A family case report of parathyroid carcinoma associated with CDC73 mutation in hyperparathyroidism-jaw tumor syndrome.

Background: Hereditary primary hyperparathyroidism (PHPT) accounts for 5-10% of all PHPT cases, necessitating genetic testing for diagnosis and management. Among these, hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disorder caused by CDC73 mutations with variable clinical presentations and incomplete symptoms. Case summary: The proband, diagnosed with PHPT, underwent parathyroidectomy at the age of 41 with pathological examination of parathyroid carcinoma (PC). Hereditary PHPT was initially suspected due to the early-onset PHPT and family history. Genetic testing identified a heterozygous CDC73 mutation, NM_024529.4: c. 687_688delAG (p. Arg229Serfs*37). Even in the absence of jaw tumors, the diagnosis of HPT-JT was confirmed based on the discovery of renal cysts. A secondary thyroidectomy was performed to reduce the risk of recurrence. Conclusion: Genetic testing is strongly recommended in cases of early-onset PHPT, family history, jaw tumors, renal and uterine involvement, atypical parathyroid tumors, and PC. This testing provides valuable information for personalized management, and counseling is available for affected families.

Multi-omics analysis reveals a macrophage-related marker gene signature for prognostic prediction, immune landscape, genomic heterogeneity, and drug choices in prostate cancer.

Introduction: Macrophages are components of the innate immune system and can play an anti-tumor or pro-tumor role in the tumor microenvironment owing to their high heterogeneity and plasticity. Meanwhile, prostate cancer (PCa) is an immune-sensitive tumor, making it essential to investigate the value of macrophage-associated networks in its prognosis and treatment. Methods: Macrophage-related marker genes (MRMGs) were identified through the comprehensive analysis of single-cell sequencing data from GSE141445 and the impact of macrophages on PCa was evaluated using consensus clustering of MRMGs in the TCGA database. Subsequently, a macrophage-related marker gene prognostic signature (MRMGPS) was constructed by LASSO-Cox regression analysis and grouped based on the median risk score. The predictive ability of MRMGPS was verified by experiments, survival analysis, and nomogram in the TCGA cohort and GEO-Merged cohort. Additionally, immune landscape, genomic heterogeneity, tumor stemness, drug sensitivity, and molecular docking were conducted to explore the relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection. Results: We identified 307 MRMGs and verified that macrophages had a strong influence on the development and progression of PCa. Furthermore, we showed that the MRMGPS constructed with 9 genes and the predictive nomogram had excellent predictive ability in both the TCGA and GEO-Merged cohorts. More importantly, we also found the close relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection by multi-omics analysis. Discussion: Our study reveals the application value of MRMGPS in predicting the prognosis of PCa patients. It also provides a novel perspective and theoretical basis for immune research and drug choices for PCa.

Causal relationship between polycystic ovary syndrome and chronic kidney disease: A Mendelian randomization study.

Objective: Polycystic ovary syndrome is one of the most common endocrine disorders among women of childbearing age. The relationship between polycystic ovary syndrome and chronic kidney disease remains unclear and controversial. In this study, we investigated the causal role of polycystic ovary syndrome in the development of chronic kidney disease using the two-sample Mendelian randomization method. Methods: Public shared summary-level data was acquired from European-ancestry genome wide association studies. We finally obtained 12 single nucleotide polymorphisms as instrumental variables, which were associated with polycystic ovary syndrome in European at genome-wide significance (P < 5 × 10-8). Inverse-variance weighted method was employed in the Mendelian randomization analysis and multiple sensitivity analyses were implemented. Outcome data were obtained from the Open GWAS database. Results: A positive causal association was observed between polycystic ovary syndrome and chronic kidney disease (odds ratio [OR]=1.180, 95% confidence interval [CI]: 1.038-1.342; P=0.010). Further analyses clarified that causal relationship exist between polycystic ovary syndrome and some serological indicators of chronic kidney disease (fibroblast growth factor 23: OR= 1.205, 95% CI: 1.031-1.409, P=0.019; creatinine: OR= 1.012, 95% CI: 1.001-1.023, P=0.035; cystatin C: OR= 1.024, 95% CI: 1.006-1.042, P=0.009). However, there was no causal association of polycystic ovary syndrome with other factors in the data sources we employed. Conclusions: Our results indicate an important role of polycystic ovary syndrome in the development of chronic kidney disease. This study suggests that regular follow-up of renal function in patients with polycystic ovary syndrome is necessary for the early treatment of chronic kidney disease.

Ectopic insulinoma diagnosed by 68Ga-Exendin-4 PET/CT: A case report and review of literature.

RATIONALE: Ectopic insulinomas are extremely rare and challenging to diagnose for clinicians. Precise preoperative localization is essential to successful treatment. PATIENT CONCERNS: A 23-year-old man presented with a 1-year history of recurrent hypoglycemia. DIAGNOSIS: Examinations in the local hospital did not reveal any pancreatic lesion. After admission, a fasting test and a 5-hour oral glucose tolerance test (OGTT) suggested a diagnosis of endogenous hyperinsulinemic hypoglycemia. Enhanced volume perfusion computed tomography (VPCT) revealed 2 nodules in the tail of the pancreas, a nodule in the gastric antrum, and a nodule in the hilum of the spleen. To differentiate which nodule was responsible for hypoglycemia, we performed 68Ga-Exendin-4 PET/CT and 68Ga-DOTATATE PET/CT which helped to make a conclusive diagnosis that the lesion in the gastric antrum was an ectopic insulinoma. INTERVENTIONS: The patient was cured with minimally invasive laparoscopic resection of the tumor. OUTCOMES: The symptoms were relieved and the blood glucose level remained normal after surgery. CONCLUSIONS: This case shows that 68Gallium-exendin-4 PET/CT is useful for precise localization and thereby successful treatment of insulinoma, especially for occult insulinomas and those derived from an ectopic pancreas.

Vitamin D deficiency is associated with thyroid autoimmunity: results from an epidemiological survey in Tianjin, China.

PURPOSE: The pathogenesis of Hashimoto's thyroiditis (HT) is unclear, although some studies have identified an association between vitamin D deficiency and thyroid autoantibody positivity. This study aimed to investigate vitamin D status, and its relationships with thyroid autoantibody positivity and HT, via a large epidemiological survey. METHODS: The epidemiological survey was conducted in Tianjin, China. All participants underwent testing for serum 25-hydroxyvitamin D (25OHD), thyroid function, and thyroid autoantibodies, and some participants underwent testing to evaluate CD4+ T-cell differentiation and concentrations of related cytokines. RESULTS: The study included 1812 participants and revealed prevalences of 13.1% for thyroid peroxidase antibodies (i-TPOAb) and 14.0% for thyroglobulin antibodies (i-TgAb). Logistic regression analysis revealed that thyroid autoantibody positivity was associated with sex, age, and 25OHD classification. An increased likelihood of i-TPOAb positivity was associated with 25OHD deficiency (odds ratio [OR]: 2.428, 95% confidence interval [CI]: 1.383-4.261) and 25OHD inadequacy (OR: 1.198, 95% CO: 0.828-1.733; p = 0.008). An increased likelihood of i-TgAb positivity was associated with 25OHD deficiency (OR: 2.366, 95% CI: 1.366-4.099) and 25OHD inadequacy (OR: 1.263, 95% CI: 0.883-1.807; p = 0.009). Relative to healthy subjects, patients with HT had significantly higher proportions of Th1 and Th17 cells, as well as higher concentrations of related cytokines. CONCLUSIONS: This study revealed that vitamin D deficiency was associated with thyroid autoantibody positivity, and that vitamin D deficiency seems to be involved in the pathological mechanism underlying HT. Large randomized controlled trials are needed to investigate the effects of vitamin D supplementation on HT.

1,25(OH)2D3 provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway.

The over-activation of Toll-like receptors (TLRs) is a typical immune response to injury. Previous work has suggested that controlling the over-activation of TLR4-MyD88-NF-κB may represent a new therapeutic option for diabetic kidney disease (DKD). 1,25(OH)2D3 has also been shown to exert a protective effect on DKD, although the mechanism involved has yet to be elucidated. The aim of this study was to investigate whether 1,25(OH)2D3 protects against DKD by down-regulating the innate immune TLR-NF-κB pathway. NRK-52E cells were cultured under normal or high-glucose conditions. We then used siRNA to knock down TLR4 expression under high-glucose conditions. NRK-52E cells cultured under high-glucose conditions, and streptozotocin (STZ)-induced diabetic rats, were treated with different doses of 1,25(OH)2D3 and used as in vitro and in vivo models, respectively. Renal biochemical indicators were then measured to evaluate the influence of 1,25(OH)2D3 treatment on DKD in diabetic rats. Histological analysis was also performed to determine the extent of infiltration by inflammatory cells and tubulointerstitial fibrosis. Using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence, we determined the expression levels of TLR4, MyD88, NF-κB p65, MCP-1 and α-SMA to investigate whether 1,25(OH)2D3 could reduce the development of tubulointerstitial fibrosis. Knocking down TLR4 abolished the tubulointerstitial fibrosis caused by high-glucose conditions. High doses of 1,25(OH)2D3 consistently reduced the expression of TLR4-MyD88-NF-κB in NRK-52E cells. Moreover, high doses of 1,25(OH)2D3 had an obvious protective effect on kidney injury and inhibited the infiltration of inflammatory cells and tubulointerstitial fibrosis in diabetic rats. In conclusion, high doses of 1,25(OH)2D3 protected against tubulointerstitial fibrosis both in vitro and in vivo by downregulating the expression of TLR4-MyD88-NF-κB.

Clinical Characteristics of 76 Patients with IgG4-Related Hypophysitis: A Systematic Literature Review.

BACKGROUND: IgG4-related hypophysitis (IgG4-RH) is a rare disease, and its prevalence remains unclear. In recent years, an increasing number of cases have been reported because of the increasing recognition of this disease. We aimed to summarize case reports of IgG4-RH and outline the clinical features and outcomes. METHODS: We performed PubMed search of articles using the search terms "hypophysitis [AND] IgG4." Consequently, only 54 English articles (76 cases) met Leporati's diagnostic criteria. RESULTS: Of the 76 cases, the ratio of men to women was 1.5 : 1, and the age at diagnosis was 54.1 ± 17.8 years. The median IgG4 concentration was 405.0 mg/dl. Anterior hypopituitarism, isolated central diabetes insipidus, and panhypopituitarism were observed in 14 (18.4%), 12 (15.8%), and 44 (57.9%) cases, respectively. The sequence of anterior hormone deficiency was as follows: gonadotropin (68.4%), ACTH (63.2%), TSH (59.2%), GH (48.7%), and prolactin (42.1%). The median number of involved organs was 1.5, and the lung (18.4%), retroperitoneum (17.1%), kidney (15.8%), submandibular glands (14.5%), and pancreas (13.2%) were the common involved organs. Elevated IgG4 concentration and normal IgG4 level were in 42 (76.4%) and 13 (23.6%) cases, respectively. Patients with elevated serum IgG4 concentration were older (60.9 ± 14.3 vs 45.6 ± 17.4, p=0.001) and male-prone (78.6% vs 40.4%, p=0.003) and had a susceptibility of multiple organ involvement (78.6% vs 35.0%, p=0.001) compared to those with normal serum IgG4 levels. Males were older at disease onset (61.5 ± 12.6 vs 42.9 ± 18.8, p < 0.001) and had a higher IgG4 concentration (425.0 vs 152.5, p=0.029) and a greater number of involved organs (2.0 vs 0.0, p=0.001), while isolated hypophysitis was more prominent in female (63.3% vs 26.1%, p=0.001). CONCLUSION: In this review, we found that there were different characteristics between different genders. Patients with elevated serum IgG4 level in terms of some clinical features were also different from those with normal serum IgG4 level. However, the data in this review were limited by bias and confounding. Further clinical studies with larger sample sizes are warranted.

Effect of hypercortisolism on bone mineral density and bone metabolism: A potential protective effect of adrenocorticotropic hormone in patients with Cushing's disease.

Objective To investigate the effects of Cushing's disease (CD) and adrenal-dependent Cushing's syndrome (ACS) on bone mineral density (BMD) and bone metabolism. Methods Data were retrospectively collected for 55 patients with hypercortisolism (CD, n = 34; ACS n = 21) from January 1997 to June 2014. BMD was examined in all patients, and bone turnover markers were tested in some patients. Healthy controls (n = 18) were also recruited. Results The lumbar spine and femoral neck BMD were significantly lower in the ACS and CD groups than in the control group. Lumbar BMD was significantly lower in the ACS than CD group. The collagen breakdown product (CTX) concentrations were significantly higher while the osteocalcin and procollagen type I N-terminal propeptide (PINP) concentrations were significantly lower in the ACS and CD groups than in the control group. The PINP concentration was significantly lower while the CTX concentration was significantly higher in the ACS than CD group. In the CD group only, lumbar BMD and serum adrenocorticotropic hormone had a significant positive correlation. Conclusions Bone turnover markers indicated suppressed osteoblast and enhanced osteoclast activities. PINP and CTX changes might indicate bone mass deterioration. Adrenocorticotropic hormone might be protective for lumbar BMD in patients with CD.

Urinary iodine in early pregnancy is associated with subclinical hypothyroidism in Tianjin, China: an observational study.

BACKGROUND: Subclinical hypothyroidism (SH) is associated with adverse obstetric outcomes and neurodevelopment disorders. Both iodine deficiency and excess are associated with SH; however, few data regarding iodine nutrition status of pregnant women with SH are available. This study aimed to clarify whether iodine deficiency or excess is associated with SH, especially, when test results for anti-thyroid autoantibodies are negative. METHODS: A total of 115 women with SH and 104 women with euthyroidism (EH) in early pregnancy in Tianjin, China were investigated, and their serum thyroid-stimulating hormone, free thyroxine, free triiodothyronine, anti-thyroid peroxidase antibody (TPOAb), anti-thyroid globulin antibody (TGAb), urinary iodine (UIC), and urinary creatinine (UCr) concentrations were measured. Thyroid ultrasonography was performed to determine thyroid echogenicity and volume. The UIC, UIC/UCr ratio, prevalence of TPOAb and TGAb positivity, and thyroid gland volume were compared between the EH and SH groups. UIC and ultrasonographic features were analysed in subjects in the SH group who were negative for TPOAb and TGAb. RESULTS: Median UIC of SH (154.0 µg/L) and EH (150.1 µg/L) met the World Health Organization criterion for iodine sufficiency in pregnant women. Neither UIC nor the UIC/UCr ratio differed significantly between groups. The prevalence of TPOAb and TGAb positivity in the SH group was significantly higher than that in the EH group (P < 0.01). The percentage of subjects with UIC ≥ 250 µg/L in the SH group was significantly higher than that in the EH group (p = 0.004). The percentage of subjects negative for autoantibodies and UIC ≥ 250 µg/L in the SH group tended to be higher than that in subjects in the EH group negative for autoantibodies, but the difference was not statistically significant (p = 0.025, adjusted test level α = 0.0167). Eight of 18 subjects in the SH group with negative results for TPOAb and TGAb were diagnosed with Hashimoto thyroiditis by means of thyroid ultrasonography. CONCLUSIONS: Women in early pregnancy with SH in Tianjin were iodine sufficient, but still at risk of iodine deficiency as pregnancy progressed. UIC ≥ 250 µg/L was associated with increased risk of SH. Serological negative autoimmune thyroiditis and UIC ≥ 250 µg/L may play a role in pathogenesis of SH cases with negative results for autoantibodies.

Expression and cellular distribution of TLR4, MyD88, and NF-κB in diabetic renal tubulointerstitial fibrosis, in vitro and in vivo.

AIM: Inflammation and extracellular matrix hyperplasia are crucial in the pathogenesis of tubulointerstitial fibrosis (TIF) involved in diabetic nephropathy (DN). Macrophage accumulation plays a major role, but whether immune factors contribute to DN pathogenesis is not well understood. This study aimed to investigate TLR4-MyD88-NF-κB-dependent pathway's involvement in TIF pathogenesis. METHODS: STZ-induced diabetic rats and rat renal tubular epithelial NRK-52E cells cultured under high glucose conditions were used as in vivo and in vitro models, respectively. Real-time RT-PCR, western blot, immunohistochemistry and immunofluorescence were performed to examine the mRNA and protein levels of TLR4, MyD88, NF-κB, MCP-1, and α-SMA. RESULTS: Compared with 5.5 mmol/L glucose, treatment of NRK-52E cells with 25 and 50 mmol/L d-glucose resulted in significantly increased TLR4 and MyD88 mRNA and protein levels (P<0.05). TLR4 and MyD88 were detected in the cytoplasm of most NRK-52E cells cultured under high glucose. Pronounced damage in the renal tubulointerstitium was observed in diabetic rats (scores: 3.82 ± 0.65 vs. 0.38 ± 0.08, P<0.01). Compared with the normal controls, a sharp upregulation of TLR4, MyD88, NF-κB p65, MCP-1, and α-SMA mRNA and protein levels was observed in diabetic rat kidneys (P<0.05). In diabetic animals, TLR4 and MyD88 were strongly expressed in the cytoplasm, while NF-κB p65 was widely expressed in cytoplasm and nuclei of renal tubular epithelial cells. CONCLUSION: The inflammatory reaction and epithelial-mesenchymal transformation observed in renal tubulointerstitium may be the result of overactivation of the TLR4-MyD88-NF-κB-dependent innate immunity under high glucose, and may be involved in DN occurrence and progression.

1,25(OH)2D3-mediated amelioration of aortic injury in streptozotocin-induced diabetic rats.

In this study, a single tail vein injection of streptozotocin (STZ)-induced rat model was employed to study the effects of 1,25(OH)2D3 supplementation, the active form of vitamin D, on diabetes-induced aortic injury. Aortas from different groups were assessed for histopathology, toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), and nuclear factor-kappa B (NF-κB) p65 expression by hematoxylin and eosin staining, immunohistochemistry staining, reverse transcription polymerase chain reaction, and Western blot analysis. High-dose 1,25(OH)2D3 (0.3 µg/kg/day) significantly prevented diabetes-induced aortic pathological changes and collagen deposition and decreased the expression of TLR4, MyD88, and NF-κB at both mRNA and protein levels in the aorta of STZ-induced diabetic rats (P < 0.01). In vitro studies in A7r5 cells (a rat embryonic thoracic aortic smooth muscle cell line) showed that high-dose glucose (25 mmol/L) enhanced TLR4 expression at both mRNA and protein levels by fourfold and twofold, respectively, at 24 h, which were significantly diminished by 1,25(OH)2D3 (1 × 10(-7) mol/L) by 50 and 36 %, respectively. Similar effects of high-dose 1,25(OH)2D3 on the expression of MyD88 were observed. Our results indicate that vitamin D has protective effects on diabetes-induced aortic injury and attenuates the expressions of TLR4, MyD88, and NF-κB in diabetic rats.

[Clinical analysis of drug-induced Pseudo-Bartter's syndrome: a report of five cases].

OBJECTIVE: To summarize the clinical characteristics and outcomes of Pseudo-Bartter's syndrome and explore its pathogenesis. METHODS: The clinical data of 5 cases of Pseudo-Bartter's syndrome at our ward from May 2008 to December 2010 was analyzed retrospectively. RESULTS: All patients were female. Long-term regimen of purgative or diuretics was prescribed. The clinical features included normotension, hypokalemic alkalosis and activation of renin-angiotensin-aldosterone. The pathological results of 3 cases of kidney biopsy showed the hyperplasia of juxtaglomerular apparatus, thickness of arteriole, infiltration of lymphocytes and monocytes and degeneration of renal tubule. Upon a definitive diagnosis, purgative or diuretics was discontinued and supplement therapy of potassium chloride initiated. The results of laboratory tests reverted to normal ranges within 4 weeks. CONCLUSION: Purgative or diuretics should be prescribed appropriately to avoid the occurrence of Pseudo-Bartter's syndrome.