M2 macrophage infusion ameliorates diabetic glomerulopathy via the JAK2/STAT3 pathway in db/db mice.

Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1ß (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.

Exosomes derived from umbilical cord-derived mesenchymal stem cells exposed to diabetic microenvironment enhance M2 macrophage polarization and protect against diabetic nephropathy.

The role of mesenchymal-stem-cell-derived exosomes (MSCs-Exo) in the regulation of macrophage polarization has been recognized in several diseases. There is emerging evidence that MSCs-Exo partially prevent the progression of diabetic nephropathy (DN). This study aimed to investigate whether exosomes secreted by MSCs pre-treated with a diabetic environment (Exo-pre) have a more pronounced protective effect against DN by regulating the balance of macrophages. Exo-pre and Exo-Con were isolated from the culture medium of UC-MSCs pre-treated with a diabetic mimic environment and natural UC-MSCs, respectively. Exo-pre and Exo-Con were injected into the tail veins of db/db mice three times a week for 6 weeks. Serum creatinine and serum urea nitrogen levels, the urinary protein/creatinine ratio, and histological staining were used to determine renal function and morphology. Macrophage phenotypes were analyzed by immunofluorescence, western blotting, and quantitative reverse transcription polymerase chain reaction. In vitro, lipopolysaccharide-induced M1 macrophages were incubated separately with Exo-Con and Exo-pre. We performed microRNA (miRNA) sequencing to identify candidate miRNAs and predict their target genes. An miRNA inhibitor was used to confirm the role of miRNAs in macrophage modulation. Exo-pre were more potent than Exo-Con at alleviating DN. Exo-pre administration significantly reduced the number of M1 macrophages and increased the number of M2 macrophages in the kidney compared to Exo-Con administration. Parallel outcomes were observed in the co-culture experiments. Moreover, miR-486-5p was distinctly expressed in Exo-Con and Exo-pre groups, and it played an important role in macrophage polarization by targeting PIK3R1 through the PI3K/Akt pathway. Reducing miR-486-5p levels in Exo-pre abolished macrophage polarization modulation. Exo-pre administration exhibited a superior effect on DN by remodeling the macrophage balance by shuttling miR-486-5p, which targets PIK3R1.

Comparing the accuracy of four machine learning models in predicting type 2 diabetes onset within the Chinese population: a retrospective study.

OBJECTIVE: To evaluate the effectiveness of machine learning (ML) models in predicting 5-year type 2 diabetes mellitus (T2DM) risk within the Chinese population by retrospectively analyzing annual health checkup records. METHODS: We included 46,247 patients (32,372 and 13,875 in training and validation sets, respectively) from a national health checkup center database. Univariate and multivariate Cox analyses were performed to identify factors influencing T2DM risk. Extreme Gradient Boosting (XGBoost), support vector machine (SVM), logistic regression (LR), and random forest (RF) models were trained to predict 5-year T2DM risk. Model performances were analyzed using receiver operating characteristic (ROC) curves for discrimination and calibration plots for prediction accuracy. RESULTS: Key variables included fasting plasma glucose, age, and sedentary time. The LR model showed good accuracy with respective areas under the ROC (AUCs) of 0.914 and 0.913 in training and validation sets; the RF model exhibited favorable AUCs of 0.998 and 0.838. In calibration analysis, the LR model displayed good fit for low-risk patients; the RF model exhibited satisfactory fit for low- and high-risk patients. CONCLUSIONS: LR and RF models can effectively predict T2DM risk in the Chinese population. These models may help identify high-risk patients and guide interventions to prevent complications and disabilities.

[Comparison of Different Doses of ACTH Used in ACTH Stimulation Test to Determine the Subtypes of Primary Aldosteronism]. / ä¸åŒå‰‚é‡ä¿ƒè‚¾ä¸Šè ºçš®è´¨æ¿€ç´ å ´å¥‹è¯•éªŒåœ¨åŽŸå‘æ€§é†›å›ºé ®å¢žå¤šç—‡åˆ†åž‹è¯Šæ–­ä¸­çš„æ¯”è¾ƒ.

Objective: To compare the diagnostic value of adrenocorticotropic hormone (ACTH) stimulation test (AST) with different doses of ACTH combined with midnight administration of 1 mg dexamethasone for the determination of the subtypes of primary hyperaldosteronism (PA). Methods: This is a prospective observational study. Patients diagnosed with PA in the Department of Endocrinology, the First Medical Center of of Chinese PLA General Hospital from January 1, 2020 to September 30, 2022 underwent AST with different doses of ACTH. All patients received 1 mg dexamethasone at midnight for inhibition. Then, the patients were randomly assigned to 25-unit and 50-unit ACTH treatment groups by a ratio of 1:2. Subtype classification and diagnosis of aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) was made on the basis of adrenal venous blood samples and/or postoperative pathology and clinical follow-up findings. Receiver operating characteristics (ROC) curves were plotted to examine the diagnostic efficacy and the difference of AST by varying doses of ACTH in distinguishing APA and IHA. Results: A total of 82 patients, including 49 patients with APA (59.8%) and 33 patients with IHA (40.2%), were enrolled. There were 29 patients in the 25-unit ACTH group (35.4%) and 53 patients in the 50-unit ACTH group (64.6%). There were no significant differences in age, sex, blood pressure, minimum serum potassium, and biochemical parameters between the 25-unit and 50-unit groups. After ACTH stimulation, plasma aldosterone concentration (PAC), cortisol (F), and PAC/F at different points of time showed no statistical difference between the two groups (P>0.05). The area under the curve (AUC) of PAC in the 25-unit group was higher than that of PAC/F. The AUC of PAC reached the maximum at 90 minutes (0.948, 95% confidence interval [CI]: 0870-1.000) and the optimal cutoff was 38.0 ng/dL, which had a sensitivity of 92.9% and a specificity of 86.7% for differentiating APA and IHA. Similar to the 25-unit group, the maximum AUC of PAC in the 50-unit group was greater than that of PAC/F. The AUC of PAC reached the maximum 90 minutes (0.930, 95% CI: 0.840-0.994) and the optimal cutoff was 39.6 ng/dL, which had a sensitivity of 91.2% and a specificity of 83.3%. The AUC of PAC at different points of time in the 25-unit ACTH group (0.862-0.948) was greater than that of 50-unit ACTH group (0.823-0.930), but the difference was not statistical significance. Conclusion: AST with 25-unit or 50-unit ACTH combined with small-dose dexamethasone can be used in PA subtype determination, ie, differentiation between APA and IHA. The optimal PAC cut-off values for 25-unit or 50-unit ACTH are similar, being 38.0 ng/dL and 39.6 ng/dL, respectively, and both cutoff values show higher sensitivity and specificity at 90 min. The AST with 25-unit ACTH has the smaller dose and the better safety. Therefore, it is recommended for the diagnosis of PA subtypes.

The phenotype and related gene expressions of macrophages in adipose tissue of T2D mice following MSCs infusion.

BACKGROUND: Infusion of mesenchymal stem cells (MSCs) induces polarization of M2 macrophages in adipose tissue of type 2 diabetes (T2D) mice. Studies have shown that M2 macrophages were divided into four sub-phenotypes (M2a, M2b, M2c and M2d) with different functions, and manuscripts have also confirmed that macrophages co-cultured with MSCs were not matched with known four phenotype macrophages. Therefore, our study explored the phenotype and related gene expressions of macrophages in the adipose tissue of T2D mice with/without MSCs infusion. METHODS: We induced a T2D mouse model by using high-fat diets and streptozotocin (STZ) injection. The mice were divided into three groups: the control group, the T2D group, and the MSCs group. MSCs were systemically injected once a week for 6 weeks. The phenotype of macrophages in adipose tissue was detected via flow cytometric analysis. We also investigated the gene expression of macrophages in different groups via SMART-RNA-sequencing and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The present study found that the macrophages of adipose tissue in the MSCs group were polarized to the M2 phenotype mixed with four sub-phenotypes. Besides, M2a and M2c held a dominant position, while M2b and M2d (tumor-associated macrophages, TAMs) exhibited a decreasing trend after infusion of MSCs. Moreover, the MSCs group did not appear to express higher levels of tumor-associated, inflammation-associated, or fibrosis-associated genes in comparison to the T2D group. CONCLUSION: The present results unveiled that the macrophage phenotype was inclined to be present in a hybridity state of four M2 sub-phenotypes and the genes related to tumor-promoting, pro-inflammation and pro-fibrosis were not increased after MSCs injection.

Predictive factors that influence the clinical efficacy of umbilical cord-derived mesenchymal stromal cells in the treatment of type 2 diabetes mellitus.

BACKGROUND: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.

Efficacy of Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Type 2 Diabetes Assessed by Retrospective Continuous Glucose Monitoring.

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been proved a promising clinical strategy for the treatment of diabetes, and time in range (TIR) has been demonstrated a new metric of glycemic control links to diabetes complications. To further assess the therapeutic effect of UC-MSCs on TIR, a phase II study investigating the efficacy of UC-MSCs in Chinese adults with type 2 diabetes (T2D) assessed by retrospective continuous glucose monitoring (CGM) was conducted. In this randomized and placebo-controlled trial, a total of 73 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 37) or placebo (n = 36) 3 times at 4-week intervals and followed up for 48 weeks. The primary endpoint was the changes in TIR and glycosylated hemoglobin (HbA1c). TIR and HbA1c were both significantly improved in UC-MSCs and placebo groups after 48 weeks of therapy compared with baseline. Compared with placebo group, UC-MSCs group exhibited more pronounced changes at 9 and 48 weeks from baseline in TIR (26.54 vs. 15.84 and 21.36 vs. 6.32) and HbA1c (-1.79 vs. -0.96 and -1.36 vs. -0.51). More patients in UC-MSCs group achieved the glycemic control target of TIR ≥ 70% and HbA1c < 7% at 9 and 48 weeks than in placebo group (59.5% vs. 27.8% and 43.2% vs. 11.1%). The C-peptide area under the curve (AUCC-pep) was an independent risk factor associated with efficacy in T2D undergoing UC-MSCs intervention. These results illustrate that UC-MSCs administration via intravenous infusion is an effective approach for ameliorating TIR.

Prevalence of obesity and associated complications in China: A cross-sectional, real-world study in 15.8 million adults.

AIM: To evaluate the prevalence of overweight/obesity and associated complications from a large, cross-sectional, nationwide database in China. MATERIALS AND METHODS: Data were obtained from 519 Meinian health check-up centres across 243 cities. Eligible participants were aged ≥18 years, with a routine check-up in 2019 (N = 21 771 683) and complete height, weight, sex and region data. The unadjusted prevalence rates of overweight/obesity were calculated by age, sex and region. In addition, the nationwide prevalence rates of overweight and obesity were standardized according to the 2010 China census by age group and sex. The prevalence of obesity-related complications by body mass index (BMI) groups was calculated using logistic regression. RESULTS: There were 15 770 094 eligible participants (median age 40 years; mean BMI 24.1 kg/m2 ; 52.8% male). By Chinese BMI classification, 34.8% were overweight and 14.1% were obese. Overweight and obesity were more prevalent in male than female participants (standardized: overweight 40.2% vs. 27.4%; obesity 17.6% vs. 9.6%, respectively). The prevalence of assessed complications was higher in participants with overweight/obesity versus those with normal BMI (P < 0.001 for trends). The most prevalent complications in participants with overweight/obesity were fatty liver disease, prediabetes, dyslipidaemia and hypertension. The number of complications increased with higher BMI. CONCLUSIONS: Overweight/obesity and related complications are highly prevalent in this population. These data may better inform management and prevention public health strategies in China.

The association between brachial-ankle pulse-wave velocity and adverse cardiovascular events in 5719 community participants a prospective cohort study.

BACKGROUND: The brachial-ankle pulse-wave velocity (baPWV) is regarded as the gold standard in the evaluation of arterial stiffness. Its prognostic significance for major adverse cardiovascular events (MACE) has been demonstrated. However, the factors influencing the association between baPWV and MACE risk have not been determined. In this study, we investigated the association of baPWV and MACE risk and whether it is affected by the risk factors for different cardiovascular diseases (CVDs). METHODS: This was a prospective cohort study that initially enrolled 6850 participants from 12 communities in Beijing. The participants were divided into three subgroups according to their baPWV values. The primary outcome was the first occurrence of MACE, defined as hospitalization from cardiovascular diseases, first occurrence of a nonfatal myocardial infarction, or nonfatal stroke. Cox proportional hazards regression and restricted cubic spline analyses were used to examine the association between baPWV and MACE. The effect of CVD risk factors on the relationship between baPWV and MACE was explored in subgroup analyses. RESULTS: The final study population consisted of 5719 participants. During a median follow-up of 34.73 months, MACE occurred in 169 participants. The restricted cubic spline analysis indicated a positive linear relationship between baPWV and MACE risk. After adjustment for cardiovascular risk factors, the hazard ratio (HR) for MACE risk per SD increase in baPWV was 1.272 [95% confidence interval (CI): 1.149-1.407, P  < 0.001], and the HR for MACE in the high-baPWV vs. the low-baPWV group was 1.965 (95% CI: 1.296-2.979, P  = 0.001). Adding baPWV to the conventional cardiovascular risk factors significantly improved the model's prediction performance and the net reclassification (NRI) [NRI: 0.379 (95% CI: 0.072-0.710), P  = 0.025] in MACE discrimination. However, in the subgroup analysis, two CVD risk factors, stable coronary heart disease and hypertension, showed significant interaction effects ( Pinteraction both < 0.05). This result indicated that the effect of CVD risk factors must be taken into account when assessing the relationship between baPWV and MACE. CONCLUSION: baPWV is a potential marker to improve the identification of MACE risk in the general population. A positive linear correlation was firstly determined between baPWV and MACE risk, but it may not be valid in participants with stable coronary heart disease and hypertension.

Association between hemoglobin glycation index and 5-year major adverse cardiovascular events: the REACTION cohort study.

BACKGROUND: The hemoglobin glycation index (HGI) was developed to quantify glucose metabolism and individual differences and proved to be a robust measure of individual glycosylated hemoglobin (HbA1c) bias. Here, we aimed to explore the relationship between different HGIs and the risk of 5-year major adverse cardiovascular events (MACEs) by performing a large multicenter cohort study in China. METHODS: A total of 9791 subjects from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a Longitudinal Study (the REACTION study) were divided into five subgroups (Q1-Q5) with the HGI quantiles (≤5th, >5th and ≤33.3th, >33.3th and ≤66.7th, >66.7th and ≤95th, and >95th percentile). A multivariate logistic regression model constructed by the restricted cubic spline method was used to evaluate the relationship between the HGI and the 5-year MACE risk. Subgroup analysis between the HGI and covariates were explored to detect differences among the five subgroups. RESULTS: The total 5-year MACE rate in the nationwide cohort was 6.87% (673/9791). Restricted cubic spline analysis suggested a U-shaped correlation between the HGI values and MACE risk after adjustment for cardiovascular risk factors ( χ2 = 29.5, P <0.001). After adjustment for potential confounders, subjects with HGIs ≤-0.75 or >0.82 showed odds ratios (ORs) for MACE of 1.471 (95% confidence interval [CI], 1.027-2.069) and 2.222 (95% CI, 1.641-3.026) compared to subjects with HGIs of >-0.75 and ≤-0.20. In the subgroup with non-coronary heart disease, the risk of MACE was significantly higher in subjects with HGIs ≤-0.75 (OR, 1.540 [1.039-2.234]; P = 0.027) and >0.82 (OR, 2.022 [1.392-2.890]; P <0.001) compared to those with HGIs of ≤-0.75 or >0.82 after adjustment for potential confounders. CONCLUSIONS: We found a U-shaped correlation between the HGI values and the risk of 5-year MACE. Both low and high HGIs were associated with an increased risk of MACE. Therefore, the HGI may predict the 5-year MACE risk.

Analysis of characteristics of four patients with adrenal unicentric Castleman disease.

Background: Castleman Disease (CD) is a group of diseases with characteristic lymph node histopathology, characterized by marked enlargement of deep or superficial lymph nodes. Adrenal CD is rarely reported, and an accurate preoperative diagnosis of adrenal CD is difficult. Method: We report four cases of CD in the adrenal gland confirmed by pathology and review the characteristics of this rare disease, highlighting the necessity of diagnostic evaluation and follow-up of the patients. Results: All of the patients sought medical advice because of adrenal incidentalomas. No significant abnormalities were presented in the biochemistry or endocrine systems. The imaging suggested a moderate-to-large mass with uneven moderate contrast enhancement of the adrenal region, similar to a pheochromocytoma. All cases were misdiagnosed as pheochromocytomas before operation and finally confirmed by histopathology. Three cases were pathologically diagnosed as hyaline vascular CD, and one case was diagnosed as plasma cell CD. All the patients are alive without recurrence after a median follow-up of 8 years. Conclusion: The adrenal CD should be considered after excluding pheochromocytoma and malignancy in the adrenal region. The long-term prognosis of patients with complete resection of the mass is excellent.

Analysis of clinical features and 7-year all-cause mortality in older male patients with non-thyroidal illness syndrome on general wards.

PURPOSE: Older patients with non-thyroidal illness syndrome (NTIS) have a poor prognosis. However, there are few studies on the association of NTIS and mortality among older inpatients on general wards. In a 7-year retrospective observational study, we aimed to investigate the clinical features of NTIS and the association of NTIS and all-cause mortality in older inpatients. METHODS: A total of 959 older male inpatients whose average age was 86.3 ± 8.1 years were enrolled and divided into the NTIS group and non-NTIS group. Cox models were performed to explore the association of thyroid hormone level and mortality. RESULTS: Patients had more respiratory disease and chronic kidney disease in the NTIS than in the non-NTIS group, especially in primary nursing care, respiratory failure and haemodialysis patients; serum total protein, albumin, prealbumin, haemoglobin, uric acid and high-density lipoprotein cholesterol levels were lower, and urea nitrogen and fasting blood glucose levels were higher, in the NTIS than in the non-NTIS group. Patients in the NTIS group had a lower survival rate over 7 years follow-up (P < 0.01). A lower free T3 level was associated with all-cause mortality with a HR of 1.50 (1.36, 1.66). Lower free T4 level was associated with reduced all-cause mortality with a HR of 0.91 (0.88, 0.94) even after adjusting for confounding factors (P < 0.01). CONCLUSIONS: Among older male inpatients, the survival rate was lower in the NTIS group. A reduced free T3 level with low albumin and Hb levels was associated with all-cause mortality; moreover, a higher free T4 in the normal range may be a strong predictor for long-term mortality risk in hospitalised older male patients.

Nomogram for Predicting Intraoperative Hemodynamic Instability in Patients With Normotensive Pheochromocytoma.

CONTEXT: Intraoperative hemodynamic instability (HI) deteriorates surgical outcomes of patients with normotensive pheochromocytoma (NP). OBJECTIVE: To characterize the hemodynamics of NP and develop and externally validate a prediction model for intraoperative HI. METHODS: Data on 117 patients with NP (derivation cohort) and 40 patients with normotensive adrenal myelolipoma (NAM) who underwent laparoscopic adrenalectomy from January 2011 to November 2021 were retrospectively collected. Data on 22 patients with NP (independent validation cohort) were collected from another hospital during the same period. The hemodynamic characteristics of patients with NP and NAM were compared. Machine learning models were used to identify risk factors associated with HI. The final model was visualized via a nomogram. RESULTS: Forty-eight (41%) out of 117 patients experienced HI, which was significantly more than that for NAM. A multivariate logistic regression including age, tumor size, fasting plasma glucose, and preoperative systolic blood pressure showed good discrimination measured by area under curve (0.8286; 95% CI 0.6875-0.9696 and 0.7667; 95% CI 0.5386-0.9947) for predicting HI in internal and independent validation cohorts, respectively. The sensitivities and positive predictive values were 0.6667 and 0.7692 for the internal and 0.9167 and 0.6111 for the independent validations, respectively. The final model was visualized via a nomogram and yielded net benefits across a wide range of risk thresholds in decision curve analysis. CONCLUSION: Patients with NP experienced HI during laparoscopic adrenalectomy. The nomogram can be used for individualized prediction of intraoperative HI in patients with NP.

The Inverse Association of Serum Magnesium with Papillary Thyroid Cancer in Thyroid Nodules: a Cross-Sectional Survey Based on Thyroidectomy Population.

Magnesium is considered to play a role in preventing cancer. However, the association between serum magnesium and papillary thyroid cancer (PTC) remains unknown. We retrospectively reviewed records of all patients who underwent thyroidectomy with thyroid nodules confirmed pathologically as benign nodule or PTC at our institution from January 2016 to December 2020. Data including demographic characteristics, laboratory tests, and pathological features were analyzed in 5709 adult patients eventually. The subjects with benign nodules had a higher mean serum magnesium level than those with PTC (P < 0.001), and the proportions of PTCs decreased across quartiles of serum magnesium within the normal range. After adjustment for confounders, patients with the lowest quartile of serum magnesium had a higher prevalence of PTC than those with the highest quartile (OR = 1.421, 95%CI: 1.125-1.795, P for trend = 0.005), and the risk of PTC was 0.863 (95%CI: 0.795-0.936) for a per-SD change in serum magnesium. The contribution of serum magnesium remained in subgroup analysis (P for interaction for all analyses > 0.05). Based on the ROC curve, the cut-off value of serum magnesium used to differentiate benign nodules from PTCs was 935 µmol/L. Combining serum magnesium with other clinical indicators can improve the efficacy of predicting PTC. Our results showed that lower serum magnesium within the normal range was associated with a greater risk of PTC among patients with thyroid nodules considering thyroidectomy. Serum magnesium may be an independent protective factor against PTC and provide additional information on the odds of malignancy in uncertain thyroid nodules in combination with other clinical factors.

The first compound heterozygous mutations in SLC12A3 and PDX1 genes: a unique presentation of Gitelman syndrome with distinct insulin resistance and familial diabetes insights.

Background: Gitelman Syndrome (GS) patients frequently exhibit disrupted glucose metabolism, attributed to hypokalemia, hypomagnesemia and heightened aldosterone. This study delved into the genetic underpinnings linked to insulin resistance and diabetes in a GS patient, contextualized within his family history. Methods: The hydrochlorothiazide and furosemide loading test were performed to ascertain the presence of GS. Oral glucose tolerance test (OGTT) evaluated glucose metabolism and insulin sensitivity. Whole-exome sequencing, validated by Sanger sequencing, was employed to confirm gene mutations, which were then tracked among the patient's relatives. Results: Symptoms and laboratory examination confirmed the clinical diagnosis of GS. Comprehensive whole-exome sequencing, augmented by Sanger sequencing validation, revealed a compound heterozygous mutation within the SLC12A3 gene (c.1108G>C in exon 9, c.676G>A in exon 5 and c.2398G>A in exon 20) in the patient. The OGTT affirmed diabetes and heightened insulin resistance, distinct from previous patients with GS we evaluated. Further genetic analysis identified a missense heterozygous mutation (c.97C>G in exon 1) within the PDX1 gene, inherited from the patient's diabetic mother without GS. Furthermore, the patient's brother, with impaired glucose tolerance but regular potassium levels, also bore this mutation, hinting at additional impacts of the PDX1 gene mutation on glucose metabolism regulation beyond the known impacts of GS. Conclusion: This study unveils unprecedented compound heterozygous mutations in the SLC12A3 and PDX1 genes in a GS patient. These findings illuminate the potential complex genetic factors influencing glucose metabolism disruptions in GS. Take-home message: This research uncovers a novel combination of SLC12A3 and PDX1 gene mutations in a Gitelman Syndrome patient, revealing intricate genetic factors that potentially disrupt glucose metabolism and shedding light on familial diabetes links.

Development and validation of a new predictive model for macrosomia at late-term pregnancy: A prospective study.

Objective: Fetal macrosomia is defined as a birth weight more than 4,000 g and is associated with maternal and fetal complications. This early metabolic disease may influence the entire life of the infant. Currently, macrosomia is predicted by using the estimated fetal weight (EFW). However, the EFW is inaccurate when the gestational week is gradually increasing. To assess precisely the risk of macrosomia, we developed a new predictive model to estimate the risk of macrosomia. Methods: We continuously collected data on 655 subjects who attended regular antenatal visits and delivered at the Second Hospital of Hebei Medical University (Shijiazhuang, China) from November 2020 to September 2021. A total of 17 maternal features and 2 fetal ultrasonographic features were included at late-term pregnancy. The 655 subjects were divided into a model training set and an internal validation set. Then, 450 pregnant women were recruited from Handan Central Hospital (Handan, China) from November 2021 to March 2022 as the external validation set. The least absolute shrinkage and selection operator method was used to select the most appropriate predictive features and optimize them via 10-fold cross-validation. The multivariate logistical regressions were used to build the predictive model. Receiver operating characteristic (ROC) curves, C-indices, and calibration plots were obtained to assess model discrimination and accuracy. The model's clinical utility was evaluated via decision curve analysis (DCA). Results: Four predictors were finally included to develop this new model: prepregnancy obesity (prepregnancy body mass index ≥ 30 kg/m2), hypertriglyceridemia, gestational diabetes mellitus, and fetal abdominal circumference. This model afforded moderate predictive power [area under the ROC curve 0.788 (95% confidence interval [CI] 0.736, 0.840) for the training set, 0.819 (95% CI 0.744,0.894) for the internal validation set, and 0.773 (95% CI 0.713,0.833) for the external validation set]. On DCA, the model evidenced a good fit with, and positive net benefits for, both the internal and external validation sets. Conclusions: We developed a predictive model for macrosomia and performed external validation in other regions to further prove the discrimination and accuracy of this predictive model. This novel model will aid clinicians in easily identifying those at high risk of macrosomia and assist obstetricians to plan accordingly.

Parathyroid carcinoma: Report of 10 patients and literature review.

OBJECTIVE: Parathyroid carcinoma (PC) is a rare disease with high rates of misdiagnosis and recurrence. This report summarized the clinical and pathological characteristics of 10 patients with PC at our hospital, to improve the early recognition and prognosis of PC. METHODS: The clinical manifestations, imaging findings, pathological features, treatments, and prognostic data of 10 patients diagnosed with PC at the First Medical Center, Chinese PLA General Hospital from 2003 to 2021 were analyzed. RESULTS: There were 7 male and 3 female patients with PC whose average age was 41.4 ± 9.4 years. All patients had bone involvement (bone pain and/or osteoporosis), meanwhile 6 patients had kidney stones and 7 patients had palpable neck masses. Five patients presented with tumor metastasis, invading lymph nodes, lung, liver, or bone. Laboratory examinations revealed elevated serum total calcium (4.15 ± 0.81 mmol/L), parathyroid hormone (PTH, 1236.1 ± 519.9 pg/mL) and alkaline phosphatase (405.8 ± 219.0 IU/L) levels. Especially, hypercalcemic crisis occurred in 9 patients. The diagnosis of PC depended on histopathological features of the parathyroid tumor, including capsular and/or vascular invasion. All patients underwent at least en bloc resection. In the follow-up, six patients with relatively high preoperative PTH levels (1519.5 ± 436.8 pg/mL) relapsed postoperatively. Two patients with the Ki-67 index ≥ 10% in parathyroid tumor tissue and distant metastasis died within 2 years after the operation. CONCLUSION: Severe bone pain, kidney stones, hypercalcemic crisis, and markedly elevated PTH usually indicate PC. A markedly elevated PTH level, tumor metastasis, and the Ki-67 index ≥ 10% may be indicators of poor prognosis.

Bone and mineral metabolism in patients with primary aldosteronism: A systematic review and meta-analysis.

Purpose: Patients with primary aldosteronism (PA) tend to exhibit a high prevalence of osteoporosis (OP) that may vary by whether PA is unilateral or bilateral, and responsive to PA treatment. To explore relationships between bone metabolism, PA subtypes, and treatment outcomes, we performed a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane databases were searched for clinical studies related to PA and bone metabolism markers. Articles that met the criteria were screened and included in the systematic review; the data were extracted after evaluating their quality. R software (ver. 2022-02-16, Intel Mac OS X 11.6.4) was used for the meta-analysis. Results: A total of 28 articles were subjected to systematic review, of which 18 were included in the meta-analysis. We found that PA patients evidenced a lower serum calcium level (mean difference [MD] = -0.06 mmol/L, 95% confidence interval [CI]: -0.10 ~ -0.01), a higher urine calcium level (MD = 1.29 mmol/24 h, 95% CI: 0.81 ~ 1.78), and a higher serum parathyroid hormone (PTH) level (MD = 2.16 pmol/L, 95% CI: 1.57 ~ 2.75) than did essential hypertension (EH) subjects. After medical treatment or adrenal surgery, PA patients exhibited a markedly increased serum calcium level (MD = -0.08 mmol/L, 95% CI: -0.11 ~ -0.05), a decreased urine calcium level (MD = 1.72 mmol/24 h, 95% CI: 1.00 ~ 2.44), a decreased serum PTH level (MD = 2.67 pmol/L, 95% CI: 1.73 ~ 3.62), and an increased serum 25-hydroxyvitamin D (25-OHD) level (MD = -6.32 nmol/L, 95% CI: -11.94 ~ -0.70). The meta-analysis showed that the ser um PTH level of unilateral PA patients was significantly higher than that of bilateral PA patients (MD = 0.93 pmol/L, 95% CI: 0.36 ~ 1.49) and the serum 25-OHD lower than that of bilateral PA patients (MD = -4.68 nmol/L, 95% CI: -7.58 ~ 1.77). There were, however, no significant differences between PA and EH patients of 25-OHD, or BMD of femoral neck and lumbar spine. BMDs of the femoral neck or lumbar spine did not change significantly after treatment. The meta-analytical results were confirmed via sensitivity and subgroup analyses. Conclusion: Excess aldosterone was associated with decreased serum calcium, elevated urinary calcium, and elevated PTH levels; these effects may be enhanced by low serum 25-OHD levels. The risks of OP and fracture might be elevated in PA patients, especially unilateral PA patients, but could be reduced after medical treatment or adrenal surgery. In view, however, of the lack of BMD changes, such hypothesis needs to be tested in further studies.

Diabetic microenvironment preconditioning of adipose tissue-derived mesenchymal stem cells enhances their anti-diabetic, anti-long-term complications, and anti-inflammatory effects in type 2 diabetic rats.

BACKGROUND: Mesenchymal stem cells (MSCs) exert anti-diabetic effects and improve long-term complications via secretory effects that regulate macrophage polarisation and attenuate inflammation. Enhancing the efficacy of MSCs needs to be explored further. The in vitro culture microenvironment influences the secretory profile of MSCs. Therefore, we hypothesised that a diabetic microenvironment would promote the secretion of cytokines responsible for macrophage polarisation, further attenuating systemic inflammation and enhancing the effects of MSCs on type 2 diabetes (T2D) and long-term diabetic complications. METHODS: Preconditioned adipose-derived mesenchymal stem cells (pre-ADSCs) were obtained after co-cultivating ADSCs in a diabetic metabolic environment (including high sugar, advanced glycation end-product, and lipopolysaccharides). The regulatory effects of pre-ADSCs on macrophages were observed in vitro. A T2D rat model was induced with a high-fat diet for 32 weeks combined with an intraperitoneal injection of streptozotocin. Sprague-Dawley (SD) rats were divided into four groups: normal group, diabetes without treatment group (PBS), ADSC treatment group, and pre-ADSC treatment group. ADSCs and pre-ADSCs were intravenously administered weekly to SD rats for 6 months, and then glucose homeostasis and long-term diabetic complications were evaluated in each group. RESULTS: The secretion of cytokines related to M2 macrophage polarisation (IL-6, MCP-1, etc.) was increased in the pre-ADSC group in the in vitro model. Pre-ADSC treatment significantly maintained blood glucose homeostasis, reduced insulin resistance, promoted islet regeneration, and ameliorated the complications related to diabetes in rats (chronic kidney disease, non-alcoholic steatohepatitis, lung fibrosis, and cataract) compared to the ADSC group (P < 0.05). Additionally, the number of anti-inflammatory M2 macrophage phenotypes was enhanced in tissues following pre-ADSC injections. Moreover, the expression of pro-inflammatory genes (iNOS, TNF-α, IL-1ß) was reduced whereas that of anti-inflammatory genes (Arg1, CD206, and Il-10) was increased after cultivation with pre-ADSCs. CONCLUSION: Diabetic microenvironment-preconditioned ADSCs effectively strengthen the capacity against inflammation and modulate the progress of long-term T2D complications.

Case report: coexistence of primary hyperparathyroidism with giant toxic nodular goiter.

BACKGROUND: The coexistence of primary hyperparathyroidism (PHPT) and giant toxic nodular goiter is very rare. Moreover, PHPT could be easily overlooked because hyperthyroidism may also lead to hypercalcemia. A 99mTc-MIBI scan of the parathyroid glands is often negative when they are concomitant. CASE PRESENTATION: Here, we report a rare case of the coexistence of giant toxic nodular goiter and PHPT that had been ignored for many years but was successfully treated with an ultrasound-guided parathyroid adenoma microwave ablation (MWA). CONCLUSION: Reoperation for PHPT carries an increased risk of cure failure and complications. Thermal ablation has been proven effective in inactivating hyperfunctioning parathyroid lesions and in normalizing both serum parathyroid hormone (PTH) and calcium.