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Department of Clinical Biochemistry (KB3014), Department of Technology, Department of Clinical Biochemistry, Department of Biomedical Sciences, Department of Clinical Medicine, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
Search for other papers by Christina Christoffersen in
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Department of Clinical Biochemistry (KB3014), Department of Technology, Department of Clinical Biochemistry, Department of Biomedical Sciences, Department of Clinical Medicine, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
Search for other papers by Jens P Goetze in
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Disruption of the circadian rhythm can lead to obesity and cardiovascular disease. In white adipose tissue, activation of the natriuretic peptide receptors (NPRs) stimulates lipolysis. We have previously shown that natriuretic peptides are expressed in a circadian manner in the heart, but the temporal expression profile of their cognate receptors has not been examined in white adipose tissue. We therefore collected peri-renal white adipose tissue and serum from WT mice. Tissue mRNA contents of NPRs – NPR-A and NPR-C, the clock genes Per1 and Bmal1, and transcripts involved in lipid metabolism were quantified at 4-h intervals: in the diurnal study, mice were exposed to a period of 12 h light followed by 12 h darkness (n=52). In the circadian study, mice were kept in darkness for 24 h (n=47). Concomitant serum concentrations of free fatty acids, glycerol, triglycerides (TGs), and insulin were measured. Per1 and Bmal1 mRNA contents showed reciprocal circadian profiles (P<0.0001). NPR-A mRNA contents followed a temporal pattern (P=0.01), peaking in the dark (active) period. In contrast, NPR-C mRNA was expressed in an antiphase manner with nadir in the active period (P=0.007). TG concentrations in serum peaked in the active dark period (P=0.003). In conclusion, NPR-A and NPR-C gene expression is associated with the expression of clock genes in white adipose tissue. The reciprocal expression may thus contribute to regulate lipolysis and energy homeostasis in a diurnal manner.
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Department of Endocrinology, Ull Care A/S, Psychiatric Research Unit, The Cardiovascular Institute, The National Research Center for the Working Environment, Faculty of Health and Medical Sciences, Herlev University Hospital, Herlev, Denmark
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The aim of this study was to test i) whether patients having diabetes and ischemic heart disease (IHD), i.e., patients suffering from two chronic diseases, demonstrate a higher degree of chronic stress when compared with patients suffering from IHD alone, and ii) whether suffering from the two chronic diseases results in an elevation in specific elements of the chronic stress concept. A total of 361 participants with IHD were included, of whom 47 suffered from concomitant diabetes. Stress was measured by pressure pain sensitivity (PPS) and by the following questionnaires: the Major Depression Inventory (MDI), the SF-36 Quality of Life questionnaire (SF-36 QOL), the WHO-5 Well-being Index, and the clinical stress signs (CSSs) scale. Participants with diabetes and IHD had a higher MDI score, a lower SF-36 physical component summary score, and a lower score of several sub-measurements of the SF-36 mental component score when compared with patients with IHD without diabetes. No significant differences were observed regarding stress measured by the PPS measure, the WHO-5 Well-being Index, or the number of CSSs. In conclusion, the combination of diabetes and IHD seems to be associated with increased depressive symptoms, lower overall physical QOL, and reduced mental QOL on several sub-elements of the questionnaire. This should be recognized in the management of patients with double diagnoses.
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We tested the hypothesis that overweight/obese men aged 50–70 years will have a greater salivary cortisol, salivary alpha amylase and heart rate (HR) responses to psychological stress compared with age matched lean men. Lean (BMI=20–25 kg/m2; n=19) and overweight/obese (BMI=27–35 kg/m2; n=17) men (50–70 years) were subjected to a well-characterised psychological stress (Trier Social Stress Test, TSST) at 1500 h. Concentrations of cortisol and alpha amylase were measured in saliva samples collected every 7–15 min from 1400 to 1700 h. HR was recorded using electrocardiogram. Body weight, BMI, percentage body fat, resting systolic and diastolic blood pressure and mean arterial pressure were significantly higher (P<0.05) in overweight/obese men compared with lean men. Both groups responded to the TSST with a substantial elevation in salivary cortisol (372%), salivary alpha amylase (123%) and HR (22%). These responses did not differ significantly between the groups (time×treatment interaction for salivary cortisol, salivary alpha amylase and HR; P=0.187, P=0.288, P=0.550, respectively). There were no significant differences between the groups for pretreatment values, peak height, difference between pretreatment values and peak height (reactivity) or area under the curve for salivary cortisol, salivary alpha amylase or HR (P>0.05 for all). The results showed that, for men with a moderate level of overweight/obesity who were otherwise healthy, the response of salivary cortisol, salivary alpha amylase and HR to acute psychological stress was not impaired.
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Purpose
Although resection is the primary treatment strategy for pheochromocytoma, surgery is associated with a high risk of morbidity. At present, there is no nomogram for prediction of severe morbidity after pheochromocytoma surgery, thus the aim of the present study was to develop and validate a nomogram for prediction of severe morbidity after pheochromocytoma surgery.
Methods
The development cohort consisted of 262 patients who underwent unilateral laparoscopic or open pheochromocytoma surgery at our center between 1 January 2007 and 31 December 2016. The patients’ clinicopathological characters were recorded. The least absolute shrinkage and selection operator (LASSO) binary logistic regression model was used for data dimension reduction and feature selection, then multivariable logistic regression analysis was used to develop the predictive model. An independent validation cohort consisted of 128 consecutive patients from 1 January 2017 and 31 December 2018. The performance of the predictive model was assessed in regards to discrimination, calibration, and clinical usefulness.
Results
Predictors of this model included sex, BMI, coronary heart disease, arrhythmia, tumor size, intraoperative hemodynamic instability, and surgical duration. For the validation cohort, the model showed good discrimination with an AUROC of 0.818 (95% CI, 0.745, 0.891) and good calibration (Unreliability test, P = 0.440). Decision curve analysis demonstrated that the model was also clinically useful.
Conclusions
A nomogram was developed to facilitate the individualized prediction of severe morbidity after pheochromocytoma surgery and may help to improve the perioperative strategy and treatment outcome.
Leiden Institute for Brain and Cognition, Leiden, The Netherlands
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Leiden Institute for Brain and Cognition, Leiden, The Netherlands
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Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
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Leiden Institute for Brain and Cognition, Leiden, The Netherlands
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The presence of an additional X or Y chromosome (sex chromosome trisomies, SCT) is associated with an increased risk for neurodevelopmental difficulties, including socio-emotional problems, across the life span. Studying emotion regulation in young children with SCT could signal deviations in emotional development that serve as risk markers to guide clinical care. This study explored the presence and variety of emotion regulation strategies in 75 SCT children and 81 population-based controls, aged 1–7 years, during a frustration-inducing event in which physiological (heart rate) and observational data (behavioral responses) were collected. Children with SCT were equally physiologically aroused by the event as compared to controls. However, they showed more emotion regulation difficulties in terms of behavior compared to controls that were not explicable in terms of differences in general intellectual functioning. Specifically, they had a more limited range of behavioral alternatives and tended to rely longer on inefficient strategies with increasing age. The field of practice should be made aware of these early risk findings regarding emotion regulation in SCT, which may potentially lay the foundation for later socio-emotional problems, given the significant impact of emotion regulation on child and adult mental health outcomes. The current results may help to design tailored interventions to reduce the impact of the additional sex chromosome on adaptive functioning, psychopathology, and quality of life.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Patients with pheochromocytoma and paraganglioma (PPGL) are treated with α-adrenoceptor antagonists to improve peroperative hemodynamics. However, preoperative blood pressure targets differ between institutions. We retrospectively compared per- and postoperative hemodynamics in 30 patients with PPGL that were pretreated with phenoxybenzamine aiming at different blood pressure targets at two separate endocrine departments. All patients were subsequently undergoing laparoscopic surgery at Department of Urology, Herlev University hospital. Fourteen patients were treated targeting to symptomatic and significant orthostatic hypotension and 16 patients to a seated blood pressure below 130/80 mmHg. As a control group, we included 34 patients undergoing laparoscopic adrenalectomy for other reasons. The group titrated to orthostatic hypotension required a higher dose of phenoxybenzamine to achieve the blood pressure target. This group had less intraoperative systolic and diastolic blood pressure fluctuation (Mann–Whitney U test; P < 0.05) and less periods with heart rate above 100 b.p.m. (Mann–Whitney U test; P = 0.04) as compared to the group with a preoperative blood pressure target below 130/80 mmHg. Peroperative use of intravenous fluids were similar between the two groups, but postoperatively more intravenous fluids were administered in the group with a target of ortostatism. Overall, the control group was more hemodynamic stable as compared to either group treated for PPGL. We conclude that phenoxybenzamine pretreatment targeting ortostatic hypotension may improve peroperative hemodynamic stability but causes a higher postoperative requirement for intravenous fluids. Overall, PPGL surgery is related to greater hemodynamic instability compared to adrenalectomy for other reasons.
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Follicular thyroid cancer (FTC) is the second most common type of thyroid cancers. In order to develop more effective personalized therapies, it is necessary to thoroughly evaluate patient-derived cell lines in in vivo preclinical models before using them to test new, targeted therapies. This study evaluates the tumorigenic and metastatic potential of a panel of three human FTC cell lines (WRO, FTC-238, and TT1609-CO2) with defined genetic mutations in two in vivo murine models: an orthotopic thyroid cancer model to study tumor progression and a tail vein injection model to study metastasis. All cell lines developed tumors in the orthotopic model, with take rates of 100%. Notably, WRO-derived tumors grew two to four times faster than tumors arising from the FTC-238 and TT2609-CO2 cell lines. These results mirrored those of a tail vein injection model for lung metastasis: one hundred percent of mice injected with WRO cells in the tail vein exhibited aggressive growth of bilateral lung metastases within 35 days. In contrast, tail vein injection of FTC-238 or TT2609-CO2 cells did not result in lung metastasis. Together, our work demonstrates that these human FTC cell lines display highly varied tumorigenic and metastatic potential in vivo with WRO being the most aggressive cell line in both orthotopic and lung metastasis models. This information will be valuable when selecting cell lines for preclinical drug testing.
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Medical Microbiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Physiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.
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Aims/hypothesis
The macrophage-specific glycoprotein sCD163 has emerged as a biomarker of low-grade inflammation in the metabolic syndrome and related disorders. High sCD163 levels are seen in acute sepsis as a result of direct lipopolysaccharide-mediated shedding of the protein from macrophage surfaces including Kupffer cells. The aim of this study was to investigate if low-grade endotoxinemia in human subjects results in increasing levels of sCD163 in a cortisol-dependent manner.
Methods
We studied eight male hypopituitary patients and eight age- and gender-matched healthy controls during intravenous low-dose LPS or placebo infusion administered continuously over 360 min. Furthermore, we studied eight healthy volunteers with bilateral femoral vein and artery catheters during a 360-min infusion with saline and low-dose LPS in each leg respectively.
Results:
Systemic low-grade endotoxinemia resulted in a gradual increase in sCD163 from 1.65 ± 0.51 mg/L (placebo) to 1.92 ± 0.46 mg/L (LPS) at 220 min, P = 0.005 and from 1.66 ± 0.42 mg/L (placebo) to 2.19 ± 0.56 mg/L (LPS) at 340 min, P = 0.006. A very similar response was observed in hypopituitary patients: from 1.59 ± 0.53 mg/L (placebo) to 1.83 ± 0.45 mg/L (LPS) at 220 min, P = 0.021 and from 1.52 ± 0.53 mg/L (placebo) to 2.03 ± 0.44 mg/L (LPS) at 340 min, P < 0.001. As opposed to systemic treatment, continuous femoral artery infusion did not result in increased sCD163.
Conclusion:
Systemic low-grade endotoxinemia resulted in increased sCD163 to levels seen in the metabolic syndrome in both controls and hypopituitary patients. This suggests a direct and cortisol-independent effect of LPS on the shedding of sCD163. We observed no effect of local endotoxinemia on levels of serum sCD163.
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Objective
Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.
Design
A total of 16 females and 40 males, ages 23–68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort.
Results
Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.
Conclusions
This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
