Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment.

OBJECTIVE: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery. DESIGN: 2-Deoxy-2-[18F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using 14C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or ob/ob mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis. RESULTS: The AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation. CONCLUSION: Bariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.

Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.

BACKGROUND: There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. METHODS: From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1-2 years. Ultrasonographic findings at baseline and after 6-8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. RESULTS: Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6-8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025-1.832; p < 0.05). Among patients with hepatic steatosis, only individuals with fibrosis showed significant association with atherosclerosis progression (AOR: 1.615, 95% CI 1.005-2.598; p < 0.05). The association between hepatic fibrosis and atherosclerosis progression was significant in all metabolic subgroups regardless of age, body mass index, presence of metabolic syndrome, or insulin sensitivity (all p < 0.05). Furthermore, subjects with hepatic steatosis & fibrosis and ≥ 4 components of metabolic syndrome criteria showed markedly increased risk of atherosclerosis progression (AOR: 2.430, 95% CI 1.087-5.458; p < 0.05). CONCLUSIONS: Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Radiomics model predicts granulation pattern in growth hormone-secreting pituitary adenomas.

PURPOSE: To investigate whether radiomic features from magnetic resonance image (MRI) can predict the granulation pattern of growth hormone (GH)-secreting pituitary adenoma patients. METHODS: Sixty-nine pathologically proven acromegaly patients (densely granulated [DG] = 50, sparsely granulated [SG] = 19) were included. Radiomic features (n = 214) were extracted from contrast-enhancing and total tumor portions from T2-weighted (T2) MRIs. Imaging features were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression model with fivefold cross-validation. Diagnostic performance for predicting granulation pattern was compared with that for qualitative T2 signal intensity assessment and T2 relative signal intensity (rSI) using the area under the receiver operating characteristics curve (AUC). RESULTS: Four significant radiomic features from the contrast-enhancing tumor (1 from shape, 1 from first order feature, and 2 from second order features) were selected by LASSO for model construction. The radiomics model showed an AUC, accuracy, sensitivity, and specificity of 0.834 (95% confidence interval [CI] 0.738-0.930), 73.7%, 74.0%, and 73.9%, respectively. The radiomics model showed significantly better performance than the model using qualitative T2 signal intensity assessment (AUC 0.597 [95% CI 0.447-0.747], P = 0.009) and T2 rSI (AUC 0.647 [95% CI 0.523-0.759], P = 0.037). CONCLUSION: Radiomic features may be useful biomarkers to differentiate granulation pattern of GH-secreting pituitary adenoma patients, and showed better performance than qualitative assessment or rSI evaluation.

4-Methylumbelliferone suppresses hyaluronan and adipogenesis in primary cultured orbital fibroblasts from Graves' orbitopathy.

PURPOSE: In Graves' orbitopathy (GO), hyaluronan secreted by orbital fibroblasts contributes to orbital tissue expansion. The goal of this research was to evaluate the potential benefit of 4-methylumbelliferone (4-MU), a hyaluronan synthase (HAS) inhibitor, in primary cultured orbital fibroblasts from Graves' orbitopathy. METHODS: We assessed the viability of orbital fibroblasts using a live/dead cell assay. Hyaluronan synthesis was evaluated by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qPCR). Adipogenesis was assessed by Oil Red O staining and qPCR of adipogenic transcription factors. RESULTS: In orbital fibroblasts treated with 4-MU (up to 1000 µM), cell viability was preserved by 90%. 4-MU significantly inhibited HAS gene expression and hyaluronan production (*P < 0.05). With respect to adipogenesis, 4-MU suppressed the accumulation of lipids and reduced the number of adipocytes, while decreasing expression of adipogenic transcription factors. CONCLUSIONS: 4-MU represents a promising new therapeutic agent for GO based on its ability to inhibit hyaluronan production and adipogenesis, without decreasing cell viability.

The Prognosis of Papillary Thyroid Cancer with Initial Distant Metastasis is Strongly Associated with Extensive Extrathyroidal Extension: A Retrospective Cohort Study.

BACKGROUND: Extensive extrathyroidal extension (ETE) has a significant role in the prognosis of papillary thyroid cancer (PTC) without distant metastasis, but its role in PTC with initial distant metastasis has never been studied. This study aimed to evaluate the prognostic significance of extensive ETE regarding disease progression, survival, and remission in PTC patients with initial distant metastasis. METHODS: This retrospective cohort study included PTC patients with initial distant metastasis who underwent total thyroidectomy with a median follow-up period of 6.7 years. The prognostic significance of extensive ETE was assessed in terms of time to tumor progression (TTP), cancer-specific survival (CSS), and cumulative incidence of remission with all-cause death as the competing event. RESULTS: The study enrolled 64 patients. Of these patients, 21 (32.8%) had extensive ETE, which was associated with a shorter TTP (adjusted hazard ratio [HR], 4.10; p = 0.015) and a lower CSS rate (p = 0.002, log-rank), particularly for patients 55 years of age or older with stage 4b disease (10-year CSS rate: 33.3% in those with and 92.3% in those without extensive ETE; p = 0.017). Additionally, remission was observed only in patients without extensive ETE (10-year cumulative incidence of remission: 0.0% in those with and 29.3% in those without extensive ETE; p = 0.013). CONCLUSIONS: Extensive ETE of the primary lesion results in poorer prognoses for PTC patients with initial distant metastasis. The high CSS rate for patients with stage 4b PTC but no extensive ETE indicates that the prognosis of this patient population should be distinguished from that of other stage 4 cases.

Lipidomic differentiation of Graves' ophthalmopathy in plasma and urine from Graves' disease patients.

Approximately 50% of patients with Graves' disease (GD) develop retracted eyelids with bulging eyes, known as Graves' ophthalmopathy (GO). However, no simple diagnostic blood marker for distinguishing GO from GD has been developed yet. The objective of this study was to conduct comprehensive profiling of lipids using plasma and urine samples from patients with GD and GO undergoing antithyroid therapy using nanoflow ultrahigh performance liquid chromatography electrospray ionization tandem mass spectrometry. Plasma (n = 86) and urine (n = 75) samples were collected from 23 patients with GD without GO, 31 patients with GO, and 32 healthy controls. Among 389 plasma and 273 urinary lipids that were structurally identified, 281 plasma and 191 urinary lipids were quantified in selected reaction monitoring mode. High-abundance lipids were significantly altered, indicating that the development of GD is evidently related to altered lipid metabolism in both plasma and urine. Several urinary lysophosphatidylcholine species were found to be increased (3- to 10-fold) in both GD and GO. While the overall lipid profiles between GD and GO were similar, significant changes (area under receiver operating curve > 0.8) in GO vs. GD were observed in a few lipid profiles: 58:7-TG and (16:1,18:0)-DG from plasma, 16:1-PC and 50:1-TG from urine, and d18:1-S1P from both plasma and urine samples. An altered metabolism of lipids associated with the additional development of ophthalmopathy was confirmed with the discovery of several candidate markers. These can be suggested as candidate markers for differentiating the state of GO and GD patients based on plasma or urinary lipidomic analysis. Graphical abstract.

Waist-to-calf circumstance ratio is an independent predictor of hepatic steatosis and fibrosis in patients with type 2 diabetes.

BACKGROUND AND AIM: Although a combination of central obesity and decreased skeletal muscle mass has been associated with various cardiometabolic disorders, its influence on the presence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) is unclear. We investigated whether waist-to-calf circumference ratio (WCR) predicts NAFLD or hepatic fibrosis in T2D. METHODS: Patients with T2D (n = 5507) were enrolled in this study. Hepatic steatosis was diagnosed using abdominal ultrasound and predicting score. NAFLD was defined as 'hepatic steatosis absent other causes of chronic liver disease,' such as virus or alcoholism. Degree of hepatic fibrosis was calculated using non-invasive serum biomarker-based models. Insulin resistance was assessed by short insulin tolerance test. RESULTS: The prevalence of NAFLD and obesity (BMI ≥ 25 kg/m2 , Asian definition) were 46.4% and 38.9%, respectively. NAFLD prevalence was higher with increasing WCR tertiles: lowest tertile (36% in men, 28% in women) versus highest tertile (53.8% in men, 58.2% in women, both P < 0.001 after stratification by insulin resistance status. Increasing WCR tertiles were independently associated with presence of NAFLD: odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.22-1.68 and OR = 1.56, 95% CI = 1.31-1.86, in the middle and highest tertiles, respectively. Furthermore, patients with NAFLD and the highest WCR tertile had significant fibrosis (OR = 8.62, 95% CI = 1.39-53.36, P = 0.021). Also, WCR was correlated with risk of sarcopenia (OR = 3.18, 95% CI = 2.50-4.05, P < 0.001, highest tertile). CONCLUSIONS: Higher WCR is associated with increased risk of NAFLD and hepatic fibrosis independent of insulin resistance. This suggests that WCR may be a useful index to predict high risk of hepatic steatosis in T2D.

Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves' orbitopathy.

OBJECTIVE: Graves' orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO. METHODS: Orbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL)-1ß, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed. RESULTS: IL-1ß exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1ß also induced the expressions of ICAM-1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor. CONCLUSION: S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.

Correction of Lower Eyelid Retraction Using Acellular Human Dermis During Orbital Decompression.

PURPOSE: To investigate the surgical outcome of grafting acellular human dermis compared with concurrent lower eyelid retractor recession during swinging eyelid orbital decompression for correction of lower eyelid retraction in patients with Graves' orbitopathy. METHODS: Institutional Review Board-approved retrospective nonrandomized study of 54 Graves' orbitopathy patients (95 eyes) from 2008 to 2012. Patients who received decompression were divided into 3 groups: Group 1 with conjunctival lengthening using 0.3-mm thickness AlloDerm (36 eyes), Group 2 with inferior retractor recession (33 eyes), and Group 3 with decompression only (26 eyes). Outcome measures included lower eyelid height, inferior sclera show, cosmetic appearance, and complications. RESULTS: Baseline clinical characteristics and the degree of improvement of exophthalmos were not different between groups. Preoperative MRD2 was higher in group 1 (8.0 mm) than in groups 2 (6.9 mm, p < 0.001) and 3 (6.6 mm, p < 0.001). Mean improvement of MRD2 as well as postoperative improvement of inferior scleral show at postoperative 4 to 6 months were significantly higher in group 1 (2.7 mm) than in groups 2 (1.8 mm, p < 0.001) and 3 (1.2 mm, p < 0.001). CONCLUSION: Simultaneous correction of lower eyelid retraction using thin AlloDerm during swinging eyelid orbital decompression maximizes improvement of lower eyelid retraction compared with concurrent inferior retractor recession.

c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.

BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also, we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF (V600E) mutant anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response. © 2015 Wiley Periodicals, Inc.

Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in α-cells of mouse pancreatic islets.

Olfactory receptors (ORs) are extensively expressed in olfactory as well as non-olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic α-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in α-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca(2+) mobilization in pancreatic α-cells. The azelaic acid-induced Ca(2+) response as well as glucagon secretion was concentration- and time-dependent manner. Olfr544 was expressed in α-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 µM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca(2+) mobilization in α-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases.

Association Between Obesity and BRAFV600E Mutation Status in Patients with Papillary Thyroid Cancer.

BACKGROUND: The prevalence of papillary thyroid cancer (PTC) is thought to be related to obesity, which affects the prognosis for PTC patients. However, the mechanisms implicated in the relationship between obesity and PTC is a matter for debate. In this study, we aimed to gain insight into the relationship between obesity and the clinicopathological features of PTC, including the BRAFV600E mutation. METHODS: The medical records of 1121 PTC patients were reviewed and the relationships between anthropometric factors, biochemical parameters, and clinicopathological parameters, including BRAFV600E mutation status, were analyzed. RESULTS: Body mass index (BMI) showed a strong association with advanced TNM stage (p < 0.001) and BRAFV600E mutation status (p = 0.008). We also found that BRAFV600E (+) patients had a higher body weight (p = 0.024) and a higher BMI (p = 0.003) than patients with BRAFV600E (-) PTC. In addition, BRAFV600E (+) PTC patients had a significantly higher incidence of extrathyroidal extension (p = 0.025) and more advanced T, N, TNM stage (p < 0.001) than BRAFV600E (-) PTC patients. Consistent with this observation, female BRAFV600E (+) PTC patients had a higher BMI (p = 0.011) and more aggressive tumor behaviors than female BRAFV600E (-) PTC patients. In multivariate analysis, BMI was persistently associated with BRAFV600E mutation in the entire cohort (odds ratio [OR] 1.387; 95 % CI 1.036-1.859; p = 0.028) and in the female subcohort (OR 1.221; 95 % CI 1.014-1.631; p = 0.046). CONCLUSION: The positive association between BMI and BRAFV600E supports the hypothesis that excessive bodyweight influences tumor progression.

