Publications by authors named "Jürgen Kratzsch"

212 Publications

Genome-wide association and transcriptome analysis suggests total serum ghrelin to be linked with GFRAL.

Eur J Endocrinol 2021 May 10;184(6):847-856. Epub 2021 May 10.

Department of Psychiatry and Psychotherapy, Clinical Chemistry and Molecular Diagnostics.

Objective: Ghrelin is an orexigenic peptide hormone involved in the regulation of energy homeostasis, food intake and glucose metabolism. Serum levels increase anticipating a meal and fall afterwards. Underlying genetic mechanisms of the ghrelin secretion are unknown.

Methods: Total serum ghrelin was measured in 1501 subjects selected from the population-based LIFE-ADULT-sample after an overnight fast. A genome-wide association study (GWAS) was performed. Gene-based expression association analyses (transcriptome-wide association study (TWAS)) are statistical tests associating genetically predicted expression to a certain trait and were done using MetaXcan.

Results: In the GWAS, three loci reached genome-wide significance: the WW-domain containing the oxidoreductase-gene (WWOX; P = 1.80E-10) on chromosome 16q23.3-24.1 (SNP: rs76823993); the contactin-associated protein-like 2 gene (CNTNAP2; P = 9.0E-9) on chromosome 7q35-q36 (SNP: rs192092592) and the ghrelin And obestatin prepropeptide gene (GHRL; P = 2.72E-8) on chromosome 3p25.3 (SNP: rs143729751). In the TWAS, the three genes where the expression was strongest associated with serum ghrelin levels was the ribosomal protein L36 (RPL36; P = 1.3E-06, FDR = 0.011, positively correlated), AP1B1 (P = 1.1E-5, FDR = 0.048, negatively correlated) and the GDNF family receptor alpha like (GFRAL), receptor of the anorexigenic growth differentiation factor-15 (GDF15), (P = 1.8E-05, FDR = 0.15, also negatively correlated).

Conclusions: The three genome-wide significant genetic loci from the GWA and the genes identified in the TWA are functionally plausible and should initiate further research.
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http://dx.doi.org/10.1530/EJE-20-1220DOI Listing
May 2021

The effect of depressive symptomatology on the association of vitamin D and sleep.

BMC Psychiatry 2021 04 6;21(1):178. Epub 2021 Apr 6.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Centre, Semmelweisstrasse 10, D-04103, Leipzig, Germany.

Background: Sleep disorders and vitamin D deficiency are highly prevalent health problems. Few studies examined the effect of vitamin D concentrations on objectively measured sleep with high methodological quality and temporal proximity. Previous analysis within the LIFE-Adult-Study suggested that a lower concentration of serum vitamin D was associated with both shorter and later night sleep. However, no conclusion about underlying mechanisms could be drawn. We addressed the question whether this relationship is explained by the presence of depressive syndromes, which are linked to both vitamin D deficiency and sleep disturbances.

Methods: It was investigated whether the association of vitamin D concentrations and night sleep parameters is mediated or moderated by depressive symptomatology. We investigated a subset (n = 1252) of the community sample from the LIFE-Adult-Study, in which sleep parameters had been objectively assessed using actigraphy, based on which two sleep parameters were calculated: night sleep duration and midsleep time. Serum 25(OH) D concentrations were measured using an electrochemiluminescence immunoassay. Depressive symptomatology was evaluated with the Centre for Epidemiological Studies Depression Scale. The mediation effect was analyzed by using Hayes' PROCESS macro tool for SPSS for Windows.

Results: The depressive symptomatology was neither significantly associated with night sleep duration nor midsleep time. The associations between vitamin D concentrations and night sleep duration/midsleep time through mediation by depressive symptomatology were not significant. Corresponding moderator analyses were also non-significant.

Conclusion: The associations between vitamin D concentrations and night sleep parameters (sleep duration and midsleep time) seem to be neither mediated nor moderated by depressive symptomatology.
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http://dx.doi.org/10.1186/s12888-021-03176-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025511PMC
April 2021

Socioeconomic Status Is Related to Pubertal Development in a German Cohort.

Horm Res Paediatr 2020 17;93(9-10):548-557. Epub 2021 Mar 17.

LIFE - Leipzig Research Center for Civilization Diseases, Leipzig University, Leipzig, Germany,

Introduction: Current health literature suggests that there has been a decline in the age of pubertal onset and that pubertal onset/duration of puberty may, besides weight status, be influenced by socioeconomic context.

Objective: The goal of this study was to determine whether pubertal onset/duration and puberty-triggering hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) vary according to socioeconomic status (SES). Moreover, we aimed to propose cutoff values of serum LH and FSH for predicting gonadarche in boys.

Methods: 2,657 apparently healthy children and adolescents between 5.5 and 18 years from the area of Leipzig were recruited from the LIFE Child study. Age at pubertal onset/end of puberty was given in 738/573 children, respectively. Anthropometric parameters of puberty, blood measurements of LH and FSH, and questionnaires assessing SES were evaluated.

Results: Lower SES was associated with earlier thelarche and longer duration of puberty in overweight/obese girls, whereas age of menarche was not affected. In boys with low SES, a trend versus earlier puberty onset can be seen. Lower SES was significantly associated with boys' age at mutation. No significant differences in boys' and girls' serum levels of LH and FSH during puberty according to SES were observed. Serum LH levels of 0.56 IU/L and serum FSH levels of 1.74 IU/L showed the best prediction of gonadarche in boys.

Conclusion: Puberty onset/duration and boys' age at mutation is affected by SES. The proposed cutoff levels for serum LH and FSH could provide a serological tool to determine gonadarche in boys.
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http://dx.doi.org/10.1159/000513787DOI Listing
March 2021

The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction.

Eur Heart J 2021 Feb 27. Epub 2021 Feb 27.

Heart Center Leipzig at University of Leipzig, Department of Internal Medicine/Cardiology, Strümpellstr.. 39, 04289 Leipzig, and Leipzig Heart Institute, Leipzig, Germany.

Background : Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score.

Methods And Results : A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively).

Conclusions : A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS.
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http://dx.doi.org/10.1093/eurheartj/ehab110DOI Listing
February 2021

Age-Related Association of Calcitonin with Parameters of Anthropometry, Bone and Calcium Metabolism during Childhood.

Horm Res Paediatr 2020 11;93(6):361-370. Epub 2020 Dec 11.

Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (ILM), University Hospital Leipzig, Leipzig, Germany,

Introduction: The thyroid parafollicular hormone calcitonin (CT) shows particularly high blood levels in early childhood, a period of high bone turnover, which decrease with increasing age. Data about the physiological role of CT during infancy, childhood, and adolescence are contradictory or lacking.

Objective: We hypothesize that CT demonstrates age-related correlations with parameters of bone growth and turnover as well as with parameters of calcium homeostasis.

Methods: 5,410 measurements of anthropometric data and venous blood samples were collected from 2,636 participants of the LIFE Child study, aged 2 months-18 years. Univariate correlations and multiple regression analysis were performed between serum CT and anthropometric indicators (height standard deviation scores [SDS] and BMI-SDS), markers of calcium (Ca) homeostasis (Ca, parathyroid hormone, 25-OH vitamin D, and phosphate [P]), bone formation (procollagen type 1 N-terminal propeptide [P1NP], osteocalcin), and bone resorption (β-CrossLaps).

Results: CT was significantly associated with Ca (β = 0.26, p < 0.05) and P1NP/100 (β = 0.005, p < 0.05) in children aged 2 months-1.1 years. These relations were independent of age and sex and could not be confirmed in children aged 1.1-8 years. Independent of age, sex, puberty, P, and height SDS CT showed a significant positive relation to Ca (β = 0.26; p < 0.001) in children aged 8-18 years.

Conclusions: Our findings suggest a unique association between CT and Ca in periods of rapid bone growth and point to a possible involvement of CT in promoting bone formation during the first year of life.
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http://dx.doi.org/10.1159/000512107DOI Listing
December 2020

Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity.

Metabolism 2021 03 19;116:154438. Epub 2020 Nov 19.

Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany. Electronic address:

Background: Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated.

Cases And Methods: We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR.

Results: Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2.

Conclusions: The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.
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http://dx.doi.org/10.1016/j.metabol.2020.154438DOI Listing
March 2021

How Reliable are Commercially Available Glypican4 ELISA Kits?

Exp Clin Endocrinol Diabetes 2020 Oct 16. Epub 2020 Oct 16.

Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Leipzig.

Objective: Glypican4 is an interesting new adipokine, which seems to play an important role in developmental processes and is potentially associated with metabolic changes in obesity and type 2 diabetes mellitus. Currently, only a few studies examined glypican4 in human blood, mainly in adults.

Design, Patients And Measurements: The aim of our study was to investigate glypican4 serum levels in lean, overweight, and obese children and adolescents, to unravel a possible association between glypican4 serum levels and parameters of obesity and insulin resistance. In order to determine a suitable method for investigating glypican4 serum levels, we validated two commercially available human glypican4 ELISA kits, using serum and plasma samples of an obese, insulin-resistant patient, and a healthy control subject, a human recombinant glypican4 protein fragment and glypican4-overexpressing cell lysate.

Results: Using ELISA kit #1 we were not able to detect values above background level, apart from standard curve values. ELISA kit #2 initially seemed suitable to measure glypican4, but further validation experiments showed non-linearity of serial dilutions, no recognition of a human recombinant glypican4 protein fragment and non-linearity in the recovery of glypican4-overexpressing cell lysate. In addition, there was a considerable decrease (approx. 68%) of measured values between two experiments, performed at different time points with aliquots of the same serum sample. Contrary to that, further experiments found sample stability not to be compromised.

Conclusions: Extensive evaluation of the performance of two commercially available ELISA kits led to the conclusion that none of them is applicable for the measurement of glypican4 in human blood samples.
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http://dx.doi.org/10.1055/a-1257-0774DOI Listing
October 2020

Hormonal Blood Pressure Regulationduring General Anesthesia Usinga Standardized Propofol Dosagein Children and Adolescents SeemsNot to Be Affected by Body Weight.

J Clin Med 2020 Jul 6;9(7). Epub 2020 Jul 6.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, DRK Hospital Berlin-Koepenick, 12559 Berlin, Germany.

Obesity in pediatric surgical patients is a challenge for the anesthesiologist. Despite potentially beneficial properties, propofol might also induce hypotension. This study examined whether a dose adjustment in overweight children could avoid hypotension and if there would be differences regarding hormonal regulation in children under anesthesia. Fifty-nine children undergoing surgery under general anesthesia were enrolled in this prospective observational trial. Participants were allocated into two groups according to their BMI. The induction of anesthesia was conducted using propofol ("overweight": 2 mg/kgBW, "regular": 3.2 mg/kgBW). The maintenance of anesthesia was conducted as total intravenous anesthesia. Hormone levels of renin, angiotensin II, aldosterone, copeptin, norepinephrine and epinephrine were assessed at different timepoints. Blood pressure dropped after the administration of propofol in both groups, with a nadir 2 min after administration-but without a significant difference in the strength of reduction between the two groups. As a reaction, an increase in the plasma levels of renin, angiotensin and aldosterone was observed, while levels of epinephrine, norepinephrine and copeptin dropped. By adjusting the propofol dosage in overweight children, the rate of preincision hypotension could be reduced to the level of normal-weight patients with a non-modified propofol dose. The hormonal counter regulation was comparable in both groups. The release of catecholamines and copeptin as an indicator of arginine vasopressin seemed to be inhibited by propofol.
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http://dx.doi.org/10.3390/jcm9072129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408938PMC
July 2020

Association of sleep characteristics with adiposity markers in children.

J Pediatr Endocrinol Metab 2020 Jul;33(7):845-852

IFB Adiposity Diseases, Leipzig University, Leipzig, Germany.

Background Accumulating evidence suggests a relationship between sleep alterations and overweight/obesity in children. Our aim was to investigate the association of sleep measures other than obstructive sleep apnea or sleep duration with overweight/obesity and metabolic function in children. Methods We conducted a prospective cohort study in school- aged children (aged 5 to 8 years, prepubertal, and 12 to 15 years, pubertal) with overweight/obesity and normal-weight children. All children underwent a standardized in-laboratory polysomnography followed by a fasting blood assessment for glucose and metabolic testing. Subjective sleep measures were investigated by a 7-day sleep diary and questionnaire. We analyzed prepubertal and pubertal groups separately using logistic regression and partial correlation analyses. Results A total of 151 participants were analyzed. Overweight/obese children had significantly higher odds for arousal index (prepubertal children: 1.28, Confidence interval (CI): 1.06, 1.67; pubertal children: 1.65, CI: 1.19, 2.29) than normal-weight children, independent of age and gender. In prepubertal children, arousal-index was positively associated with C-peptide (r=0.30, p=0.01), whereas Minimum O2 saturation was negatively associated with triglycerides (r=-0.34, p=0.005), adjusting for age and sex. However, associations were attenuated by further adjustment for body mass index standard deviation scores (BMI-SDS). In pubertal children, higher level of apnea-hypopnea-index and pCO2 predicted increased lipoprotein (a) levels (r=0.35, p=0.03 and r=0.40, p=0.01, respectively), independent of age, sex, and BMI-SDS. A negative association was found between pCO2 and high-density lipoprotein (HDL)-cholesterol (r=-0.40, p=0.01). Conclusions Overall, we report that sleep quality as measured by arousal index may be compromised by overweight and obesity in children and warrants attention in future intervention programs.
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http://dx.doi.org/10.1515/jpem-2019-0517DOI Listing
July 2020

Pro-neurotensin depends on renal function and is related to all-cause mortality in chronic kidney disease.

Eur J Endocrinol 2020 Sep;183(3):233-244

Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far.

Methods: In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice.

Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals.

Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.
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http://dx.doi.org/10.1530/EJE-20-0087DOI Listing
September 2020

Prospective evaluation of aldosterone LC-MS/MS-specific cutoffs for the saline infusion test.

Eur J Endocrinol 2020 Aug;183(2):191-201

Medical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital of Leipzig, Leipzig, Germany.

Objective: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT).

Design And Methods: From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification.

Results: Overall, proposed assay-specific PACLC-MS/MS cutoff values for the SIT achieved higher diagnostic accuracy than established PACIA values with a sensitivity and specificity of 87.5% (95% CI: 71.0-96.5) and 97% (95% CI: 89.6-99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2-99.2) and 92.5% (95% CI: 83.4-97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PACLC-MS/MS cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8-99.9) and 92.5% (95% CI: 83.4-97.5), respectively.

Conclusions: The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.
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http://dx.doi.org/10.1530/EJE-20-0030DOI Listing
August 2020

Spot urine iodine levels below the WHO recommendation are not related to impaired thyroid function in healthy children and adolescents.

Eur J Nutr 2021 Feb 11;60(1):493-502. Epub 2020 May 11.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany.

Purpose: Iodine deficiency in childhood and adolescence may lead to later thyroid dysfunction, stunted growth and cognitive impairment. The World Health Organization (WHO) has issued recommended age-dependent urine iodine concentration targets, but a critical threshold beyond which clinical sequelae are to be expected remains undefined. Our study aimed to investigate spot urine iodine concentration in a typical Central European cohort of children and adolescents, and consider the implications of these values in regard to laboratory parameters for evaluating thyroid function.

Methods: Using the Sandell-Kolthoff method, spot urine iodine concentration was measured cross-sectionally from 1802 healthy children and adolescent in the age range of 0.25-18 years within the LIFE-Child epidemiological study based in and around the city of Leipzig (Germany). Additionally, serum thyroid biomarkers of these subjects were measured and correlated to urine iodine levels.

Results: In our cohort, 61.39% of boys and 65.91% of girls had an iodine level of < 100 µg/L (57%, 67%, 65% of the age groups 0-5, 6-12 and 13-18 years), the median iodine excretion was 86 µg/L in boys and 80 µg/L in girls. The iodine levels revealed no significant correlation with the thyroid biomarkers TSH, FT4 and FT3. Moreover, iodine values revealed no correlation with levels of antibodies against thyroid peroxidase or thyroglobulin.

Conclusion: In our cohort of children and adolescents, the relatively high number of iodine levels below the WHO recommendation appears not to be related to clinical or subclinical thyroid diseases in the respective participants.
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http://dx.doi.org/10.1007/s00394-020-02268-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867514PMC
February 2021

Relationship between deciduous molar hypomineralisation and parameters of bone metabolism in preschool children.

Int Dent J 2020 Aug 11;70(4):303-307. Epub 2020 Feb 11.

Department of Pediatric Dentistry, University of Leipzig, Leipzig, Germany.

Background: The aetiology of deciduous molar hypomineralisation (DMH) is still largely unknown.

Aim: The aim of the study was to elucidate the occurrence of DMH as a function of the parameters of bone metabolism, as it is suspected that abnormalities in these parameters may affect the mineralisation of teeth.

Design: In a prospective cohort study, 958 children aged 1-6 years were examined. The inclusion criteria were: a blood sample to determine the parameters of bone metabolism; and documentation of enamel mineralisation using the European Academy of Paediatric Dentistry (EAPD) criteria. Multivariable methods were applied to analyse the incidence of DMH relative to the concentrations of serum calcium, phosphate, vitamin D, vitamin B12 and alkaline phosphatase, taking into account the effects of age, gender and height.

Results: The proportion of children diagnosed with DMH was 4.0% (38 of 958). A significant difference between DMH-affected and non-DMH-affected children was found only in the serum concentration of calcium (2.47 ± 0.08 mmol/l vs. 2.52 ± 0.10 mmol/l, respectively, P = 0.004). The risk of DMH significantly increased, by 1.63-fold (95% CI: 1.03-2.57), if the calcium level dropped by 0.1 mmol/l, regardless of age, gender or adjusted height. During the follow-up examination of 17 DMH-affected subjects, the calcium level remained consistently low 1 year later (t-test, P > 0.05).

Conclusion: Children with DMH showed consistently subclinically lower serum calcium levels. No associations were found for other parameters.
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http://dx.doi.org/10.1111/idj.12550DOI Listing
August 2020

Hair Cortisol Concentration in Healthy Children and Adolescents Is Related to Puberty, Age, Gender, and Body Mass Index.

Horm Res Paediatr 2019 18;92(4):237-244. Epub 2019 Dec 18.

Department of Women & Child Health, Hospital for Children and Adolescents, Centre for Paediatric Research, Leipzig University, Leipzig, Germany.

Introduction: Hair cortisol concentrations (HCC) have been found to be related to various common childhood diseases, like otitis media, conjunctivitis, respiratory viral infections, and asthma. However, the confounding effects of age, gender, body mass index (BMI), pubertal stage (Tanner stages), socioeconomic status (SES) as well as of some hair maintenance procedures on HCC are still not well examined.

Methods: A population-based cohort of 434 children aged between 5 and 18 years was examined for HCC between January 2012 and February 2015 in the context of the Leipzig Research Centre for Civilization Diseases (LIFE) Child study. Thereby, anthropometric data, gender, BMI, SES and pubertal status were assessed. HCC was measured by liquid chromatography mass spectrometry.

Results: In the total cohort, HCC levels ranged between 0.95 and 29.86 pg/mg. In prepuberty, boys showed significantly higher HCC than girls (6.54 vs. 3.73 pg/mg, p < 0.05). During puberty HCC values in both genders converged. Higher BMI was significantly associated with higher HCC in both genders. In girls, HCC did not differ depending on Tanner stages. In boys, HCC was significantly higher in Tanner stage 1 than in stages 2-5.

Conclusion: Measuring cortisol concentration in hair gives information about long-term release of cortisol. We have found that puberty, gender, and BMI had a profound effect on HCC. As a result, further research should take into account the potentially confounding role of puberty, gender and BMI and may use the results of our study as a reference at determining values of HCC in healthy children.
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http://dx.doi.org/10.1159/000504914DOI Listing
May 2020

Hypo- and hyperthyroidism in early life - new developments.

J Pediatr Endocrinol Metab 2019 Nov;32(11):1199-1201

Hospital for Children and Adolescents, Department of Women and Child Health, Center of Paediatric Research, University of Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1515/jpem-2019-0509DOI Listing
November 2019

Higher fasting ghrelin serum levels in active smokers than in former and never-smokers.

World J Biol Psychiatry 2020 12 4;21(10):748-756. Epub 2019 Oct 4.

Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.

Objectives: Ghrelin, an orexigenic peptide hormone, promotes drug reward and is suspected to play a role in nicotine dependence. However, there is little data on whether ghrelin levels are associated with active and/or former smoking. The relationship between ghrelin serum levels and smoking status in a population-based sample of individuals was studied.

Methods: Total ghrelin was determined after an overnight fast in 1519 subjects participating in a population-based cohort study ('LIFE-Adult'). Tobacco consumption was assessed using both the questionnaire and interview. Generalised linear models with gamma distribution and log-link function were performed to analyse the association of total serum ghrelin with smoking status and the association between serum ghrelin and the amount of tobacco consumed in active smokers.

Results: Ghrelin levels were positively associated with active, but not former smoking (OR = 1.095;  = .002). This association was not moderated by sex (interaction of 'active smoking' and sex:  = .346). Ghrelin levels were not associated with the amount of tobacco consumed in active smokers.

Conclusions: This study provides evidence that total ghrelin serum levels are positively associated with active smoking. No association was found for former smokers. A unique feature of the study is the large sample size.
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http://dx.doi.org/10.1080/15622975.2019.1671610DOI Listing
December 2020

A Metabolic Obesity Profile Is Associated With Decreased Gray Matter Volume in Cognitively Healthy Older Adults.

Front Aging Neurosci 2019 2;11:202. Epub 2019 Aug 2.

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

Obesity is a risk factor for cognitive decline and gray matter volume loss in aging. Studies have shown that different metabolic factors, e.g., dysregulated glucose metabolism and systemic inflammation, might mediate this association. Yet, even though these risk factors tend to co-occur, they have mostly been investigated separately, making it difficult to establish their joint contribution to gray matter volume structure in aging. Here, we therefore aimed to determine a metabolic profile of obesity that takes into account different anthropometric and metabolic measures to explain differences in gray matter volume in aging. We included 748 elderly, cognitively healthy participants (age range: 60 - 79 years, BMI range: 17 - 42 kg/m) of the LIFE-Adult Study. All participants had complete information on body mass index, waist-to-hip ratio, glycated hemoglobin, total blood cholesterol, high-density lipoprotein, interleukin-6, C-reactive protein, adiponectin and leptin. Voxelwise gray matter volume was extracted from T1-weighted images acquired on a 3T Siemens MRI scanner. We used partial least squares correlation to extract latent variables with maximal covariance between anthropometric, metabolic and gray matter volume and applied permutation/bootstrapping and cross-validation to test significance and reliability of the result. We further explored the association of the latent variables with cognitive performance. Permutation tests and cross-validation indicated that the first pair of latent variables was significant and reliable. The metabolic profile was driven by negative contributions from body mass index, waist-to-hip ratio, glycated hemoglobin, C-reactive protein and leptin and a positive contribution from adiponectin. It positively covaried with gray matter volume in temporal, frontal and occipital lobe as well as subcortical regions and cerebellum. This result shows that a metabolic profile characterized by high body fat, visceral adiposity and systemic inflammation is associated with reduced gray matter volume and potentially reduced executive function in older adults. We observed the highest contributions for body weight and fat mass, which indicates that factors underlying sustained energy imbalance, like sedentary lifestyle or intake of energy-dense food, might be important determinants of gray matter structure in aging.
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http://dx.doi.org/10.3389/fnagi.2019.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688742PMC
August 2019

A Rapid Chemiluminescence Assay for Measurement of Folate in Small Volumes of Breast Milk.

Molecules 2019 Jul 27;24(15). Epub 2019 Jul 27.

Nestlé Research, Société des Produits Nestlé, 1000 Lausanne, Switzerland.

Early life exposure to folate has long lasting effects on development and health. Newborns obtain part of their folate from maternal milk. Studies on health effects of milk folate require rapid, affordable and reliable measurements in large numbers of samples from cohort studies. Recently, a competitive chemiluminescence assay for quantification of folate has become available for automated diagnostic measurement of folate in human serum or plasma. We tested if this method ("FOLA" from Siemens Healthcare) could also be used for human milk. To minimize interference and matrix effects, samples had to be skimmed, diluted seven times with demineralized water, and heated for 5 min at 90 °C. Folate could thus be measured in a linear range between 8.4 and 111.7 nM, with recoveries for the most relevant form, 5-methyltetrahydrofolate (5-MeTHF), of 96%-107%. Results were comparable to those with a recently validated Liquid Chromatography/Mass Spectrometry method (Y = 0.998X - 0.2; R = 0.807). The FOLA method was subsequently used for samples from the LIFE Child cohort in Germany, providing first data of breast milk folate in this country (range: 6.2-100.7 nM). This technique could indeed prove useful for large cohorts with multiple samplings.
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http://dx.doi.org/10.3390/molecules24152730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695834PMC
July 2019

Association of serum 25-hydroxyvitamin D concentrations with sleep phenotypes in a German community sample.

PLoS One 2019 5;14(7):e0219318. Epub 2019 Jul 5.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, Germany.

Background: Sleep disorders and vitamin D deficiency are among the most common health problems. Few studies investigated the effect of vitamin D on objectively recorded sleep with sound methodological quality and reasonable temporal proximity.

Objective: To investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) concentrations and objective sleep parameters assessed within close temporal proximity in a population-based sample. It is expected that higher serum 25(OH)D concentrations are associated with 1) better objective sleep outcomes (longer sleep duration, higher sleep efficiency, earlier mid-sleep time) and 2) more positive subjective sleep evaluations.

Methods: A subset of participants (n = 1045) from the LIFE-Adult-Study was analysed. Measurement of serum 25(OH)D vitamin was performed using an electrochemiluminescence immunoassay. Actigraphic assessments were performed using SenseWear Pro 3 devices. The following objective sleep parameters were calculated: total sleep duration, night sleep duration, night sleep efficiency, midsleep time and wake after sleep onset (WASO). Subjective sleep evaluations were assessed via questionnaire (sleep quality (PSQI), daytime sleepiness (ESS)). Data were analysed applying a multiple linear regression model with a stepwise approach.

Results: The regression models revealed significant associations of serum 25(OH)D concentration with night sleep duration and midsleep time. No association was found for total sleep duration and night sleep efficiency. Higher serum 25(OH)D concentration was further associated with shorter WASO in males but longer WASO in females. Moreover, serum 25(OH)D concentration did not show any significant association with subjective sleep quality and daytime sleepiness.

Conclusion: The results indicate that a higher concentration of serum 25(OH)D is associated with longer and earlier night sleep. Although the present study was able to demonstrate an association between serum 25(OH)D concentration and objective sleep parameters, no conclusion about underlying mechanisms or causal inferences can be drawn.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219318PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611612PMC
March 2020

Sex hormones in association with general joint laxity and hypermobility in the temporomandibular joint in adolescents-results of the epidemiologic LIFE child study.

J Oral Rehabil 2019 Nov 2;46(11):1023-1030. Epub 2019 Jul 2.

LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.

Objectives: The aim of this cross-sectional study was to investigate whether sex hormones (testosterone, oestradiol, sex-hormone-binding globulin = SHBG) are associated with general joint laxity (GJL) and hypermobility or derangements of the temporomandibular joint (TMJ) in adolescents.

Methods: Within the LIFE Child study, 970 adolescents (10-18 years) were included. GJL was assessed using the Beighton test. Maximum mouth opening (MMO) and clinical clicking sounds as signs of disc displacement (DD) in the TMJ were assessed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Serum levels of sex hormones were assessed using standardised laboratory analyses.

Results: Hypermobile joints were found in 54.9% (N = 532) of the sample; females were more affected than males (61.4% vs. 51.8%, P < 0.001). Using logistic regression analyses, the odds ratio (OR) for having >1 hypermobile joints increased to 1.15 (95% confidence interval [CI]: 1.04-1.27) in males and 1.09 (95% CI: 1.02-1.17) in females per 10 units of the SHBG serum level, compared to those without hypermobile joints-after controlling for the effect of age, adjusted BMI, pubertal development (Tanner scale), testosterone as well as oestradiol levels. Female subjects with >1 hypermobile joints showed a higher OR (1.89; 95% CI: 1.05-3.43) for having clinical clicking sounds in the TMJ and a 3.28 times higher OR (95% CI: 1.44-7.44) for MMO ≥ 55 mm.

Conclusions: We observed age- and gender-independent associations of higher SHBG serum levels with GJL in adolescents. Moreover, hypermobile female adolescents show a more frequent hypermobility of the TMJ and clinical signs of DD.
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http://dx.doi.org/10.1111/joor.12834DOI Listing
November 2019

Genetic Association Study of Eight Steroid Hormones and Implications for Sexual Dimorphism of Coronary Artery Disease.

J Clin Endocrinol Metab 2019 11;104(11):5008-5023

Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany.

Context: Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed.

Objective: Our main objective was to identify genetic loci influencing steroid hormone levels. As a secondary aim, we searched for causal effects of steroid hormones on CAD.

Design: We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, dehydroepiandrosterone sulfate (DHEAS), estradiol, and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, maximum n = 7667), and progesterone, 17-hydroxyprogesterone, androstenedione, and aldosterone in LIFE-Heart only (maximum n = 2070). All genome-wide significant loci were tested for sex interactions. Furthermore, we tested whether previously reported CAD single-nucleotide polymorphisms were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian randomization (MR) approaches.

Results: We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEAS, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism, that is, CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, for example, to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone, and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits.

Conclusion: Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sexual dimorphism in other complex diseases.
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http://dx.doi.org/10.1210/jc.2019-00757DOI Listing
November 2019

Advancement in steroid hormone analysis by LC-MS/MS in clinical routine diagnostics - A three year recap from serum cortisol to dried blood 17α-hydroxyprogesterone.

J Steroid Biochem Mol Biol 2019 09 31;192:105389. Epub 2019 May 31.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Liebigstraße 27a, 04103 Leipzig, Germany. Electronic address:

Steroid analysis by LC-MS/MS in daily clinical routine diagnostics requires high-throughput conditions including fast chromatographic separation. Hereby, signal interferences may occur due to limited specificity in complex biologic matrices. During the last three years of routine steroid analysis in our laboratory and roughly 50,000 measurements, about 1% was affected by interferences, mainly serum cortisol (>90%) and dried blood 17α-hydroxyprogesterone (17-OHP). To overcome specificity problems, enhanced chromatography, ionization polarity switching, and detection via two-stage fragmentation (MS) using a quadrupole linear ion trap were investigated in our study. Signal interferences of serum cortisol were eliminated by applying a protocol for automated method switching without changing the basic high-throughput LC-MS/MS setup. This approach includes negative ionization and extended chromatography from 4 to 6.6 min using the fourfold column length. From 9 samples affected by cortisol interference using the high-throughput method, 8 could be reliably analyzed applying the method switching protocol. Moreover, the applicability of the high-throughput method as second tier analysis in congenital adrenal hyperplasia (CAH) diagnostics from dried blood was verified with 100% diagnostic specificity. In addition, the combination of fast LC and MS detection enables specific quantitation of 17-OHP from dried blood spots on a screening time scale. This approach may be an alternative to the newborn screening for CAH by immunoassay due to its higher specificity, reducing the number of false positive results by 90%. In this work we recap experiences from three years of clinical routine steroid analysis via LC-MS/MS and present a unique analytical setup that enables both high-throughput and enhanced resolution analysis of steroid hormones in serum and dried blood.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105389DOI Listing
September 2019

Biological Significance of Anti-GH Antibodies in Children Treated with rhGH.

Horm Res Paediatr 2019 4;91(1):17-24. Epub 2019 Apr 4.

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.

Background: The occurrence of antidrug antibodies is common in children treated with recombinant human growth hormone (rhGH). However, their clinical significance is unclear.

Objective: This study aimed to examine the clinical significance of anti-GH antibodies by analyzing the phenotype of patients who tested positive in relation to the quantity of anti-GH antibodies.

Method: In this laboratory-based retrospective study encompassing a time span of 6 years, all positive samples were identified, and senders were contacted. Anti-GH antibodies were measured using a radioprecipitation assay; positive samples underwent a confirmatory assay.

Results: Out of a total of 104 samples from 66 patients, positive test results were found in 28 samples from 13 patients. Clinical data were available from all but one. The group with positive test results comprised 6 patients with a normal response to GH provocative tests (group A) and 6 with an insufficient response or with isolated GH deficiency (IGHD) type 1A (group B). Diagnoses in group A were neurosecretory dysfunction, bioinactive GH syndrome and constitutional delay of growth and puberty. Diagnoses in group B were IGHD type 1A, septo-optic dysplasia, and cerebral midline defect with multiple pituitary hormone deficiency. Insufficient growth response to rhGH was absent except in one sibling pair with IGHD type 1A and a patient with cerebral midline defect. These patients had the highest concentrations of anti-GH antibodies.

Conclusions: The biological significance of anti-GH antibodies seems to be limited to patients with high concentrations of anti-GH antibodies. For all other patients, we recommend a careful "wait and see" strategy and monitoring antibody titers.
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http://dx.doi.org/10.1159/000497409DOI Listing
November 2019

The Bone Markers Sclerostin, Osteoprotegerin, and Bone-Specific Alkaline Phosphatase Are Related to Insulin Resistance in Children and Adolescents, Independent of Their Association with Growth and Obesity.

Horm Res Paediatr 2019 22;91(1):1-8. Epub 2019 Mar 22.

Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany,

Background/aims: Sclerostin, osteoprotegerin, and bone-specific alkaline phosphatase (B-ALP), which are primarily related to bone metabolism, have been linked with insulin resistance in adults. We aimed to evaluate the association of these markers with growth, obesity, and parameters of insulin resistance in lean and obese children and adolescents.

Methods: We measured sclerostin, osteoprotegerin, and B-ALP in fasting and oral glucose tolerance test (oGTT) serum samples from 1,325 children and adolescents, and during 24-h profiles and after exercise and glucose exposure in young adults.

Results: In addition to the positive relationship with height standard deviation scores (SDS), sclerostin (r = 0.035, p < 0.001) and B-ALP (r = 0.06, p = 0.028) increased, whereas osteoprotegerin (r = -0.098, p < 0.001) decreased with BMI SDS. Furthermore, B-ALP correlated with fasting- and oGTT-derived markers of glucose and insulin metabolism suggestive of insulin resistance. To evaluate potential confounding diurnal variation of bone markers, we performed 24-h profiles. B-ALP and osteoprotegerin had lower night-time levels. Exercise acutely and transiently increased B-ALP and osteoprotegerin levels, but glucose ingestion had no effect.

Conclusions: Besides their association with growth, sclerostin and osteoprotegerin levels are altered in childhood obesity. Particularly B-ALP was related to insulin resistance indices. Our findings accent the link between bone, growth, and insulin resistance.
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http://dx.doi.org/10.1159/000497113DOI Listing
November 2019

Gene Alterations in Children Born Small for Gestitional Age (SGA).

Open Access Maced J Med Sci 2018 Nov 10;6(11):2040-2044. Epub 2018 Nov 10.

University of Leipzig, Leipzig, Germany.

Background: Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children.

Aim: To investigate whether alterations in gene are present in SGA born children.

Patients And Methods: We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA).

Results: The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean.

Conclusions: gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.
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http://dx.doi.org/10.3889/oamjms.2018.416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290431PMC
November 2018

Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study.

Eur Heart J 2019 01;40(1):34-46

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstr. 20, Leipzig, Germany.

Aims: It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).

Methods And Results: One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training-but not RT-acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.

Conclusion: This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.
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http://dx.doi.org/10.1093/eurheartj/ehy585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312574PMC
January 2019

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation.

Eur J Endocrinol 2019 Jan;180(1):K1-K13

Department of Women and Child Health, University of Leipzig Hospitals and Clinics, Leipzig, Germany.

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.
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http://dx.doi.org/10.1530/EJE-18-0601DOI Listing
January 2019

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

Stress 2019 01 29;22(1):93-102. Epub 2018 Oct 29.

a Integrated Research and Treatment Center (IFB) Adiposity Diseases , Leipzig University Medical Center , Leipzig , Germany.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH r = 0.87, p = .001; cortisol r = 0.86, p = .002; amygdala: ACTH r = 0.86, p = .002; cortisol r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.
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http://dx.doi.org/10.1080/10253890.2018.1511698DOI Listing
January 2019

Stress-related hormones in association with periodontal condition in adolescents-results of the epidemiologic LIFE Child study.

Clin Oral Investig 2019 Apr 5;23(4):1793-1802. Epub 2018 Sep 5.

Department of Cariology, Endodontology and Periodontology, University of Leipzig, Liebigstrasse 12, 04103, Leipzig, Germany.

Objectives: The aim of this study was to investigate the associations between blood levels of stress-related hormones and early signs of periodontal disease in children and adolescents.

Materials And Methods: Within the LIFE (Leipzig research center for civilization diseases) Child study, 498 adolescents (10 to 18 years) were included. Early signs of periodontal inflammation were measured by probing depth (PD) at six index teeth (16, 11, 26, 36, 31, 46). Blood levels of stress-related hormones (cortisol, dehydroepiandosterone-sulfate [DHEA-S]) and, additionally interleukine-6 (IL-6) were measured. Socioeconomic status, oral hygiene, orthodontic appliances, and nutritional status, recorded by body-mass-index-standard-deviation-score (BMI-SDS), were considered as confounding factors. Additionally, in 98 participants, an oral chairside active matrix metalloproteinase-8 (aMMP-8) test was performed. Statistical tests are the Mann-Whitney U tests, chi-squared tests and multivariate logistic regression model.

Results: IL-6, BMI-SDS as well as positive aMMP-8 test result were significantly associated with maximum PD > 3 mm (p < 0.05). However, no statistically significant associations between stress-related hormones (cortisol and DHEA-S) and presence of maximum PD > 3 mm were found (p > 0.05). Higher DHEA-S and BMI were associated with positive aMMP-8 result, even after adjusting for age and gender (p = 0.027, p = 0.026).

Conclusion: The results reveal no associations between PD and stress-related hormones cortisol and DHEA-S. aMMP-8 test result might be associated with DHEA-S level. Nutritional status seems to influence periodontal disease in adolescents.

Clinical Relevance: DHEA-S and BMI-SDS show associations with early signs of periodontal disease in adolescents aged 10 to 18 years. This association should be confirmed by the investigation of high-risk groups.
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http://dx.doi.org/10.1007/s00784-018-2599-3DOI Listing
April 2019

Omentin-1 and NAMPT serum concentrations are higher and CK-18 levels are lower in children and adolescents with type 1 diabetes when compared to healthy age, sex and BMI matched controls.

J Pediatr Endocrinol Metab 2018 Sep;31(9):959-969

University of Leipzig, Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, 04103 Leipzig, Germany, Phone: +49 341 97 22200, Fax: +49 341 97 22209.

Background Adipokines were shown to affect glucose homeostasis and β-cell function in patients with pancreatic dysfunction which is associated with changes in the adipose tissue secretory profile. However, information about adipokines associated with β-cell dysfunction is lacking in pediatric patients with type 1 diabetes. Methods (1) We compared serum concentrations of nicotinamide phosphoribosyltransferase (NAMPT), omentin-1 and caspase-cleaved cytokeratin 18 fragment M30 (CK-18) in pediatric type 1 diabetes patients (n=245) and healthy age, sex and body mass index standard deviation score (BMI-SDS) matched controls (n=243). (2) We investigated the influence of insulin treatment on serum concentrations of NAMPT, omentin-1 and CK-18 in groups of patients with type 1 diabetes stratified according to the duration of their disease: at onset (n=50), ≥6 months and <5 years (n=185), ≥5 and <10 years (n=98), and ≥10 years (n=52). Results Patients at onset compared with healthy controls demonstrated no significant differences in NAMPT levels (p=0.129), whereas omentin-1 levels were elevated (p<0.001) and CK-18 levels were lowered (p=0.034). In contrast, NAMPT and omentin-1 were elevated and CK-18 serum levels were lower in longstanding patients compared to healthy controls (p<0.001). NAMPT serum levels did not change significantly during the duration of type 1 diabetes (p=0.546). At onset, omentin-1 and CK-18 levels were higher than in any group of longstanding type 1 diabetes (p<0.025). Conclusions Altered serum levels of NAMPT, omentin-1 and CK-18 in pediatric type 1 diabetes patients indicate metabolic changes caused by adipose tissue dysregulation which do not normalize during insulin therapy.
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http://dx.doi.org/10.1515/jpem-2018-0353DOI Listing
September 2018