This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children’s Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, eight patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. In conclusion, ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children’s families has an important guiding significance for treatment planning and prognosis assessment.
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Zi-Di Xu, Wei Zhang, Min Liu, Huan-Min Wang, Pei-Pei Hui, Xue-Jun Liang, Jie Yan, Yu-Jun Wu, Yan-Mei Sang, Cheng Zhu and Gui-Chen Ni
Linfei Yang, Xiao Yu and Yongchao Yang
Although the upregulation of autotaxin (ATX) is associated with many solid tumours, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The expression of ATX in pNEN tissues and pNEN cell line BON1 was analysed by Western blot, PCR and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with siRNAs against ATX or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The following results were obtained. The expression of ATX in pNEN tissues was significantly increased compared with that in normal pancreatic tissues. High ATX expression was strongly correlated with tumour grade, lymph node metastasis and tumour-node-metastasis stage. Furthermore, ATX downregulation notably inhibited the metastatic capacity of pNEN cells, whereas STAT3 knockdown was found to downregulate the expression of ATX. ATX expression was upregulated in BON1 cells upon stimulation with IL-6, and this was accompanied by activation/phosphorylation of STAT3. Western blot analysis of human pNEN tissue extracts confirmed increased ATX expression and STAT3 phosphorylation with elevated expression levels of IL-6. In conclusion, ATX is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with STAT3 activation.
Søs Dragsbæk Larsen, Christine Dalgård, Mathilde Egelund Christensen, Sine Lykkedegn, Louise Bjørkholt Andersen, Marianne Andersen, Dorte Glintborg and Henrik Thybo Christesen
Low foetal vitamin D status may be associated with higher blood pressure (BP) in later life.
To examine whether serum 25-hydroxyvitamin D2+3 (s-25OHD) in cord and pregnancy associates with systolic and diastolic BP (SBP; DBP) in children up to 3 years of age.
Prospective, population-based cohort study.
We included 1594 singletons from the Odense Child Cohort with available cord s-25OHD and BP data at median age 3.7 months (48% girls), 18.9 months (44% girls) or 3 years (48% girls). Maternal s-25OHD was also assessed at gestational ages 12 and 29 weeks. Multiple regression models were stratified by sex a priori and adjusted for maternal educational level, season of birth and child height, weight and age.
In 3-year-old girls, SBP decreased with −0.7 mmHg (95% CI −1.1; −0.3, P = 0.001) and DBP with −0.4 mmHg (95% CI −0.7; −0.1, P = 0.016) for every 10 nmol/L increase in cord s-25OHD in adjusted analyses. Moreover, the adjusted odds of having SBP >90th percentile were reduced by 30% for every 10 nmol/L increase in cord s-25OHD (P = 0.004) and by 64% for cord s-25OHD above the median 45.1 nmol/L (P = 0.02). Similar findings were observed between pregnancy s-25OHD and 3-year SBP, cord s-25OHD and SBP at 18.9 months, and cord s-25OHD and DBP at 3 years. No consistent associations were observed between s-25OHD and BP in boys.
Cord s-25OHD was inversely associated with SBP and DBP in young girls, but not in boys. Higher vitamin D status in foetal life may modulate BP in young girls. The sex difference remains unexplained.
Zhen-yu Song, Qiuming Yao, Zhiyuan Zhuo, Zhe Ma and Gang Chen
Previous studies investigating the association of circulating 25-hydroxyvitamin D level with prognosis of prostate cancer yielded controversial results. We conducted a dose–response meta-analysis to elucidate the relationship. PubMed and EMBASE were searched for eligible studies up to July 15, 2018. We performed a dose–response meta-analysis using random-effect model to calculate the summary hazard ratio (HR) and 95% CI of mortality in patients with prostate cancer. Seven eligible cohort studies with 7808 participants were included. The results indicated that higher vitamin D level could reduce the risk of death among prostate cancer patients. The summary HR of prostate cancer-specific mortality correlated with an increment of every 20 nmol/L in circulating vitamin D level was 0.91, with 95% CI 0.87–0.97, P = 0.002. The HR for all-cause mortality with the increase of 20 nmol/L vitamin D was 0.91 (95% CI: 0.84–0.98, P = 0.01). Sensitivity analysis suggested the pooled HRs were stable and not obviously changed by any single study. No evidence of publications bias was observed. This meta-analysis suggested that higher 25-hydroxyvitamin D level was associated with a reduction of mortality in prostate cancer patients and vitamin D is an important protective factor in the progression and prognosis of prostate cancer.
Devis Pascut, Sofia Tamini, Silvia Bresolin, Pablo Giraudi, Giuseppe Basso, Alessandro Minocci, Claudio Tiribelli, Graziano Grugni and Alessandro Sartorio
Prader–Willi syndrome (PWS) represents the most common genetic-derived obesity disorder caused by the loss of expression of genes located on the paternal chromosome 15q11.2-q13. The PWS phenotype shows peculiar physical, endocrine and metabolic characteristics compared to those observed in non-syndromic essential obesity. Since miRNAs have now a well-established role in many molecular pathways, including regulatory networks related to obesity, this pilot study was aimed to characterize the expression of circulating miRNAs in PWS compared to essential obesity. The circulating miRNome of 10 PWS and 10 obese subjects, adequately matched for age, BMI and sex, was profiled throughout Genechip miRNA 4.0 microarray analysis. We identified 362 out of 2578 mature miRNAs to be expressed in serum of the studied population. The circulating miRNA signature significantly characterising the two populations include 34 differently expressed RNAs. Among them, miR-24-3p, miR-122 and miR-23a-3p highly differ between the two groups with a FC >10 in obese compared to PWS. In the obese subjects, miR-7107-5p, miR-6880-3p, miR-6793-3p and miR-4258 were associated to the presence of steatosis. A different signature of miRNAs significantly distinguished PWS with steatosis from PWS without steatosis, involving miR-619-5p, miR-4507, miR-4656, miR-7847-3p and miR-6782-5p. The miRNA target GO enrichment analysis showed the different pathway involved in these two different forms of obesity. Although the rarity of PWS actually represents a limitation to the availability of large series, the present study provides novel hints on the molecular pathogenesis of syndromic and non-syndromic obesity.
Zhou-Qing Kang, Jia-Ling Huo and Xiao-Jie Zhai
The optimal glycemic target during the perioperative period is still controversial. We aimed to explore the effects of tight glycemic control (TGC) on surgical mortality and morbidity.
PubMed, EMBASE and CENTRAL were searched from January 1, 1946 to February 28, 2018. Appropriate trails comparing the postoperative outcomes (mortality, hypoglycemic events, acute kidney injury, etc.) between different levels of TGC and liberal glycemic control were identified. Quality assessments were performed with the Jadad scale combined with the allocation concealment evaluation. Pooled relative risk (RR) and 95% CI were calculated using random effects models. Heterogeneity was detected by the I 2 test.
Twenty-six trials involving a total of 9315 patients were included in the final analysis. The overall mortality did not differ between tight and liberal glycemic control (RR, 0.92; 95% CI, 0.78–1.07; I 2 = 20.1%). Among subgroup analyses, obvious decreased risks of mortality were found in the short-term mortality, non-diabetic conditions, cardiac surgery conditions and compared to the very liberal glycemic target. Furthermore, TGC was associated with decreased risks for acute kidney injury, sepsis, surgical site infection, atrial fibrillation and increased risks of hypoglycemia and severe hypoglycemia.
Compared to liberal control, perioperative TGC (the upper level of glucose goal ≤150 mg/dL) was associated with significant reduction of short-term mortality, cardic surgery mortality, non-diabetic patients mortality and some postoperative complications. In spite of increased risks of hypoglycemic events, perioperative TGC will benefits patients when it is done carefully.
The brain hosts a vast and diverse repertoire of neuropeptides, a class of signalling molecules often described as neurotransmitters. Here I argue that this description entails a catalogue of misperceptions, misperceptions that feed into a narrative in which information processing in the brain can be understood only through mapping neuronal connectivity and by studying the transmission of electrically conducted signals through chemical synapses. I argue that neuropeptide signalling in the brain involves primarily autocrine, paracrine and neurohormonal mechanisms that do not depend on synaptic connectivity and that it is not solely dependent on electrical activity but on mechanisms analogous to secretion from classical endocrine cells. As in classical endocrine systems, to understand the role of neuropeptides in the brain, we must understand not only how their release is regulated, but also how their synthesis is regulated and how the sensitivity of their targets is regulated. We must also understand the full diversity of effects of neuropeptides on those targets, including their effects on gene expression.
Yiqiang Huang, Lin-ang Wang, Qiubo Xie, Jian Pang, Luofu Wang, Yuting Yi, Jun Zhang, Yao Zhang, Rongrong Chen, Weihua Lan, Dianzheng Zhang and Jun Jiang
Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.
Yongli Fu, Yaowu Sun, Jiankun Zhang and Yu Cheng
This meta-analysis aims to update the evidence for the effects of intensive glucose control (IGC) on the outcomes among critically ill patients. We performed a systematic literature review from inception through December, 2017 by two independent authors by searching PubMed, EMBASE and Cochrane Library. Randomized clinical trials of the effects of IGC compared with conventional glucose control were selected. Random-effect models were applied to calculate summary relative risks (RRs) for the related outcomes. Of 4247 records identified, we abstracted data from 27 relevant trials for meta-analysis. Compared with patients receiving conventional glucose control (controls), patients with IGC did not have significantly decreased risk of short-term mortality (in-hospital mortality or intensive care unit (ICU) mortality) (RR 0.99, 95% CI 0.92–1.06) or 3- to 6-month mortality (RR 1.02, 95% CI 0.97–1.08). These results remained constant among different study settings including surgical ICUs, medical ICUs or mixed ICUs. Similarly, we also found that patients with IGC did not have significantly lower risk of sepsis (RR 1.00, 95% CI 0.89–1.11) or new need for dialysis (RR 0.97, 95% CI 0.84–1.11). However, patients with IGC had almost 4-fold increase in risk of hypoglycemia (RR 4.86, 95% CI 3.16–7.46). In conclusion, in this updated meta-analysis of published trials, critically ill patients receiving IGC were found to be at neutral risk for short-term or 3- 6-month mortality, risk of sepsis or new need for dialysis, but at higher risk of hypoglycemia.
Myrtille Fouché, Yves Bouffard, Mary-Charlotte Le Goff, Johanne Prothet, François Malavieille, Pierre Sagnard, Françoise Christin, Davy Hayi-Slayman, Arnaud Pasquer, Gilles Poncet, Thomas Walter and Thomas Rimmelé
Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients (liver metastases: 59, prior carcinoid syndrome: 49, carcinoid heart disease: 7) were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol.