Correlation of lipocalin 2 and glycolipid metabolism and body composition in a large cohort of children with osteogenesis imperfecta.

PURPOSE: Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels and glycolipid metabolism, and body composition in a large cohort of patients with osteogenesis imperfecta (OI). METHODS: A total of 204 children with OI and 66 age- and gender-matched healthy children were included. Circulating levels of LCN2 and osteocalcin were measured by enzyme-linked immunosorbent assay. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated chemical analyzers. The body composition was measured by dual-energy X-ray absorptiometry. Grip strength and timed-up-and-go (TUG) were tested to evaluate the muscle function. RESULTS: Serum LCN2 levels were 37.65 ± 23.48 ng/ml in OI children, which was significantly lower than those in healthy control (69.18 ± 35.43 ng/ml, P < 0.001). Body mass index (BMI) and serum FBG level were significantly higher and HDL-C levels were lower in OI children than healthy control (all P < 0.01). Grip strength was significantly lower (P < 0.05), and the TUG was significantly longer in OI patients than healthy control (P < 0.05). Serum LCN2 level was negatively correlated to BMI, FBG, HOMA-IR, HOMA-ß, total body, and trunk fat mass percentage, and positively correlated to total body and appendicular lean mass percentage (all P < 0.05). CONCLUSIONS: Insulin resistance, hyperglycemia, obesity, and muscle dysfunction are common in OI patients. As a novel osteogenic cytokine, LCN2 deficiency may be relevant to disorders of glucose and lipid metabolism, and dysfunction of muscle in OI patients.

Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

PURPOSE: Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). METHODS: A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and ß-carboxy-terminal crosslinked telopeptide of type 1 collagen (ß-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. RESULTS: PPGL patients had a higher level of ß-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. CONCLUSIONS: PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

[The 499th case: Roux-en-Y gastric bypass, limb weakness, and ostealgia].

A 36-year-old woman was admitted to the Peking Union Medical College Hospital with a history of fractures for 2 years, limb weakness for 1 year, and ostealgia for 2 months. The patient's examination identified iron deficiency anemia, significantly decreased serum calcium and 25-hydroxyvitamin D3 levels, and increased alkaline phosphatase and parathyroid hormone levels. Imaging showed several typical signs of osteomalacia. Considering the history of Roux-en-Y gastric bypass surgery, the diagnosis was considered to be osteomalacia caused by a postoperative nutritional absorption disorder. The patient was supplemented with calcitriol, calcium, and vitamin D and gradually returned to normal physical activity. The bone metabolism indicators and bone density were significantly improved.

High prevalence of vertebral deformity in tumor-induced osteomalacia associated with impaired bone microstructure.

PURPOSE: Patients with tumor-induced osteomalacia (TIO) often suffer from irreversible height loss due to vertebral deformity. However, the prevalence of vertebral deformity in TIO patients varies among limited studies. In addition, the distribution and type of vertebral deformity, as well as its risk factors, remain unknown. This study aimed to identify the prevalence, distribution, type and risk factors for vertebral deformity in a large cohort of TIO patients. METHODS: A total of 164 TIO patients were enrolled in this retrospective study. Deformity in vertebrae T4-L4 by lateral thoracolumbar spine radiographs was evaluated according to the semiquantitative method of Genant. Bone microstructure was evaluated by trabecular bone score (TBS) and high-resolution peripheral QCT (HR-pQCT). RESULTS: Ninety-nine (99/164, 60.4%) patients had 517 deformed vertebrae with a bimodal pattern of distribution (T7-9 and T11-L1), and biconcave deformity was the most common type (267/517, 51.6%). Compared with patients without vertebral deformity, those with vertebral deformity had a higher male/female ratio, longer disease duration, more height loss, lower serum phosphate, higher bone turnover markers, lower TBS, lower areal bone mineral density (aBMD), lower peripheral volumetric BMD (vBMD) and worse microstructure. Lower trabecular vBMD and worse trabecular microstructure in the peripheral bone and lower spine TBS were associated with an increased risk of vertebral deformity independently of aBMD. After adjusting for the number of deformed vertebrae, we found little difference in clinical indexes among the patients with different types of vertebral deformity. However, we found significant correlations of clinical indexes with the number of deformed vertebrae and the spinal deformity index. CONCLUSION: We reported a high prevalence of vertebral deformity in the largest cohort of TIO patients and described the vertebral deformity in detail for the first time. Risk factors for vertebral deformity included male sex, long disease duration, height loss, abnormal biochemical indexes and bone impairment. Clinical manifestation, biochemical indexes and bone impairment were correlated with the number of deformed vertebrae and degree of deformity, but not the type of deformity.

