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Open access

Tingting Jia, Ya-nan Wang, Dongjiao Zhang and Xin Xu

Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.

Open access

Mírian Romitti, Vitor C Fabris, Patricia K Ziegelmann, Ana Luiza Maia and Poli Mara Spritzer

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18–40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional or cohort studies published until August 2017. The Ottawa–Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03 and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR = 3.27, 95% CI 2.32–4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR = 4.56, 95% CI 2.47–8.43), Europeans (OR = 3.27, 95% CI 2.07–5.15) and South Americans (OR = 1.86, 95% CI 1.05–3.29). AIDT is a frequent condition in PCOS patients and might affect thyroid function. Thus, screening for thyroid function and thyroid-specific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676.

Open access

Maurício Martins da Silva, Lueni Lopes Felix Xavier, Carlos Frederico Lima Gonçalves, Ana Paula Santos-Silva, Francisca Diana Paiva-Melo, Mariana Lopes de Freitas, Rodrigo Soares Fortunato, Leandro Miranda-Alves and Andrea Claudia Freitas Ferreira

Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS), which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10−9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to N-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.

Open access

Yang Lv, Ning Pu, Wei-lin Mao, Wen-qi Chen, Huan-yu Wang, Xu Han, Yuan Ji, Lei Zhang, Da-yong Jin, Wen-Hui Lou and Xue-feng Xu

Aim

We aim to investigate the clinical characteristics of the rectal NECs and the prognosis-related factors and construct a nomogram for prognosis prediction.

Methods

The data of 41 patients and 1028 patients with rectal NEC were retrieved respectively from our institution and SEER database. OS or PFS was defined as the major study outcome. Variables were compared by chi-square test and t-test when appropriate. Kaplan–Meier analysis with log-rank test was used for survival analysis and the Cox regression analysis was applied. The nomogram integrating risk factors for predicting OS was constructed by R to achieve superior discriminatory ability. Predictive utility of the nomogram was determined by concordance index (C-index) and calibration curve.

Results

In the univariate and multivariate analyses, tumor differentiation, N stage, M stage and resection of primary site were identified as independent prognostic indicators. The linear regression relationship was found between the value of Ki-67 index and the duration of OS (P < 0.05). Furthermore, the independent prognostic factors were added to formulate prognostic nomogram. The constructed nomogram showed good performance according to the C-index.

Conclusions

Contrary to WHO classification guideline, we found that the rectal NEC diseases are heterogeneous and should be divided as different categories according to the pathological differentiation. Besides, the nomogram formulated in this study showed excellent discriminative capability to predict OS for those patients. More advanced predictive model for this disease is required to assist risk stratification via the formulated nomogram.

Open access

Jin Kyu Oh, Young Jae Im, Kwanjin Park and Jae-Seung Paick

Although it is well known that penile growth is dependent on androgens, few clinical studies have reported successful treatment of micropenis with testosterone, likely due to concerns regarding the efficacy and safety of prolonged testosterone use. Thus, we assessed the synergenic effects of growth hormone (GH) treatments with and without testosterone on phallic growth in a rat model of micropenis. Fifty Sprague–Dawley rats were assigned to control (C), microphallus (MP), testosterone, GH (G) and GH plus testosterone (GT) treatment groups, and microphallus was induced by secondary hypogonadism. Pre-pubertal treatments with testosterone, GH or the combination were initiated from 7 days after birth and were maintained until 12 weeks of age. To assess the efficacy of treatments, phallic dimensions were determined and histological markers of cavernosal integrity were evaluated. Skeletal and gonadal safety profiles of the treatments were then assessed according to right tibial lengths and testicular weights, respectively. No monotreatments normalised penile dimensions, whereas combination treatments led to complete restoration. The combination treatment also prevented decreases in histological indicators of cavernosal integrity, including smooth muscle actin and collagen III expression levels and fat globule accumulation and sinusoidal density. These synergenic effects of GH treatments on penile growth may follow changes in androgen receptor expression levels and were accompanied by decreased testicular volume losses. Although the physiological conditions of phallic growth differ between humans and rats, this proof-of-concept study provides a strategy for circumventing the problems of testosterone monotherapy for human micropenis.

Open access

Qiuli Liu, Lin-ang Wang, Jian Su, Dali Tong, Weihua Lan, Luofu Wang, Gaolei Liu, Jun Zhang, Victor Wei Zhang, Dianzheng Zhang, Rongrong Chen, Qingyi Zhu and Jun Jiang

Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes. A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, five patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using target capture-based deep sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations. The following results were obtained. In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C>G/c.518T>A, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A>T, p.H373L/c.1459_1467del9, p.D487_F489del) in CYP17A1. To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so that appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH.

Open access

Jakob Kirkegård, Dora Körmendiné Farkas, Jens Otto Lunde Jørgensen and Deirdre P Cronin-Fenton

Objective

The association between thyroid dysfunction and gastrointestinal cancer is unclear.

Design

We conducted a nationwide population-based cohort study to examine this potential association.

Methods

We used Danish medical registries to assemble a nationwide population-based cohort of patients diagnosed with hyperthyroid or hypothyroid disease from 1978 to 2013. We computed standardized incidence ratios (SIRs) with corresponding 95% CIs as measures of the relative risk of each cancer, comparing patients with thyroid dysfunction with that expected in the general population.

Results

We included 163,972 patients, of which 92,783 had hyperthyroidism and 71,189 had hypothyroidism. In general, we found an increased risk of all gastrointestinal cancers within the first year after thyroid disease diagnosis. After more than 5 years of follow-up, patients with hyperthyroidism had a slightly increased risk of pancreatic and gallbladder and biliary tract cancer. Patients with hypothyroidism had a slightly increased risk of stomach, anal, liver, gallbladder and biliary tract, and pancreatic cancer after more than 5 years of follow-up, but the observed numbers of cancers were in general similar to the expected.

Conclusions

The increased risks of all gastrointestinal cancers in the first year following hyper- or hypothyroidism diagnosis are likely due to detection bias. After more than 5 years of follow-up, there does not seem to be a consistent causal association between thyroid disease and gastrointestinal cancer.

Open access

Natalie Rogowski-Lehmann, Aikaterini Geroula, Aleksander Prejbisz, Henri J L M Timmers, Felix Megerle, Mercedes Robledo, Martin Fassnacht, Stephanie M J Fliedner, Martin Reincke, Anthony Stell, Andrzej Januszewicz, Jacques W M Lenders, Graeme Eisenhofer and Felix Beuschlein

Background

Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure.

Objective

To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL).

Design

Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P < 0.001), found to have larger tumors (P = 0.003) and higher metanephrine and normetanephrine levels at diagnosis (P = 0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P < 0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed.

Précis

Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.

Open access

Lijuan Yuan, Xihui Chen, Ziyu Liu, Dan Wu, Jianguo Lu, Guoqiang Bao, Sijia Zhang, Lifeng Wang and Yuanming Wu

Primary hypertrophic osteoarthropathy (PHO) is a rare familial disorder with reduced penetrance for females. The genetic mutations associated with PHO have been identified in HPGD and SLCO2A1, which involved in prostaglandin E2 metabolism. Here, we report 5 PHO patients from four non-consanguineous families. Two heterozygous mutations in solute carrier organic anion transporter family member 2A1 (SLCO2A1) were identified in two brothers by whole-exome sequencing. Three heterozygous mutations and one homozygous mutation were identified in other three PHO families by Sanger sequencing. However, there was no mutation in HPGD. These findings confirmed that homozygous or compound heterozygous mutations of SLCO2A1 were the pathogenic cause of PHO. A female individual shared the same mutations in SLCO2A1 with her PHO brother but did not have any typical PHO symptoms. The influence of sex hormones on the pathogenesis of PHO and its implication were discussed.

Open access

Soraya Puglisi, Paola Perotti, Mattia Barbot, Paolo Cosio, Carla Scaroni, Antonio Stigliano, Pina Lardo, Valentina Morelli, Elisa Polledri, Iacopo Chiodini, Giuseppe Reimondo, Anna Pia and Massimo Terzolo

Objective

Metyrapone has been approved for the treatment of patients with Cushing’s syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment.

Design and methods

Before adrenalectomy, seven patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in three tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Days 14, 31, 48, 65, 82).

Results

In all patients, UFC levels decreased up to normal range from baseline to Day 82 (609 (188–1476) vs 69 (28–152) nmol/24 h, P < 0.02), with a reduction of serum and salivary cortisol levels, and no significant increase of plasma ACTH and serum DHEAS levels. Clinical improvement was reported on quality of life (+16.7 (+4.2; +52.00) points, P < 0.04) and pressure control (systolic pressure, −25 (−52; −10) mmHg, P < 0.01; diastolic pressure, −16 (−50; +2 mmHg), P < 0.03). No significant change in weight, electrolytes, glycemic and lipid profile was reported. Although in women a significant increase of testosterone and androstenedione was reported, no worsening of clinical hyperandrogenism was observed. All drug-related adverse events (nausea, fatigue, low grade fever, edema of lower limbs and facial rash) were grade 1 or 2 and generally transient.

Conclusions

This prospective pilot study demonstrated that metyrapone is effective in normalizing biochemical and clinical parameters in patients with CS due to adrenal adenoma before surgical intervention, with minimal side effects.