Unresolved subclinical hypothyroidism is independently associated with progression of chronic kidney disease.

BACKGROUND AND AIM: Patients with chronic kidney disease (CKD) often have subclinical hypothyroidism. However, few reports have investigated changes in the status of subclinical hypothyroidism in CKD patients and its clinical significance in CKD progression. METHODS: We included 168 patients with nondialysis-dependent CKD stages 2-4. The normalization of subclinical hypothyroidism during follow-up was assessed, and the association between transitions in subclinical hypothyroid status and the rate of decline of the estimated glomerular filtration rate (eGFR) was investigated. RESULTS: At baseline, 127 patients were euthyroid and 41 (24.4%) patients were diagnosed with subclinical hypothyroidism. Of these 41 patients, 21 (51.2%) spontaneously resolved to euthyroid during follow-up. The rate of eGFR decline of patients with resolved subclinical hypothyroidism was similar to that of euthyroid patients. The patients with unresolved subclinical hypothyroidism showed a steeper renal function decline than patients with euthyroidism or resolved subclinical hypothyroidism (all p < 0.05). The progression to end-stage renal disease was more frequent in those with unresolved subclinical hypothyroidism than in those who were euthyroid (p = 0.006). In multivariate linear regression for rate of eGFR decrease, unresolved subclinical hypothyroidism (ß = -5.77, p = 0.001), baseline renal function (ß = -0.12, p < 0.001) and level of proteinuria (ß = -2.36, p = 0.015) were independently associated with the rate of renal function decline. CONCLUSIONS: Half of the CKD patients with subclinical hypothyroidism did not resolve to euthyroidism, and this lack of resolution was independently associated with rapid renal function decline.

Deep Learning Analysis with Gray Scale and Doppler Ultrasonography Images to Differentiate Graves' Disease.

CONTEXT: Thyrotoxicosis requires accurate and expeditious differentiation between Graves' disease (GD) and thyroiditis to ensure effective treatment decisions. OBJECTIVE: This study aimed to develop a machine learning algorithm using ultrasonography and Doppler images to differentiate thyrotoxicosis subtypes, with a focus on GD. METHODS: This study included patients who initially presented with thyrotoxicosis and underwent thyroid ultrasonography at a single tertiary hospital. A total of 7,719 ultrasonography images from 351 patients with GD and 2,980 images from 136 patients with thyroiditis were used. Data augmentation techniques were applied to enhance the algorithm's performance. Two deep learning models, Xception and EfficientNetB0_2, were employed. Performance metrics such as accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score were calculated for both models. Image pre-processing, neural network model generation, and neural network training results verification were performed using DEEP:PHI® platform. RESULTS: The Xception model achieved 84.94% accuracy, 89.26% sensitivity, 73.17% specificity, 90.06% PPV, 71.43% NPV, and an F1 score of 89.66 for the diagnosis of GD. The EfficientNetB0_2 model exhibited 85.31% accuracy, 90.28% sensitivity, 71.78% specificity, 89.71% PPV, 73.05% NPV, and an F1 score of 89.99. CONCLUSION: Machine learning models based on ultrasound and Doppler images showed promising results with high accuracy and sensitivity in differentiating GD from thyroiditis.

Genetic analyses of the chimeric CYP11B1/CYP11B2 gene in a Korean family with glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas.

CONTEXT: Dideoxy sequencing is the most commonly used method for detecting the BRAF(V600E) mutation in thyroid cancer and melanoma. However, this gold standard method often makes less definite results in detecting the BRAF(V600E) mutation when there are relatively low amounts of the mutant template in biopsy specimens, which are invariably contaminated with normal tissues. Pyrosequencing, which measures the incorporation of each of the four nucleotides at each template position and indicates the amounts of mutant template present, may be more useful in such situations. OBJECTIVE: To investigate the diagnostic efficiency of pyrosequencing for the mutant BRAF allele in ultrasound (US)-guided fine needle aspiration biopsies (FNABs) of thyroid incidentalomas. DESIGN, SETTING AND SUBJECTS: A total of 101 thyroid incidentaloma cases were included prospectively. Cytological diagnoses of the FNAB samples were made according to the American Thyroid Association (ATA) guidelines, 2006. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing and dideoxy sequencing. RESULTS: On the basis of cytological analysis, the thyroid incidentalomas were classified into benign (n = 43), malignant (n = 30), indeterminate or suspicious neoplasm (n = 24), and nondiagnostic (n = 4) categories. Pyrosequencing detected the BRAF(V600E) mutation in 30 cases: 22 malignant cases, 7 indeterminate cases, and 1 nondiagnostic case. Dideoxy sequencing also detected the BRAF(V600E) mutation in 28 of the same cases but failed to clearly distinguish the mutant allele from the wild-type allele in one indeterminate case and one nondiagnostic case. Histopathological analysis ascertained that all BRAF(V600E)-positive cases were papillary thyroid carcinomas. CONCLUSIONS: Pyrosequencing may be suitable for detecting the BRAF(V600E) mutation in thyroid incidentaloma and may be superior to dideoxy sequencing when low amounts of the mutant template are present in the biopsy.

Significance of the expression of major histocompatibility complex class II antigen, HLA-DR and -DQ, with recurrence of papillary thyroid cancer.

Normal thyroid epithelial cells lack major histocompatibility complex (MHC) Class II antigen. Oncogenic kinases involved in papillary thyroid carcinoma (PTC) trigger the expression of Class II transactivator and MHC Class II complex. However, the relationship between MHC Class II antigen expression and clinical outcome in PTC is unknown. To investigate the frequency of MHC Class II antigen expression in PTC and to identify the effects of MHC Class II antigen expression on clinical outcomes in PTC patients, the expression of HLA-DR/-DQ antigen was analyzed in surgical specimens from 77 PTCs and 44 benign nodules (23 nodular hyperplasias, 21 follicular adenomas). Of the 77 PTC cases, 36 (46.8%) cases expressed HLA-DR and 41 (53.2%) cases expressed HLA-DQ. Next, we investigated clinicopathological characteristics and found that HLA-DR(+) and/or HLA-DQ(+) PTC tended to present without nodal metastasis. Multivariate analyses clearly showed that HLA-DR(+) or HLA-DQ(+) PTC has a low risk of recurrence (HLA-DR OR = 0.22, CI, 0.06-0.9; p = 0.03, HLA-DQ OR = 0.25, CI, 0.07-0.9, p = 0.03). The Kaplan-Meier estimate revealed a significantly lower recurrence-free probability in patients with HLA-DR(-) PTC and HLA-DQ(-) PTC (Log-rank test; chi(2) = 4.59 and 6.07, p = 0.03 and 0.01, respectively). In conclusion, PTC frequently expresses MHC Class II antigen, and the expression of MHC Class II antigen correlated inversely with the risk of recurrence of PTC.

Exenatide reverses dysregulated microRNAs in high-fat diet-induced obese mice.

Exenatide has beneficial effects on insulin sensitivity in several animal models; however, its mechanism of action remains unclear. Furthermore, the relationship between the effect of exenatide on the changes in the relative abundance of microRNAs (miRNAs), which play a role in regulating glucose and lipid metabolism, is not fully understood. Therefore, we assessed the effect of exenatide on miRNA expression in a high-fat diet (HFD)-induced mouse model of obesity. Both HFD control and exenatide-treated HFD mice showed similar body weight gain and increase in ß-cell mass. Insulin levels were significantly lower in exenatide-treated mice than in HFD control mice. The levels of miRNA-15a, 29c, 124a, and 375 in the pancreas were significantly increased in HFD control mice. Furthermore, the levels of miRNA-29c, 124a, and 146a in the liver and miRNA-15a, 29c, 124a, and 146a in the muscle were significantly increased. In contrast, the levels of miRNA-15a, 29c, 124a, and 375 in the serum were significantly decreased. These effects were reversed by treatment with exenatide. Our results provide experimental evidence that exenatide-mediated amelioration of insulin sensitivity is associated with antagonistic changes in the relative abundance of miRNA-15a, 29c, 124a, and 375 in tissues and serum, thus highlighting their usefulness as biomarkers for monitoring insulin sensitivity and response to exenatide treatment in experimental diabetes.

Identification of Intermediate- to High-Risk Papillary Thyroid Carcinoma Patients Who May Be Safely Managed without the Performance of Delayed Stimulated Thyroglobulin Measurements following Total Thyroidectomy and Radioactive Iodine Therapy.

Background. The measurement of stimulated thyroglobulin (sTg) after total thyroidectomy and remnant radioactive iodine (RAI) ablation is the gold standard for monitoring disease status in patients with papillary thyroid carcinomas (PTCs). The aim of this study was to determine whether sTg measurement during follow-up can be avoided in intermediate- and high-risk PTC patients. Methods. A total of 346 patients with PTCs with an intermediate or high risk of recurrence were analysed. All of the patients underwent total thyroidectomy as well as remnant RAI ablation and sTg measurements. Preoperative and postoperative parameters were included in the analysis. Results. Among the preoperative parameters, age below 45 years and preoperative Tg above 19.4 ng/mL were significant risk factors for predicting detectable sTg during follow-up. Among the postoperative parameters, thyroid capsular invasion, lymph node metastasis, and ablative Tg above 2.9 ng/mL were independently correlated with a detectable sTg range. The combination of ablative Tg less than 2.9 ng/mL with pre- and postoperative independent risk factors for detectable sTg increased the negative predictive value for detectable sTg up to 98.5%. Conclusions. Based on pre- and postoperative parameters, a substantial proportion of patients with PTCs in the intermediate- and high-risk classes could avoid aggressive follow-up measures.

Novel ERBB receptor feedback inhibitor 1 (ERRFI1) + 808 T/G polymorphism confers protective effect on diabetic nephropathy in a Korean population.

BACKGROUND: The identification and characterization of the gene, ERRFI1, in diabetes has not been reported. In this study, we evaluated the relationship between ERRFI1 polymorphism and characteristics of type 2 diabetes mellitus (T2DM) in Korea. SUBJECTS AND METHODS: We conduct a case-control study involving T2DM patients (n=342) and controls (n=473). RESULTS: A novel single nucleotide ERRFI1 gene polymorphism at +807(T/G) was found. G genotype frequency was 40.1% in the diabetic group and 42.7% in the control group; the difference was not significant (p=0.45). In the diabetic group, the urine albumin to creatinine ratio (ACR) was lower in the G genotype than in the T genotype (P=0.004). In males with T2DM, those with the G genotype displayed lower systolic blood pressure (P=0.01) and higher glomerular filtration rate (P=0.048) compare to those with the T genotype. In females with T2DM, urine ACR was low in those with the G genotype than in those with the T genotype (P=0.02). In the diabetic group, patients who harboring T allele had a 1.81 times higher risk of diabetic nephropathy than the G allele (95% CI 1.11-2.96, P=0.02). In females with T2DM, patients who harboring T allele had a 2.12 times higher risk of diabetic nephropathy (95% CI 1.07-4.1, P=0.03). CONCLUSIONS: We identify new loci associated with glycemic traits in diabetes and this finding indicates the potential of ERRFI1 as a novel therapeutic target of diabetic nephropathy.

Regulation of inhibitors of differentiation family proteins by thyroid-stimulating hormone in FRTL-5 thyroid cells.

Members of the inhibitors of differentiation (Id) family of helix-loop-helix (HLH) proteins are known to play important roles in the proliferation and differentiation of many cell types. Thyroid-stimulating hormone (TSH) regulates proliferation and differentiation by activating TSH receptor (TSHR) in thyrocytes. In this study, we found that Id2, one of the Id family proteins, is a major target for regulation by TSH in FRTL-5 thyroid cells. TSH rapidly increases the Id2 mRNA level in FRTL-5 thyroid cells but the Id2 protein showed biphasic regulatory patterns, being transiently reduced and subsequently induced by TSH treatment. Transient reduction of Id2 protein was noted within 2 hr of TSH treatment and was mediated by proteasomal degradation. Moreover, reduced Id2 expression correlated with the activity of the phosphatidylinositol 3 kinase pathway, which is activated by TSH. Although TSH increases the activity of the Id2 promoter, TSH-induced activation of this promoter was independent of c-Myc. Id2 did not alter TTF-1- and Pax-8-mediated effects on the regulation of the Tg promoter. Thus, in summary, we found that TSH regulates Id2 expression, but that Id2 does not alter the expression of thyroid-specific genes, such as Tg, in FRTL-5 thyroid cells.