[Clinical characteristics and molecular mechanisms of hypoparathyroidism related to GATA3 gene mutation].

Objective: To analyze the clinical characteristics and molecular mechanisms of 5 cases of hypoparathyroidism caused by GATA3 gene mutation. Methods: A total of 5 childhood-onset hypoparathyroidism patients with GATA3 mutation were identified from 198 hypoparathyroidism (aged ≤18 years) from 1975 to 2021 in Peking Union Medical College Hospital. Clinical data and biochemical indices of the 5 patients were collected and analyzed retrospectively. Genetic screening was conducted by targeted next-generation sequencing (T-NGS), and bioinformatics analysis was performed to analyze the underline mechanisms. Results: The medium onset age of hypoparathyroidism of the 5 patients was 0.5 (0.1, 1.3) years old, and the time duration from onset to confirmed diagnosis of hypoparathyroidism and hypoparathyroidism- deafness-renal dysplasia syndrome was (7.0±5.2) years and (15.0±5.4) years, respectively. The clinical manifestations included carpopedal spasm accompanied by seizures (5 cases), basal ganglia calcification (5 cases), cataract (1 case), deafness (4 cases), and renal malformations or absence (2 cases). The blood calcium and blood parathormone(PTH) before treatment was (1.65±0.31) mmol/L and (4.64±2.63) ng/L, respectively. The 5 patients carried different heterozygous mutations in GATA3 gene, which caused nonsense mutations, frameshift mutations and splice site mutations, respectively. All the GATA3 gene mutations of the 5 patients are classified as pathogenic or likely pathogenic by the Clin Var database and American College of Medical Genetics and Genomics(ACMG). Conclusions: Attention should be paid to genetic diseases in patients with childhood-onset hypoparathyroidism. The possibility of hypoparathyroidism-deafness-renal dysplasia syndrome should be considered in hypoparathyroidism patients with hearing loss or renal dysplasia. GATA3 gene screening is highly recommended for the confirmation of the diagnosis.

[The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)].

Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Group of Pancreatic Surgery, Chinese Society of Surgery, Chinese Medical Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.

Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets.

By analyzing iron status of 14 ADHR patients, we found that iron deficiency was an important trigger of ADHR. Correcting iron deficiency significantly improved patients' symptoms. Meanwhile, patients' serum phosphate showed positive correlations with iron metabolism parameters and hemoglobin-related parameters, suggesting the necessity of monitoring and correcting the iron status in ADHR. INTRODUCTION: Autosomal dominant hypophosphatemic rickets (ADHR) is unique for its incomplete penetrance, variety of disease onsets, and waxing and waning phenotypes. Iron deficiency is a trigger of ADHR. This study aimed to clarify the role of iron deficiency in ADHR. METHODS: Data of clinical manifestations and laboratory examinations were collected from patients among eight kindreds with ADHR. Multiple regression and Pearson's correlation tests were performed to test the relationships of serum phosphate levels and other laboratory variables during the patients' follow-ups. RESULTS: Among 23 ADHR patients with fibroblast growth factor 23 (FGF23) mutations, 14 patients presented with obvious symptoms. Ten patients had iron deficiency at the onset of ADHR, coinciding with menarche, menorrhagia, pregnancy, and chronic gastrointestinal bleeding. Two patients who did not have their iron status tested presented with symptoms after abortion and pregnancy in one patient each, which suggested that they also had iron deficiency at onset. Patients were treated with ferrous succinate tablets, vitamin C, and neutral phosphate and calcitriol. With correction of the iron status, the patients' symptoms showed notable improvement, with increased serum phosphate levels. Two patients' FGF23 levels also declined to the normal range. There were strong correlations between serum phosphate and serum iron levels (r = 0.7689, p < 0.0001), serum ferritin levels (r = 0.5312, p = 0.002), iron saturation (r = 0.7907, p < 0.0001), and transferrin saturation (r = 0.7875, p < 0.001). We also examined the relationships between serum phosphate levels and hemoglobin-related indices, which were significant (hemoglobin: r = 0.71, p < 0.0001; MCV: r = 0.7589, p < 0.0001; MCH: r = 0.8218, p < 0.0001; and MCHC: r = 0.7751, p < 0.0001). Longitudinal data of six patients' follow-up also showed synchronous changes in serum phosphate with serum iron levels. CONCLUSIONS: Iron deficiency plays an important role in triggering ADHR. Monitoring and correcting the iron status are helpful for diagnosing and treating ADHR. Iron metabolism parameters and hemoglobin-related parameters are positively correlated with serum phosphate levels in patients with ADHR and iron deficiency, and these might serve as good indicators of prognosis of ADHR.

The genetic polymorphisms of XPR1 and SCL34A3 are associated with Fanconi syndrome in Chinese patients of tumor-induced osteomalacia.

PURPOSE: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS. METHODS: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes. RESULTS: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS. CONCLUSIONS: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

[Diagnostic value of 4-dimensional computed tomography in preoperative localization in patients with primary hyperparathyroidism].

Objective: To provide more options for preoperative localization diagnosis in patients with primary hyperparathyroidism (PHPT), the diagnostic efficacy of parathyroid 4-dimensional computed tomography (4D-CT) in patients with PHPT was evaluated. Methods: This was a single-center retrospective study including 57 patients with surgical proved PHPT. All of the patients underwent 4D-CT, 99Tcm -sestamibi parathyroid imaging (MIBI), and ultrasonography (US) preoperatively. The reference standard for correct localization was based on operation reports and pathology confirmation. The patients were grouped according to the preoperative serum calcium levels, tumor diameter, or ectopic lesions (yes/no), respectively. The sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) of 4D-CT, MIBI and US, alone or in combination, were analyzed in total and each subgroup patients. Results: Fifty-seven patients (39 women, 18 men; mean age of 56.5 years) were evaluated, including four cases with multi-gland disease and thirteen cases with ectopic parathyroid lesions. In all the patients, similar diagnostic efficacy was found in 4D-CT (AUC: 0.943) and MIBI (AUC: 0.927), both of which were higher than that of US (AUC: 0.847) (P = 0.01 for 4D-CT vs. US; P = 0.04 for MIBI vs. US). In a subset analysis for ectopic quadrants, the diagnostic efficacy of 4D-CT was significantly higher than that of MIBI (P = 0.04) or US (P = 0.01), with the sensitivity of 100%, 69.2%, and 61.5%, and AUC of 0.989, 0.846, and 0.808 for 4D-CT, MIBI and US, respectively. Conclusions: 4D-CT has similar diagnostic efficacy for preoperative localization to MIBI in patients with PHPT, and it is superior to MIBI and US in identifying the ectopic parathyroid gland. 4D-CT can be recommended as an alternative preoperative localization method, especially when parathyroid lesions could not be precisely located by US and MIBI.

Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism.

This study evaluated bone features of PHPT using HR-pQCT. The results showed both cortical and trabecular bones were significantly impaired in PHPT patients. Male and female PHPT patients suffered similar damages in bone. HR-pQCT indices were not observed to differ in MEN1 and sporadic PHPT patients. INTRODUCTION: High-resolution peripheral quantitative CT is a novel imaging technique used to separately assess trabecular and cortical bone status of the radius and tibia in vivo. Using HR-pQCT, we aimed to evaluate bone features of primary hyperparathyroidism patients in a Chinese population and reveal similarities and differences in bone features in multiple endocrine neoplasia type 1-related PHPT and sporadic PHPT patients in the Chinese population. METHODS: A case-control study was designed. In 58 PHPT patients and 58 sex- and age-matched healthy controls, the distal radius and tibia were scanned using HR-pQCT. Areal bone mineral density (aBMD) was also determined in PHPT patients using dual-energy X-ray absorptiometry (DXA). RESULTS: In comparison with controls, PHPT patients were observed to exhibit reduced volumetric BMD at the cortical and trabecular compartments, thinner cortices, and more widely spaced trabeculae. Significant differences were still observed when comparing data of female and male patients with age-matched controls separately. MHPT patients (n = 11) were found to have lower aBMD Z-scores in the lumbar spine, trochanteric region, and total hip compared with sporadic PHPT patients (n = 47), while no differences were observed in HR-pQCT indices between the two groups. In multiple linear regression models, no significant correlations were identified between PTH and HR-pQCT indices. However, height was found to positively correlate with HR-pQCT-derived trabecular indices at both the radius and tibia. CONCLUSIONS: PHPT affects geometry, volumetric density, and microstructure in both the cortical and trabecular bones in both male and female Chinese patients. MHPT patients were observed to have reduced aBMD as determined by DXA in the lumbar spine and hip in comparison with sporadic PHPT patients. However, HR-pQCT indices were not observed to differ.

Novel SLCO2A1compound heterozygous mutation causing primary hypertrophic osteoarthropathy with Bartter-like hypokalemia in a Chinese family.

PURPOSE: Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis and pachydermia with defects in the degradation of prostaglandin E2 (PGE2). Mutations in SLCO2A1 gene-encoding prostaglandin transporter (PGT) resulted in PHO, autosomal recessive 2 (PHOAR2). The spectrum of mutations and variable clinical complications of PHOAR2 has been delineated. In this study, we investigated a Chinese PHO family with a manifestation of Bartter-like hypokalemia. METHODS: Clinical manifestations were collected and genetic analyses were performed in the PHO family. RESULTS: The 33-year-old male proband had severe hypokalemia due to potassium loss from the kidney, while his brother had mild hypokalemia. After being treated with etoricoxib, the serum potassium level of the patient increased rapidly to the normal range which corresponded with the reduction in his serum PGE2 and PE2 metabolite (PGEM) levels. A novel SLCO2A1 compound heterozygous mutation of p.I284V and p.C459R was identified in two PHO patients in this family. CONCLUSIONS: The present findings supported that the Bartter-like hypokalemia is a new complication of PHOAR2 caused by the high level of PGE2. Etoricoxib was demonstrated to be effective for the renal hypokalemia in PHO patients.

[Glucose and lipid metabolic disorders in myasthenia gravis patients and its mechanisms].

Objective: To investigate the glucose and lipid metabolic disorders in patients with myasthenia gravis (MG) without glucocorticoid therapy, and the relationships between insulin, insulin resistance, muscle strength, serum levels of osteocalcin, 25-hydroxy vitamin D (25OHD) and glucose and lipid metabolism. Methods: A total of 102 MG patients [(40±11) years old, 43 males and 59 females] without glucocorticoid treatment were enrolled in this cross-sectional study. Height, weight and the handgrip of dominant hands were measured. Serum levels of fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PBG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-hour postprandial insulin (2 h PINS), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and osteocalcin, 25OHD were detected. Insulin resistance was assessed using homeostasis model assessment of insulin resistance (HOMA-IR). Results: The proportion of impaired fasting glucose or impaired glucose tolerance, type 2 diabetes, dyslipidemia, hyperinsulinemia in male and female were 30.0%, 10.0%, 50.0%, 33.3% and 17.5%, 3.5%, 27.7%, 7.1%, respectively. Serum osteocalcin levels in male and female were 2.8 (1.7, 4.4) µg/L and 2.3 (1.3, 3.9) µg/L, respectively. And 25OHD levels in male and female were (93.5±34.9) nmol/L and (81.0±30.5) nmol/L, respectively. Handgrip of male and female was (37.0±9.4) kg and (20.5±6.3) kg. After adjusted for age, FINS (r=0.619, P<0.001), 2 h PINS (r=0.640, P<0.001), HOMA-IR (r=0.534, P<0.001) were positively correlated with 2 h PBG, and the handgrip was negatively correlated with TC (r=-0.486, P=0.026), LDL-C (r=-0.485, P=0.026) in male. FINS (r=0.352, P=0.008; r=0.300, P=0.026; r=0.646, P<0.001) and 2 h PINS (r=0.278, P=0.040; r=0.518, P<0.001; r=0.382, P=0.006) and HOMA-IR (r=0.695, P<0.001; r=0.583, P<0.001; r=0.818, P<0.001) were positively correlated with FBG, 2 h PBG, HbA1c, and the handgrip were negatively correlated with FBG (r=-0.424, P=0.016), 2 h PINS (r=-0.345, P=0.034) and positively correlated with HDL-C (r=0.389, P=0.037) in female. There was no association between osteocalcin, 25OHD and glucose and lipid metabolism. Multivariate linear regression analysis also found that there were significant relationships between handgrip, insulin, insulin resistance levels and glucose and lipid metabolic disorders. Conclusion: There was a high proportion of glucose and lipid metabolic disorders in MG patients without glucocorticoid treatment, and the mechanism may be related to insulin resistance induced by muscle weakness.

Association between bone mineral density, muscle strength, and vitamin D status in patients with myasthenia gravis: a cross-sectional study.

Myasthenia gravis (MG) patients had low proximal hip BMD, which could be explained by reduced muscle strength, elevated bone resorption markers, vitamin D deficiency, and increased PTH levels in those with MG compared to controls. INTRODUCTION: Muscle strength is closely correlated with bone mineral density (BMD) and vitamin D status. Here, we evaluated muscle strength, BMD, and vitamin D status in a large sample of Chinese patients with MG. METHODS: In this cross-sectional survey, 86 patients with MG without glucocorticoid treatment and 86 healthy controls were included. Serum levels of 25-hydroxyvitamin D [25OHD], parathyroid hormone (PTH), bone turnover markers (BTMs), and BMD were measured and compared between the two groups. Grip strength and one-leg standing time (OLST) were also assessed in MG patients. RESULTS: Low grip strength and short OLST were found in 11 (12.8%) and 12 (14.0%) MG patients, respectively. There were 3 (3.5%) MG patients with low bone mass for chronological age. Serum beta C-terminal telopeptide and PTH levels were higher (p < 0.001 and p = 0.001, respectively), and BMD at the femoral neck and trochanter were lower in MG patients (p < 0.001 and p < 0.001, respectively) compared to healthy controls. In patients with MG, grip strength was positively correlated with BMD. Serum 25OHD levels were lower in MG patients than in healthy controls (17.36 ± 6.64 vs. 22.11 ± 7.28 ng/ml, p < 0.001). CONCLUSION: Grip strength was positively correlated with BMD in Chinese patients with MG. MG patients tended to have low proximal hip BMD, which may partially be explained by reduced muscle strength, vitamin D deficiency, increased PTH levels, and elevated bone resorption markers compared to controls.

[The expression of p27Kip1 and ß-catenin in multiple endocrine neoplasia type 1-related parathyroid tumors].

Objective: To explore tissue expression of cyclin-dependent kinase inhibitor p27Kip1 and ß-catenin in multiple endocrine neoplasia type1 (MEN1)-related parathyroid tumors (MHPT). Methods: Immunohistochemistry was performed to analyze the expression of p27Kip1 and ß-catenin in parathyroid glands from 31 subjects with MHPT collected at Peking Union Medical College Hospital from 2002 to 2013. Five normal parathyroid glands were used as control. Results: In MHPT subjects, nuclear expression of p27Kip1 was absent in 4 (12.9%), weak in 10 (32.3%) and moderated staining in 17 parathyroid specimens (54.8%), respectively. While, in normal subjects, the nuclear expression of p27Kip1 was observed in all subjects and was stronger than that from MHPT subjects (P=0.001). As to the expression of ß-catenin, normal parathyroid showed a distinct to moderate membrane staining, a moderate to weak cytoplasmic staining and negative nuclear staining. Similarly, MHPT exhibited a marked to moderate membrane (P=0.087), a moderated to weak cytoplasmic (P=0.357), and negative nuclear ß-catenin staining. Conclusions: The expression of p27Kip1 is reduced or absent in MHPT tissue, and no nuclear expression of ß-catenin is observed in the tumors, which suggesting p27Kip1, but not ß-catenin nuclear accumulation, play a role in the development of the tumors.

[A genomic study of adult-onset idiopathic hypoparathyroidism in Chinese by targeted next-generation sequencing].

OBJECTIVE: Several genes have been recognized to be associated with non-surgical hypoparathyroidism. Data about gene mutations in adult-onset hypoparathyroidism patients is lacking. This study was designed to screen gene mutation in adult-onset hypoparathyroidism in Chinese through the targeted next-generation sequencing (NGS). METHODS: We recruited 17 patients with adult-onset hypoparathyroidism who were regularly followed or newly diagnosed at our centre during the past one year. Nine of them developed hypercalciuria during the treatment with calcium and vitamin D. Eight of them were newly diagnosed with no treatment. Targeted NGS was performed to screen 11 related genes, including AIRE, AP2S1, CASR, CLDN16, FAM111A, GATA3, GCM2, PTH, TBCE, TBX1 and TRPM6. RESULTS: A novel homozygosis mutation of GCMB gene[c.130G>A (p.G44S)]was identified which was predicted to be deleterious by PolyPhen2. The patient was a 36-year-old woman who suffered from paroxysmal carpopedal spasms for ten years. Before treatment, the serum calcium and phosphorus was 1.48 mmol/L and 2.29 mmol/L, respectively.Parathyroid hormonel (PTH) concentration was lower than 3.0 ng/L. Intracranial calcification and cataract were also identified. She developed hypercalciuria during treatment with calcium and vitamin D. She had no physical deformity or family history of hypoparathyroidism. CONCLUSIONS: In this study, the genetic defect was only identified in 1 patient (5.9%). In adult-onset hypoparathyroidism without other diagnostic clues, the gene mutation screening as the first choice to clarify the etiology was not recommended.

Establishment of a normal reference value of parathyroid hormone in a large healthy Chinese population and evaluation of its relation to bone turnover and bone mineral density.

UNLABELLED: A normal reference value of parathyroid hormone (PTH) was established for the first time in a large sample of healthy Chinese subjects by completely excluding interference of vitamin D deficiency. A high PTH level correlated significantly with an elevated bone turnover and a reduced bone mineral density (BMD). INTRODUCTION: The aims of this study are to establish a normal reference value for serum PTH and to evaluate the effect of parathyroid gland status on bone turnover and BMD. METHODS: Our cross-sectional study included 1436 healthy individuals from 5 different Chinese cities. Concentrations of serum PTH, 25-hydroxyvitamin D (25OHD), procollagen I N-terminal peptide (P1NP, a bone formation marker), and carboxyl-terminal telopeptide of type I collagen (ß-CTX, a bone resorption marker) were measured by electrochemiluminescence immunoassay. BMD was measured by dual-energy X-ray absorptiometry. The relation of PTH concentration to age, gender, height, and weight was examined. Reference values of PTH were established for all subjects and for subjects categorized by serum 25OHD concentrations. Correlations of PTH levels with bone turnover biomarkers and BMD were statistically analyzed. RESULTS: Reference values of PTH were 8.84-69.95 pg/mL in all the subjects and 7.48-60.73 and 5.83-56.78 pg/mL in the subjects with serum 25OHD concentrations of ≥20 and ≥30 ng/mL, respectively. Serum PTH showed a negative linear correlation with 25OHD, and the breakpoint was 18.21 ng/mL, below which the PTH level rapidly increased. The increase in PTH levels with age showed a positive linear correlation with P1NP and ß-CTX concentrations and a negative linear correlation with BMD at the lumbar spines and the femoral neck. CONCLUSIONS: A reference value of PTH was established in a large sample of healthy Chinese subjects according to 25OHD status, gender, and age. A high PTH level correlated significantly with an elevated bone turnover and a reduced BMD.

Suppressed bone turnover was associated with increased osteoporotic fracture risks in non-obese postmenopausal Chinese women with type 2 diabetes mellitus.

UNLABELLED: We found that type 2 diabetes mellitus (T2DM) was associated with increased fracture risks in non-obese postmenopausal Chinese women, and suppressed bone turnover might be the underlying mechanism. This is the first study evaluating and explaining the association of T2DM with osteoporotic fracture in Chinese population with such high homogeneity. INTRODUCTION: The aim of this study was to investigate the association of T2DM with osteoporotic fracture in postmenopausal Chinese women. METHODS: One thousand four hundred ten postmenopausal women were included and stratified into non-obese population [body mass index (BMI) < 25 kg/m(2)] and obese population (BMI ≥ 25 kg/m(2)). Each type of population was classified into diabetes group, impaired fasting glucose (IFG) group, and normal glucose group. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum C-terminal telopeptide of type I collagen (ß-CTX) and serum N-amino terminal prepeptide of type 1 procollagen (P1NP) were quantified. Vertebral fractures (VFs) and non-VFs were assessed by vertebral X-ray and questionnaire, respectively. RESULTS: Comparing to normal glucose group, diabetes group and IFG group both had lower levels of P1NP and ß-CTX, despite population types. Despite having non-decreased BMD, non-obese diabetic patients had higher risks of total fracture and VF than BMI-matched normal glucose subjects (both P < 0.05). Non-obese population was further classified by a mean value of P1NP or ß-CTX. Non-obese diabetic patients with low P1NP or high ß-CTX had higher fracture risks (both P < 0.05), comparing to non-obese normal glucose subjects with high P1NP or high ß-CTX, respectively. CONCLUSIONS: Type 2 diabetic patients had suppressed bone turnover, which might explain the increased fracture risks, independent of BMD. IFG patients might also have poor bone quality and need early prevention.

Development and validation of the Sports Athlete Foot and Ankle Score: an instrument for sports-related ankle injuries.

BACKGROUND: Many existing scoring systems assess ankle function, but there is no evidence that any of them has been validated in a group of patients with a higher demand on their ankle function. Problems include ceiling effects, not being able to detect change or they do not contain a sports-subscale. The aim of this study was to create a validated self-administered scoring system for ankle injuries in the higher performing athlete. METHODS: First, 26 patients were interviewed to solicit opinions needed to create the final score, which is modified from the Foot and Ankle Outcome Score (FAOS). Second, SAFAS was validated in a group of 25 athletes with and 14 athletes without ankle injury. It is a self-administered region specific sports foot and ankle score that contains four subscales assessing the levels of symptoms, pain, daily living and sports. RESULTS: The Spearman correlation coefficients between SAFAS and the Foot and Ankle Ability Measure (FAAM) ranged from 0.78 to 0.88. Content validity is established by key informant interviews, expert opinions and a high satisfaction rate of 75%. Cronbach's alpha indicated good internal consistency of each subscale ranging from 0.77 to 0.92. CONCLUSION: SAFAS has shown good evidence for being a valid instrudent for assessing sports-related ankle injuries in high-performing athletes.

Sentinel lymph node biopsy using carbon nanoparticles for Chinese patients with papillary thyroid microcarcinoma.

AIMS: To compare the efficacies of methylene blue (MB) and carbon nanoparticles (CNs) as tracers for sentinel lymph node biopsy (SLNB), and assess the value of SLNB in predicting the cervical LN status of patients with thyroid microcarcinoma. METHODS: This retrospective analysis comprised 200 thyroid microcarcinoma patients who underwent intraoperative SLNB. Among them, 100 patients were injected with MB dye. The other 100 patients received a CN suspension injection. Routine pathological examination was performed in all resected specimens. RESULTS: SLNs detected in the experimental and control groups were 126 and 102, respectively, of which the metastatic LNs confirmed by histopathology were 77 and 48, respectively. The staining rate of cervical level VI LNs in the experimental group was significantly higher than that in the control group (P<0.001). For the CN method, the sensitivity, specificity, accuracy rate, and false negative rate were 93.3%, 100%, 97%, and 5.2%, respectively, whereas the corresponding figures for the MB method were 80.6%, 100%, 93%, and 9.9%, respectively. The positive rate of cancer metastases for SLNs in the experimental group was 61.1%, which is significantly higher than that in the control group (47.1%; P=0.034). CONCLUSIONS: In contrast to the MB method, CNs can maintain the durability of SLN imaging and accurately forecast the LN status of patients with thyroid microcarcinoma; in addition, the CN method was found to be feasible and repeatable. The CN method better aids the screening and selection of patients who are most likely to benefit from cervical LN dissection.

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells.

AIMS/HYPOTHESIS: Amylin, a secretory protein mainly produced by pancreatic beta cells, is elevated in the circulation of patients with diseases related to acute and chronic inflammation, including acute pancreatitis, pancreas graft rejection, obesity and insulin resistance. TNF-α is involved in these disorders. We investigated the effect of TNF-α on amylin levels and the underlying mechanisms, using murine pancreatic beta cell line MIN6 and pancreatic islets. METHODS: Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear factor κB (NF-κB) activation were examined by real-time PCR and luciferase reporter assay, respectively. Amylin protein level and mitogen-activated protein kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) activation was examined by electrophoretic mobility shift assay (EMSA). RESULTS: TNF-α acutely induced amylin expression at the transcriptional level and increased proamylin and the intermediate form of amylin in MIN6 cells and islets. However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) or protein kinase Cζ (PKC(ζ)), (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-α induced amylin expression through the PKC(ζ)-extracellular signal-regulated kinase (ERK)/JNK pathways. EMSA showed that (PKC(ζ)), JNK and ERK1/2 were involved in TNF-α-induced AP1 activation, suggesting that TNF-α induces murine amylin expression through the (PKC(ζ)) - ERK1/2 - AP and PKC(ζ) - JNK - AP1 pathways. Further studies showed that TNF-α also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-κB signalling pathway and enhanced human amylin promoter activation through NF-κB and AP1. CONCLUSIONS/INTERPRETATION: TNF-α acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders.