Thyroid function spectrum in Cushing's syndrome.

PURPOSE: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing's syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship. METHODS: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS. RESULTS: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies. CONCLUSION: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study.

Impact of Daily Step Count on Diabetes Management and Complications Among Elderly Individuals - Jiangsu Province, China, 2020-2022.

What is already known about this topic?: Current literature underscores the significance of appropriate physical activity in managing diabetes, primarily utilizing self-reported data. Yet, the impact of objectively measured physical activity in older diabetic populations remains unclear. What is added by this report?: Our research on elderly diabetic patients indicated a correlation between an increased number of daily steps and improved metabolic profiles, as well as a decrease in the incidence of cardiovascular complications. What are the implications for public health practice?: Elevated daily step counts may confer significant benefits to elderly individuals with diabetes. The use of devices to monitor these steps could serve as a potent cardiovascular marker, and hold great potential as a screening or intervention tool in community-oriented settings.

Risk factors for at-risk foot and peripheral artery disease among the population with diabetes: A multicommunity-based cross-sectional study.

AIMS: This study aimed to investigate the prevalence, characteristics, and influence factors of the at-risk foot with diabetes mellitus (DM). METHODS: This study included 3030 DM patients from the at-risk foot screening program of Shanghai in China between March 21 and April 30 in 2021. Data were collected from the questionnaire survey, physical examination, and fasting blood sample. RESULTS: The prevalence of at-risk foot was 27.8% among DM patients. After adjusted, the risk of higher at-risk grade increased with age and urinary albumin creatinine ratio (OR = 1.04, 95%CI = 1.02-1.06; OR = 1.001, 95%CI = 1.000-1.002, respectively), whereas decreased with estimated glomerular filtration rate (eGFR) (OR = 0.991, 95%CI = 0.984-0.998). The incidence of peripheral artery disease (PAD) was 11.1% in all people with DM, and age, pulse rate, and low-density lipoprotein were independent risk factors for PAD. In contrast, high-density lipoprotein, eGFR, and lymphocyte-to-monocyte ratio were independent protective factors for PAD. Glycated hemoglobin HbA1c was not an independent risk factor for increased risk grade or more severe PAD. CONCLUSIONS: The at-risk foot accounted for a high percentage among DM patients. Advanced age and renal dysfunction are independent risk factors for the at-risk foot. Glycemic control does not reduce the risk grade of at-risk foot and the incidence of PAD.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies.

BACKGROUND: With the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events. METHODS: A retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month. RESULTS: 28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18-39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up. CONCLUSIONS: IAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus.

Islet ß-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet ß-cell function is beneficial to better management of T2DM. Protecting islet ß-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet ß-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus." This consensus suggests that ß-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet ß-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet ß-cell function, independent of glycemic control.

Diagnostic value of the fractional excretion of urine potassium for primary aldosteronism.

Background: Primary aldosteronism (PA) is a common form of secondary hypertension, which usually manifests low blood potassium levels. The fractional excretion of urine potassium (FEK) has been proposed as a useful tool to measure urinary potassium excretion. However, the role of the FEK in PA remains unclear. In the current study, we assessed the diagnostic value of FEK in PA. Methods: A total of 155 hypertension patients were included in this cross-sectional study, of which 62 were confirmed by a positive screening test for PA. We collected the serum, 24-hr urine samples, and spot urine samples to evaluate the diagnostic value of the spot and 24-hr FEK in the diagnosis of PA and renal potassium loss compared to other indices. The sensitivity and specificity of the related diagnostic indexes were analyzed using receiver operating characteristic (ROC) curves, and the optimal cut-point value of the diagnostic index was determined according to the Youden index (YI) (sensitivity + specificity - 1). Correlation analysis was performed between the spot FEK and 24-hr FEK using Pearson's correlation coefficient. Results: The spot FEK (7.3 vs. 5.9) and 24-hr FEK (9.3 vs. 8.0) levels were statistical differences between the PA and essential hypertension groups. PA patients had a significant tendency to lose potassium through the kidneys. We found that FEK from spot urine distinguished renal potassium loss with a sensitivity of 86.7% and a specificity of 87.1% at a cut-off of 9.8%. The sensitivity and specificity of the spot FEK in screening PA were 51.6% and 76.3%, respectively. Conclusions: FEK is significantly related to renal potassium loss. Spot FEK and 24-hr FEK performed a certain diagnostic value for PA, which may be potential indicators for the differential diagnosis of PA.

Ferroptosis related genes participate in the pathogenesis of spinal cord injury via HIF-1 signaling pathway.

BACKGROUND: Spinal cord injury (SCI) is a crushing disease without a effective and specific therapeutic strategy. Therefore, it is crucial to uncover underlying mechanism in order to identify potential treatments for SCI. Current studies show ferroptosis might pay important role in SCI. METHODS: In this study, we aimed to identify the key ferroptosis-related genes providing therapeutic targets for SCI. GSE45006, GSE19890 and GSE156999 from Gene Expression Omnibus (GEO) database were analyzed. RESULTS: A total of 61 ferroptosis-related DEGs were identified, followed by bioinformatics enrichment analyses and PPI network construction. Ten key ferroptosis-related genes were identified by Cytoscape (Cytohubba), most of which were enriched in the HIF-1 signaling pathway. Then we constructed a clip SCI rat model and qPCR was performed to assess the expressions of five genes enriched in HIF-1 signaling pathway (Stat3, Tlr4, Hmox1, Hif1a and Cybb). Finally, a ceRNA network, Stat3, Tlr4, Hmox1/miR127, miR383, miR485/rno-Mut_0003, rno-Pwwp2a_0002 was constructed and expression of mentioned molecules were validated by chip data. CONCLUSIONS: Five hub genes from HIF-1 signaling pathway were identified and might play a central role in SCI, which indicated that ferroptosis was correlated with HIF-1 signaling pathway. These results can provide a new insight into molecular mechanisms and identify potential therapeutic targets for SCI.

Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy, which is caused by mutations mainly in genes encoding BBSome complex and IFT complex. Here, we reported a 21-year-old female with BBS characterized by three primary features including obesity, retinitis pigmentosa sine pigmento and bilateral renal cysts. She also had some secondary features such as diabetes mellitus, nonalcoholic fatty liver disease, subclinical hypothyroidism and mild conductive hearing damage. Whole exome sequencing revealed two compound heterozygous mutations in exon 2 of the BBS12 gene (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) in this patient. Sanger sequencing showed that her father and mother carried c.188delC (p.T63fs) and c.1993_1995del (p.665_665del) variants, respectively, while her parents were free of BBS-related symptoms. In conclusion, this case reported two novel mutations (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) of the BBS12 gene in a girl presented with BBS, which provides novel genetic resources for studies of the disease. Meanwhile, the BBS case shows the entire development progress from her birth to adulthood, which helps facilitate clinicians' understanding of BBS.

Interaction of Hypertension and Insulin Resistance Exacerbates the Occurrence of Diabetes Mellitus in Healthy Individuals.

Objective: Hypertension and type 2 diabetes are common complications. Patients with hypertension often show insulin resistance. The purpose of this study was to investigate the correlations between different blood pressure levels and different degrees of insulin resistance, as well as their interactions, with newly diagnosed diabetes mellitus. Methods: We conducted a retrospective study on 1251 adult medical examiners who were examined in the Physical Examination Center of Zhongshan Hospital, Fudan University (Shanghai, China) during 2015. All human subjects had no history of diabetes. General clinical data, including blood pressure, fasting glucose and 2-h post-load glucose levels, and lipid profiles, were collected. HOMA-IR was separately calculated. Statistical analyses were carried out by using SPSS software (version 13.0). Results: In 1251 physical examination subjects, a total of 166 cases of newly diagnosed diabetes were detected, with a total detection rate of 13.3%. The rates of newly diagnosed diabetes in the normal blood pressure group, high-normal blood pressure group, and hypertension group were 4.9%, 10.6%, and 19.0%, respectively. Compared with the normal blood pressure group, the proportion of newly diagnosed diabetes in the hypertension group was significantly increased [OR: 2.956, 95% CI 1.736-5.032, P < 0.001]. According to the stratification of HOMA-IR level, with the first quartile group (HOMA-IR<1.21) as a reference, the risk of newly diagnosed diabetes in the fourth quartile group (HOMA-IR ≥2.68) was significantly increased. After adjusting for gender and age, for every unit increase in HOMA-IR, the risk of developing newly diagnosed diabetes increased 9.67 times [OR: 9.670, 95% CI 5.086-18.384, P < 0.001]. When hypertension was combined with insulin resistance (HOMA-IR ≥2.68), the risk of newly diagnosed diabetes was 38.32 times compared with the control group [OR: 38.315, 95% CI 9.227-159.108, P < 0.001]. Conclusions: Elevated blood pressure levels and insulin resistance levels were associated with the risk of newly diagnosed diabetes. Hypertension was an independent risk factor for newly diagnosed diabetes, and the combination of hypertension with insulin resistance further increased the risk of newly diagnosed diabetes.

Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification.

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis.

Genetic Characteristics of Incidental Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are being increasingly discovered by imaging performed for unrelated conditions. The genetic landscape of incidental PPGLs remains to be elucidated. OBJECTIVE: We aimed to describe the genetic characteristics of PPGLs discovered incidentally in a large PPGL cohort. METHODS: This retrospective cross-sectional study included 697 patients with pathology confirmed PPGLs, including 283 incidentalomas and 414 nonincidentalomas, at 2 tertiary care centers in China in 2009-2019. Tumor DNA samples were sequenced by next-generation sequencing. Identified genetic mutations were confirmed by Sanger sequencing and tested in 277 available matched blood DNA samples. RESULTS: There was a lower proportion of patients with mutations identified (53% vs 63.3%; P = 0.0067) in incidental than nonincidental PPGLs. In incidental PPGLs, HRAS (11.7%), FGFR1 (11%), and RET (9.2%) were the top 3 mutated genes, whereas HRAS (17.9%), VHL (9.2%), and NF-1 (8.7%) exhibited the highest rate of mutations in nonincidental PPGLs. In incidental pheochromocytomas, the most frequently mutated genes were RET (10.9%), HRAS (10.4%), and VHL (8.6%), while in incidental paragangliomas, FGFR1 (32.8%), HRAS (16.4%), and EPAS1 (9.8%) topped the list. The frequency of NF-1 mutations was significantly lower in incidental than nonincidental pheochromocytomas (4.1% vs 11%; P = 0.0042), while FGFR1 mutations were far more common in incidental than nonincidental paragangliomas (32.8% vs 15.3%; P = 0.0076). CONCLUSION: More than half of patients with incidental PPGLs had mutations in common susceptibility genes. The search for susceptibility genes should take both the mode of discovery (incidental vs nonincidental) and tumor location (pheochromocytoma vs paraganglioma) into consideration.

Mass spectrometry-based cortisol profiling during adrenal venous sampling reveals misdiagnosis for subtyping primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is a common form of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for subtyping PA. This study aimed to determine whether there is a difference between immunoassays and liquid chromatography-mass spectrometry (LC-MS/MS) methods for measuring cortisol levels that affect the judgement of AVS. DESIGN: This was a retrospective study. PATIENTS: Included 72 patients who were diagnosed with PA and had undergone AVS. MEASUREMENTS: Patients were grouped according to whether they received adrenocorticotropic hormone (ACTH) stimulation during AVS, and the cortisol results were measured using immunoassay and LC-MS/MS. RESULTS: There were 48 patients in the without ACTH stimulation group and 24 in the post-ACTH stimulation group during AVS (bilateral adrenal vein cannulation success rate, 56.25% vs. 83.33%). ACTH stimulation was beneficial for increasing the success rate of AVS (p < .001). Immunoassays were linearly correlated with LC-MS/MS when cortisol concentrations were <1750 nmol/L (r = .959, p < .001). When cortisol concentrations were >17,500 nmol/L, no correlation was found between the two methods (p = .093). The two methods were consistent for the detection of cortisol for evaluating the success of cannulation for AVS. Five percent of patients showed discordant lateralization of aldosterone production according to the cortisol LC-MS/MS and immunoassay results in the without ACTH group, and 15% showed discordant lateralization in the post-ACTH group. CONCLUSIONS: The immunoassay method can be used to determine whether cannulation is successful. The final decision for lateralization may be more appropriate based on LC-MS/MS results.

Association between Neutrophilic Granulocyte Percentage and Diabetes Mellitus in Cushing's Syndrome Patients: A Cross-Sectional Study.

BACKGROUND: Glucose metabolism is frequently impaired in patients with Cushing's syndrome (CS) due to chronic exposure to excess glucocorticoids. Inflammation plays an essential role in the pathophysiology of diabetes mellitus (DM). The present study aimed to investigate the potential associations of inflammatory blood cell parameters, including white blood cell (WBC) count, neutrophil count, neutrophilic granulocyte percentage (NEUT%), lymphocyte count (LYM), and lymphocyte proportion (LYM%), with diabetes mellitus in Cushing's syndrome patients. MATERIALS AND METHODS: The cross-sectional study was conducted in Zhongshan Hospital of Fudan University, China. A total of 150 patients with Cushing's syndrome were retrospectively screened from 2017 to 2019. The demographic data, clinical data, and blood samples (lipids, adrenal, glucose, and inflammatory blood cell parameters) were recorded. Statistical analyses were carried out by using the SPSS software package, version 13.0. RESULTS: In this study, the prevalence of diabetes mellitus was 38.7% in patients with Cushing's syndrome. Patients with DM had higher WBC, neutrophil, NEUT% levels than patients without DM (p < 0.05). As the NEUT% increased, a stepwise increase in glucose and glycated hemoglobin (HbA1c) level was observed. In addition, in the multivariate logistic regression, NEUT% was a significant independent risk factor for DM, regardless of gender, age, body mass index (BMI), and triglyceride and 12 midnight cortisol (12 MN cortisol) level (OR = 2.542, 95% CI 1.337-4.835, p < 0.001). CONCLUSIONS: In conclusion, elevated NEUT% level was linked to diabetes in patients with Cushing's syndrome. The neutrophilic granulocyte percentage may be referred to as a new predictor for diabetes in Cushing's syndrome patients.

p53 Inhibition Protects against Neuronal Ischemia/Reperfusion Injury by the p53/PRAS40/mTOR Pathway.

The underlying mechanisms of cerebral ischemia/reperfusion (I/R) injury are unclear. Within this study, we aimed to explore whether p53 inhibition exerts protective effects via the p53/PRAS40/mTOR pathway after stroke and its potential mechanism. Both an in vitro oxygen-glucose deprivation (OGD) model with a primary neuronal culture and in vivo stroke models (dMCAO or MCAO) were used. We found that the infarction size, neuronal apoptosis, and autophagy were less severe in p53 KO mice and p53 KO neurons after cerebral I/R or OGD/R injury. By activating the mTOR pathway, p53 knockdown alleviated cerebral I/R injury both in vitro and in vivo. When PRAS40 was knocked out, the regulatory effects of p53 overexpression or knockdown against stroke disappeared. PRAS40 knockdown could inhibit the activities of the mTOR pathway; moreover, neuronal autophagy and apoptosis were exacerbated by PRAS40 knockdown. To sum up, in this study, we showed p53 inhibition protects against neuronal I/R injury after stroke via the p53/PRAS40/mTOR pathway, which is a novel and pivotal cerebral ischemic injury signaling pathway. The induction of neuronal autophagy and apoptosis by the p53/PRAS40/mTOR pathway may be the potential mechanism of this protective effect.

Triglycerides to High-Density Lipoprotein Cholesterol Ratio Is the Best Surrogate Marker for Insulin Resistance in Nonobese Middle-Aged and Elderly Population: A Cross-Sectional Study.

OBJECTIVE: Insulin resistance (IR) is closely associated with metabolic profiles, including obesity and dyslipidemia. The aim of the present study was to examine how lipid profiles were associated with IR in nonobese middle-aged and elderly Chinese population. METHODS: This cross-sectional study included 1608 subjects. IR was defined by homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5. RESULTS: In nonobese subjects (body mass index (BMI) < 25 kg/m2, n = 996), triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (odds ratio (OR) = 1.43, 95% confidence interval (CI) 1.13-1.81, P=0.003) was an independent risk factor for IR. The best marker for predicting IR in nonobese subjects was TG/HDL-C ratio with the areas under the receiver operating characteristic curves (AUC) of 0.73 (P < 0.001). The optimal cut-off point to identifying IR for TG/HDL-C ratio was ≥1.50 in the nonobese population. Other markers like BMI, TG, and total cholesterol (TC)/HDL-C also had acceptable discriminatory power for predicting IR in nonobese population (AUC ≥ 0.7 and P < 0.001). BMI had the highest AUC of 0.647 (P < 0.001) after being adjusted, but it was not effective enough to predict IR in obese subjects (BMI ≥ 25.0, n = 612). CONCLUSIONS: The TG/HDL-C ratio may be the best reliable marker for predicting IR in the nonobese middle-aged and elderly Chinese population.

Preoperative prognostic nomogram for prophylactic steroid treatment of patients with subclinical Cushing's syndrome.

BACKGROUND: Subclinical Cushing's syndrome (SCS) is incidentally detected in a growing number of patients by advanced imaging technology. However, there is no consensus on the clinical management of SCS, especially in terms of whether prophylactic steroid treatment is necessary following adrenalectomy. In this study we developed a model based on preoperative indices for predicting postoperative adrenal insufficiency (AI) that can guide therapeutic decision-making. METHODS: A total of 27 patients with SCS who underwent adrenalectomy between August 2016 and August 2019 were enrolled and divided into AI and non-AI groups. Cox proportional hazards regression and least absolute shrinkage and selection operator analyses were performed to select relevant clinical parameters. The predictive performance of our model was evaluated by time-dependent receiver operating characteristic (ROC) curve and calibration curve analyses. RESULTS: Five clinical parameters (apolipoprotein A1, neutrophil-lymphocyte ratio, total cholesterol, platelet count, and homocysteine) were identified as the best predictors of replacement therapy (RT). The areas under the ROC curve for our prognostic model were 0.833, 0.945, and 0.967 for 3-, 4-, and 5-day non-(N)RT, respectively. The calibration curve of the 5 independent RT-related markers showed a good fit between nomogram-predicted probability of NRT and actual NRT, suggesting that our model has good predictive value. CONCLUSIONS: Our prognostic nomogram can help clinicians identify patients with AI who would benefit from RT so that timely treatment can be initiated. KEYWORDS: Subclinical Cushing's syndrome (SCS); Replacement therapy (RT); Adrenal insufficiency (AI); Nomogram; Receiver operating characteristic (ROC).

Thyroid function and non-alcoholic fatty liver disease in hyperthyroidism patients.

BACKGROUND: Although thyroid function has been demonstrated to be associated with non-alcoholic fatty liver disease (NAFLD) in different population, the prevalence and features of NAFLD in hyperthyroidism have not been reported. The present study aims to investigate the prevalence of NAFLD and association of thyroid function and NAFLD in hyperthyroidism patients. METHODS: This cross-sectional study was performed in Zhongshan Hospital, Fudan University, China. A total 117 patients with hyperthyroidism were consecutively recruited from 2014 to 2015. Thyroid function and other clinical features were measured, liver fat content was measured by color Doppler ultrasonically, NAFLD was defined in patients with liver fat content more than 9.15%. Statistical analyses were performed with SPSS software package version 13.0. RESULTS: The prevalence of NAFLD was 11.97% in hyperthyroidism. Patient with NAFLD had lower free triiodothyronine (FT3) and free thyroxine (FT4) levels than patients without NAFLD (P < 0.05). After adjusting for age, gender, metabolic parameters and inflammation factors, higher FT3 were associated with lower liver fat content (ß = - 0.072, P = 0.009) and decreased odds ratio of NAFLD (OR = 0.267, 95%CI 0.087-0.817, P = 0.021). CONCLUSIONS: FT3 level was negatively associated with the liver fat content in this population. These results may provide new evidence in the role of thyroid hormone on the regulation of liver fat content and NAFLD.

Co-Existence of Sarcoidosis and Sjögren's Syndrome with Hypercalcemia and Renal Involvement: A Case Report and Literature Review.

BACKGROUND: Sarcoidosis and Sjögren's syndrome (SS) are chronic multi-system inflammatory diseases of unknown origin that most commonly attack the salivary glands. Both of the diseases have vague and non-specific symptoms, causing difficulties for the clinicians to distinguish between the two diseases. Main diagnostic criteria of SS exclude sarcoidosis. However, a co-existence of both diseases should be noted. Here, a case of co-existing sarcoidosis and Sjögren's syndrome is reported, complicated with severe hypercalcemia and renal failure, in addition to a literature review. CASE PRESENTATION: A 71-year-old man visited our hospital complaining of daily progressive oral dryness, thirst, and blurred vision with a feeling of dry eyes for a one-year duration. His physical examination showed enlargement of both sides of cervical and supraclavicular lymph nodes. Lung auscultation showed decreased breath sounds with bibasilar inspiratory crackles. However, initial laboratory results revealed severe hypercalcemia with moderate hypercalciuria and renal failure. The final diagnosis was co-existing SS and sarcoidosis according to clinical, radiological, and laboratory data. The patient received oral prednisone therapy for 18 months. After a follow-up of years, the serum calcium concentration, renal function, and chest CT scan remained normal after prednisone treatment stopped for more than 18 months. CONCLUSION: In the literature, calcium metabolic disorder and renal involvement have not been reported among patients with Sarcoidosis and Sjögren's syndrome, suggesting that calcium metabolic disorder may be underestimated. Serum and urine calcium concentration should be measured in addition to routine laboratory tests.

The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic ß-cells.

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in ß-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic ß-cells. ß-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic ß-cells.

Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway.

The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1α staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1α activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1α and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway.