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Open access

Yiqiong Ma, Zhaowei Chen, Yu Tao, Jili Zhu, Hongxia Yang, Wei Liang and Guohua Ding

Aims

Previous studies showed that abnormal mitochondrial structure and function were involved in the pathological process of diabetic nephropathy (DN). The dynamic mitochondrial processes, including fusion and fission, maintain the mass and quantity of mitochondria. Podocyte injury is a critical factor in the development and progression of DN. The present study evaluated the mitochondrial fission of podocytes in patients with DN.

Methods

We recruited 31 patients with biopsy-confirmed DN. A quantitative analysis of the mitochondrial morphology was conducted with electron microscopy using a computer-assisted morphometric analysis application to calculate the aspect ratio values. Immunofluorescence assays were used to evaluate protein colocalization in the glomeruli of patients.

Results

The urine protein level was significantly increased in DN patients compared to non-DN patients (P < 0.001), and the mitochondria in the podocytes from DN patients were more fragmentated than those from patients without DN. The mitochondrial aspect ratio values were negatively correlated with the proteinuria levels (r = −0.574, P = 0.01), and multiple regression analysis verified that the mitochondrial aspect ratio was significantly and independently associated with the urine protein level (β = −0.519, P = 0.007). In addition, Drp1, a mitochondrial fission factor, preferentially combines with AKAP1, which is located in the mitochondrial membrane.

Conclusions

In the podocytes of DN patients, mitochondrial fragmentation was increased, and mitochondrial aspect ratio values were correlated with the proteinuria levels. The AKAP1-Drp1 pathway may contribute to mitochondrial fission in the pathogenesis of DN.

Open access

Agnieszka Adamska, Aleksandra Maria Polak, Anna Krentowska, Agnieszka Łebkowska, Justyna Hryniewicka, Monika Leśniewska and Irina Kowalska

Objective

PCOS women are characterized by insulin resistance and have higher tendency to the development of hepatic steatosis. Fetuin-B has been introduced as a hepatokine/adipokine, which is increased in hepatic steatosis and may be connected with glucose metabolism disturbances. The aim of the study was to evaluate the relationships between serum fetuin-B concentration and indices of insulin resistance, insulin secretion and markers of liver steatosis in PCOS women in comparison to the control group.

Patients and methods

The study group included 108 women – 57 women with PCOS and 51 women matched for age and BMI as a control group. Serum concentration of fetuin-B was estimated. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment β cell function (HOMA-β) were calculated. Fatty liver index (FLI), lipid accumulation product (LAP) and visceral adiposity index (VAI) were used as markers of liver steatosis.

Results

We found higher serum concentration of fetuin-B and FLI in PCOS women in comparison to the control group (all P < 0.05). We observed a positive relationship between serum fetuin-B concentration and HOMA-β (r = 0.43, P = 0.01), HOMA-IR (r = 0.31, P = 0.01), FLI (r = 0.29, P = 0.02), VAI (r = 0.29, P = 0.02) and LAP (r = 0.32, P = 0.01) in PCOS women. We also noticed a relationship between HOMA-IR and FLI (r = 0.42, P = 0.01), VAI (r = 0.38, P = 0.004) and LAP (r = 0.41, P = 0.001) in this group. Multiple regression analysis revealed that HOMA-β (β = 0.39, P = 0.002) and LAP (β = 0.27, P = 0.02) were independently connected with serum fetuin-B levels in women with PCOS.

Conclusions

Serum fetuin-B levels are higher in women with PCOS and are independently connected with HOMA-β and hepatic steatosis.

Open access

Matilde Calanchini, Michael Tadman, Jesper Krogh, Andrea Fabbri, Ashley Grossman and Brian Shine

Background

The 24-h urinary output of 5-hydroxyindoleacetic acid (5-HIAA) is used to monitor disease progression and treatment responses of neuroendocrine neoplasms (NENs). Several conditions are required for 5-HIAA assay, involving urine collection/preservation and food/drug restrictions.

Aim

To evaluate the correlation between 5-HIAA concentration in a spot urine sample and the output in a 24-h urine collection, and whether spot urine specimens can replace 24-h collection.

Methods

Patients with NENs or symptoms suggestive of NENs were asked to provide a separate spot urine at the end of the 24-h urine collection for 5-HIAA assessment. The upper reference limit for 24-h urinary 5-HIAA was 40 µmol/24 h. 5-HIAA measurements in spot urine samples were corrected for variation in urine flow rate by expressing results as a ratio to creatinine concentration.

Results

We included 136 paired urinary samples for 5-HIAA assessment from 111 patients (100 NENs). The correlation between 5-HIAA values measured in 24-h and spot urines was r = +0.863 (P < 0.001) and r = +0.840 (P < 0.001) including only NEN patients. Using the 24-h urinary 5-HIAA as reference method, the AUC on ROC analysis for spot urinary 5-HIAA was 0.948 (95% CI, 0.914–0.983; P < 0.001), attaining a sensitivity of 83% and specificity of 95% using 5.3 mol/mmol as cut-off for the spot urine. The AUC among NEN patients alone was 0.945 (95% CI, 0.904–0.987; P < 0.001).

Conclusions

The ratio of 5-HIAA to creatinine in a spot urine could replace the measurement of 5-HIAA output in a 24-h urine collection, especially for follow-up of patients with known elevated 5-HIAA levels.

Open access

Lesley A Hill, Zeynep Sumer-Bayraktar, John G Lewis, Eva Morava, Morten Thaysen-Andersen and Geoffrey L Hammond

Objective

Discrepancies in ELISA measurements of human corticosteroid-binding globulin (CBG) using detection monoclonal antibodies that recognize an epitope (9G12) within its reactive center loop (RCL), versus an epitope (12G2) in a different location, have suggested that CBG with a proteolytically cleaved RCL exists in blood samples. We have previously been unable to verify this biochemically, and sought to determine if N-glycosylation differences account for discrepancies in ELISA measurements of CBG.

Methods and subjects

Molecular biological, biochemical and glycopeptide analyses were used to examine how N-glycosylation at specific sites, including at N347 within the RCL, affect CBG ELISA or steroid-binding capacity assay (BCA) measurements. Plasma from patients with congenital disorders of glycosylation (CDG) was also examined in these assays as examples of N-glycosylation defects.

Results

We demonstrate that an N-glycan at N347 within the CBG RCL limits the 9G12 antibody from recognizing its epitope, whereas the 12G2 antibody reactivity is unaffected, thereby contributing to discrepancies in ELISA measurements using these two antibodies. Qualitative differences in N-glycosylation at N238 also negatively affect the steroid-binding of CBG in the absence of an N-glycan at N347 caused by a T349A substitution. Desialylation increased both ELISA measurements relative to BCA values. Similarly, plasma CBG levels in both ELISAs were much higher than BCA values in several CDG patients.

Conclusions

Plasma CBG measurements are influenced by variations in N-glycosylation. This is important given the increasing number of CDG defects identified recently and because N-glycosylation abnormalities are common in patients with metabolic and liver diseases.

Open access

Tiina Vesterinen, Teijo Kuopio, Maarit Ahtiainen, Aija Knuuttila, Harri Mustonen, Kaisa Salmenkivi, Johanna Arola and Caj Haglund

Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.

Open access

Elham Barazeghi, Per Hellman, Gunnar Westin and Peter Stålberg

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.

Open access

Kristine Zøylner Swan, Steen Joop Bonnema, Marie Louise Jespersen and Viveque Egsgaard Nielsen

Thyroid nodular disease is common, but predicting the risk of malignancy can be difficult. In this prospective study, we aimed to assess the diagnostic accuracy of shear wave elastography (SWE) in predicting thyroid malignancy. Patients with thyroid nodules were enrolled from a surgical tertiary unit. Elasticity index (EI) measured by SWE was registered for seven EI outcomes assessing nodular stiffness and heterogeneity. The diagnosis was determined histologically. In total, 329 patients (mean age: 55 ± 13 years) with 413 thyroid nodules (mean size: 32 ± 13 mm, 88 malignant) were enrolled. Values of SWE region of interest (ROI) for malignant and benign nodules were highly overlapping (ranges for SWE-ROImean: malignant 3–100 kPa; benign 4–182 kPa), and no difference between malignant and benign nodules was found for any other EI outcome investigated (P = 0.13–0.96). There was no association between EI and the histological diagnosis by receiver operating characteristics analysis (area under the curve: 0.51–0.56). Consequently, defining a cut-off point of EI for the prediction of malignancy was not clinically meaningful. Testing our data on previously proposed cut-off points revealed a low accuracy of SWE (56–80%). By regression analysis, factors affecting EI included nodule size >30 mm, heterogeneous echogenicity, micro- or macrocalcifications and solitary nodule. In conclusion, EI, measured by SWE, showed huge overlap between malignant and benign nodules, and low diagnostic accuracy in the prediction of thyroid malignancy. Our study supports that firmness of thyroid nodules, as assessed by SWE, should not be a key feature in the evaluation of such lesions.

Open access

Sara Storvall, Helena Leijon, Eeva Ryhänen, Johanna Louhimo, Caj Haglund, Camilla Schalin-Jäntti and Johanna Arola

Introduction

Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown.

Aim

Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas.

Methods

We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics.

Results

All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression.

Conclusions

Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.

Open access

Boni Xiang, Ran Tao, Xinhua Liu, Xiaoming Zhu, Min He, Zengyi Ma, Yehong Yang, Zhaoyun Zhang, Yiming Li, Zhenwei Yao, Yongfei Wang and Hongying Ye

Objective

The aim of this study was to evaluate thyroid functions in Cushing’s syndrome (CS), the dynamic changes of thyroid hormones and antithyroid antibodies in Cushing’s disease (CD) pre- and postoperatively.

Design and methods

This is a retrospective study enrolling 118 patients with CS (102 CD, 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)). Thyroid functions (thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4 and free T4 (FT4)) were measured in all CS at the time of diagnosis and in all CD 3 months after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. Twenty-eight remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th and 12th month after surgery.

Results

TSH, T3 and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P = 0.000), T3 (P = 0.000) and FT3 (P = 0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3 and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients’ thyroid functions returned to normal. Thyroid hormones (including TSH, T3 and FT3) were negatively associated with serum cortisol levels both before and after surgery. No significant changes of antithyroid autoantibodies were observed.

Conclusions

TSH, T3 and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3 and FT3 increased significantly, even above the reference range, but returned to normal 1 year after surgery in most cases. Antithyroid antibodies did not change significantly after remission of CD.

Open access

Jingya Zhou, Meng Zhang, Lin Lu, Xiaopeng Guo, Lu Gao, Weigang Yan, Haiyu Pang, Yi Wang and Bing Xing

Objective

To investigate the validity of discharge ICD-10 codes in detecting the etiology of endogenous Cushing’s syndrome (CS) in hospitalized patients.

Methods

We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CS etiology-related ICD-10 codes or code combinations by comparing hospital discharge administrative data (DAD) with established diagnoses from medical records.

Results

Coding for patients with adrenocortical adenoma (ACA) and those with bilateral macronodular adrenal hyperplasia (BMAH) demonstrated disappointingly low sensitivity at 78.8% (95% CI: 70.1–85.6%) and 83.9% (95% CI: 65.5–93.9%), respectively. BMAH had the lowest PPV of 74.3% (95% CI: 56.4–86.9%). In confirmed ACA patients, the sensitivity for ACA code combinations was higher in patients initially admitted to the Department of Endocrinology before surgery than that in patients directly admitted to the Department of Urology (90.0 vs 73.1%, P = 0.033). The same phenomenon was observed in the PPV for the BMAH code (100.0 vs 60.9%, P = 0.012). Misinterpreted or confusing situations caused by coders (68.1%) and by the omission or denormalized documentation of symptomatic diagnosis by clinicians (26.1%) accounted for the main source of coding errors.

Conclusions

Hospital DAD is an effective data source for evaluating the etiology of CS but not ACA and BMAH. Improving surgeons’ documentation, especially in the delineation of symptomatic and locative diagnoses in discharge abstracts; department- or disease-specific training for coders and more multidisciplinary collaboration are ways to enhance the applicability of administrative data for CS etiologies.