Extracapsular en bloc resection in pituitary adenoma surgery.

PURPOSE: A pituitary pseudocapsule often contains tumor tissue and should be removed for radical resection. It can be used as a surgical plane for more radical resection of the tumor in many cases of pituitary adenomas. We evaluated the advantages and disadvantages of extracapsular en bloc capsulectomy. METHODS: From 1992 until 2011, 1,089 treated patients were grouped according to the resection technique: en bloc capsulectomy, fragmented capsulectomy, or piecemeal resection. Their surgical and endocrinological outcomes and complications were evaluated. RESULTS: Extracapsular tumor resection was performed in 263 patients; en bloc capsulectomy in 94 patients and fragmented capsulectomy in 169, whereas piecemeal resection was performed in 826. Extracapsular resection was performed more frequently in prolactin- and thyroid-stimulating hormone-secreting tumors. Total resection was more frequently achieved in extracapsular resection and its chance was 100% when tumors were removed in an en bloc fashion. For the functioning pituitary adenomas, endocrinological remission was achieved in all patients whose tumors were removed in an en bloc fashion and there was no recurrence. Postoperative cerebrospinal fluid (CSF) rhinorrhea developed in 4.2 and 2.7% in the extracapsular resection group and the piecemeal resection groups, respectively. The chance of postoperative aggravation of pituitary function was not statistically different between groups. CONCLUSIONS: Extracapsular resection is critical for radical tumor resection and endocrinological remission. The removal of a pseudocapsule does not increase the risk of postoperative hypopituitarism nor postoperative CSF rhinorrhea.

Clinical characteristics of Graves' orbitopathy in patients showing discrepancy between levels from TBII assays and TSI bioassay.

OBJECTIVE: To investigate clinical characteristics of patients with Graves' orbitopathy (GO) who showed discrepancies between levels of thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII). DESIGN: Comparative case series. PATIENTS: A total of 317 patients with GO in whom Mc4-TSI and M22-TRAb (third-generation TBII) were measured simultaneously. Patients were divided into four groups according to TRAb levels as followings: Group 1, TBII and TSI < median value; Group 2, TBII ≥ median, TSI < median; Group 3, TBII < median, TSI ≥ median; Group 4, both TBII and TSI ≥ median. MEASUREMENT: Endocrine and ophthalmic clinical manifestations in each group. RESULTS: The median value of M22-TRAb was 6·11 IU/l and that of Mc4-TSI was 415·1 (SRR%). One hundred seventeen patients were classified as Group 1, 41 patients as Group 2, 41 patients as group 3 and 118 patients as group 4. Mean CAS was significantly higher in Groups 3 (2·2) and 4 (2·2) than in Groups 1 (1·6) and 2 (1·4; P = 0·001, ANOVA). Mean modified NOSPECS scores were significantly higher (P < 0·001, ANOVA) in Groups 3 (4·1) and 4 (4·1) than in Groups 1 (3·1) and 2 (2·3). The proportion of patients with hyperthyroidism was larger in Group 2 (85·4% [35/41 patients]) than in Group 3 (48·8% [20/41 patients]; P = 0·002). CONCLUSIONS: GO is more active and severe in patients with predominant Mc4-TSI than in patients with predominant M22-TRAb. Patients with hyperthyroidism were more likely to be included with patients with predominant M22-TRAb than with predominant Mc4-TSI.

Antioxidant activity of caffeoyl-prolyl-histidine amide and its effects on PDGF-induced proliferation of vascular smooth muscle cells.

Caffeic acid (CA) is one of the antioxidants found in plants, which protects vascular cells against vascular injuries from oxidative stress. In our previous study, caffeoyl-prolyl-histidine amide (CA-L-Pro-L-His-NH2; CA-PH; a CA derivative) was synthesized, which exhibited a strong antioxidant activity with sufficient stability. In this study, we investigated the role of CA-PH in vascular smooth muscle cells (VSMCs) and confirmed the enhanced antioxidant activity of CA-PH compared with that of CA. In in vitro tube assays, CA-PH showed a higher free-radical-scavenging activity and lipid-peroxidation-inhibition activity than those of CA. In VSMCs, CA-PH significantly reduced hydrogen peroxide-induced ROS generation and increased the expression of heme oxygenase-1. Moreover, CA-PH effectively inhibited the platelet-derived growth factor-induced cellular proliferation of VSMCs, which was confirmed by a decrease in the expression of the proliferating cell nuclear antigen and the phosphorylation of Akt.

Development of a Mature B Lymphocyte Probe through Gating-Oriented Live-Cell Distinction (GOLD) and Selective Imaging of Topical Spleen.

B lymphocytes play a pivotal role in the adaptive immune system by facilitating antibody production. Young B cell progenitors originate in the bone marrow and migrate to the spleen for antigen-dependent maturation, leading to the development of diverse B cell subtypes. Thus, tracking B cell trajectories through cell type distinction is essential for an appropriate checkpoint assessment. Despite its significance, monitoring specific B cell subclasses in live states has been hindered by a lack of suitable molecular tools. In this study, we introduce CDoB as the first mature B cell-selective probe, enabling real-time discrimination of three classified stages in B-cell development: progenitor, transitional, and mature B cells, through a single analysis using CyTOF. The selective mechanism of CDoB, elucidated as gating-oriented live-cell distinction (GOLD), targets SLC25A16, identified through systematic screening of SLC-CRISPRa and CRISPRi libraries. CDoB selectively brightens mature B cells in the mitochondrial area using SLC25A16 as the main gate, and the staining intensity correlates positively with the expression level of SLC25A16 along the B cell maturation continuum. In spleen tissues, CDoB demonstrates selective marking in mature B cell areas in live tissue status, representing the first performance achieved by a small-molecule fluorescent probe.

Nationwide survey of acromegaly in South Korea.

CONTEXT: It was previously reported in Korea that there were 1.4 case per million per year of acromegaly. This was low in comparison with the extrapolated values of Western European countries. We expected that the incidence of acromegaly would be much higher now because of recently improved medical facilities, diagnostic tools and coverage of medical insurance to all the population of South Korea. OBJECTIVE: The purpose of this nationwide survey was to examine the incidence and prevalence of patients with acromegaly, mode of treatment and outcome of surgical treatment of recent 5 years. DESIGN AND PATIENTS: We requested and collected the medical records of all possible patients with acromegaly from 74 secondary or tertiary medical institutes in Korea from 2003 to 2007 retrospectively. MEASUREMENTS: Date of diagnosis and treatment, tumour size, pre- and postoperative hormonal level, treatment modality and usage of medication were collected. RESULTS: During 5 years, 1350 patients with acromegaly had been registered. The average annual incidence was 3.9 cases per million during this period, and prevalence had increased up to 27.9 cases per million in 2007. Male/female ratio was 1:1.2, and mean age at diagnosis was 44.1 years. Macroadenoma was dominant (82.9%). Transsphenoidal adenoidectomy was used the most as primary treatment (90.4%). CONCLUSIONS: This Korean acromegaly survey offers a realistic overview of the predominant epidemiological characteristics of acromegaly in Korea. Annual incidence was at a similar level with western countries. Efforts to diagnose and control the disease earlier are recommended.

Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using subconjunctival triamcinolone injections.

BACKGROUND: To evaluate the efficacy of subconjunctival triamcinolone injection for treating upper eyelid retraction caused by thyroid-associated ophthalmopathy (TAO). METHODS: Prospective single blind randomized clinical trial. Patients diagnosed with TAO-associated eyelid retraction and/or swelling <6 months before study onset were randomly assigned to triamcinolone-injected (group I; 55 patients, 75 eyes) or observation-only (group II; 40 patients, 59 eyes) populations. Group I received 1-3 injections of 20 mg triamcinolone acetate into the subconjunctival eyelid, between the conjunctiva and Muller's muscle, at 3-week intervals. Group I was followed up at 3, 6, 9, and 24 weeks post-injection, and group II was evaluated at 9 and 24 weeks after initial visit. Eyelid swelling and retraction were each graded on a 0-3 scale. Treatment was stopped after 1-2 injections if both swelling and retraction resolved completely or if retraction and swelling scored 0/1 or 1/0 without functional or cosmetic patient concerns. Treatment success was defined at 9 and 24 weeks post-injection if eyelids were normal or when treatment was terminated because of early clinical resolution. We compared baseline clinical data between success and failure group evaluated at 9 and 24 weeks in group I, and investigated short-term and long-term success prognostic factor using multiple logistic regression analysis in each group I and II. RESULTS: Swelling and retraction decreased significantly more in group I than in group II. Significantly more eyes had severe swelling (≥ grade 2) in group I (67 %) than in group II (34 %) upon initial evaluation (p < 0.01); this difference disappeared at 9 and 24 weeks. Fewer severely retracted eyes were observed in group I than in group II at 9 and 24 weeks (p < 0.01). Significantly more eyes in group I achieved success at both 9 and 24 weeks (59 %, 75 %) than in group II (39 %, 57 %) (p = 0.03, p = 0.04 respectively). Higher initial retraction grades (2-3) predicted a higher chance of post-injection failure versus the reference group (grade 0-1) at 9 and 24 weeks in group I, with adjusted odds ratios (aOR) 45.4 (95 % CI = 5.9-351.1, p < 0.01) and aOR 11.6 (95 % CI = 2.3-58.5, p < 0.01) respectively. Similarly in group II, initial retraction grade was associated with the failure at 9 and 24 weeks, with aOR 10.3 (95 % CI = 1.8-59.6, p < 0.01) and aOR 5.9 (95 % CI = 1.3-25.9, p < 0.05) respectively. Transient intraocular pressure elevation was observed in three eyes of two patients, although all ocular pressures were normalized within 1 month using anti-glaucoma medication. CONCLUSIONS: Subconjunctival triamcinolone injections were very effective in resolving eyelid swelling and retraction in recent-onset TAO. However, the symptom-reducing effect of triamcinolone was modest and less effective in patients initially presenting with severe retraction grades. As intraocular pressure may rise after steroid injection at upper eyelid, the treatment should be avoided in patients suspected to have glaucoma.

Comparison of metabolic ratios of urinary estrogens between benign and malignant thyroid tumors in postmenopausal women.

BACKGROUND: Estrogen metabolism may be associated with the pathophysiological development of papillary thyroid carcinoma (PTC). METHODS: To evaluate the differential estrogen metabolism between benign and malignant PTCs, estrogen profiling by gas chromatography-mass spectrometry was applied to urine samples from postmenopausal patients with 9 benign tumors and 18 malignant stage I and III/IV PTCs. RESULTS: The urinary concentration of 2-methoxyestradiol was significantly lower in the stage I malignant patients (3.5-fold; P < 0.025) than in the benign group. The metabolic ratios of 16α-OH-estrone/estrone and estriol/estradiol, which are responsible for 16α-hydroxylase activity, were increased more than 2.5-fold in the advanced-stage malignant PTC (P < 0.02 each). The more than 6.2-fold decrease in the urinary 2-/16α-hydroxylase ratio in stage III/IV malignant PTC was consistent with the ratio in postmenopausal patients with endocrine gland cancers. In addition, reductive 17ß-hydroxysteroid dehydrogenase (17ß-HSD; estradiol/estrone or estriol/16α-OH-estrone) was present at significantly higher levels in subjects with stage III/IV malignant PTCs than in benign subjects (>3.5-fold difference; P < 0.002). In particular, the estriol/16α-OH-estrone ratio differentiated between the benign and early-stage malignant patients (P < 0.01). CONCLUSIONS: Increased 16α-hydroxylation and/or a decreased 2-/16α-ratio, as well increased reductive 17ß-HSD, with regard to estrogen metabolism could provide potential biomarkers. The devised profiles could be useful for differentiating malignant thyroid carcinomas from benign adenomas in postmenopausal women.

Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine.

The clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.