine the regulatory pathway involved. Here we demonstrate that treatment with 200μM fenofibrate for 36 hours following transfection had a dramatic effect on podocyte morphology, induced several podocyte specific protein expression markers (G protein-coupled receptor 137B, chloride intracellular channel 5, and nephrin) and resulted in insulin-stimulated GLUT4 translocation. In addition, Nucleobindin-2 was found to constitutively associate with Septin 7 (the repressor of GLUT4 translocation), and knockdown of Nucleobindin-2 was found to completely abrogate insulin-stimulated GLUT4 translocation. Together, these data suggest that Nucleobindin-2 may repress Septin7-induced inhibition of insulin-stimulated GLUT4 translocation in podocytes.