Berlin, Germany


Berlin, Germany
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Hulur I.,University of Chicago | Hermanns P.,Johannes Gutenberg University Mainz | Nestoris C.,Endokrinologikum | Heger S.,Childrens Hospital Auf der Bult | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Dual oxidases (DUOX1 and DUOX2) play a crucial role in the generation of hydrogen peroxide required in the oxidation of iodide and the synthesis of thyroid hormone. Heterodimerization with specific maturation factors (DUOXA1 and DUOXA2) is essential for the maturation and function of the DUOX enzyme complexes. Biallelic loss-of-function mutations of DUOX2 result in congenital hypothyroidism (CH), whereas a single reported case of homozygous DUOXA2 mutation (Y246X) has been associated with mild CH. Objective: We now report an infant with transient CH due to a complex genetic alteration of the DUOX/DUOXA system. Results: Our patient was born to euthyroid nonconsanguineous parents and presented with an elevated TSH and enlarged thyroid gland at neonatal screening. Genetic analysis revealed a missense mutation (C189R) on the maternal DUOXA2 allele. The mutant DUOXA2 protein showed complete loss-of-function in reconstituting DUOX2 in vitro. The apparent C189R homozygosity of the proband in the absence of the same mutation in the father led to detailed gene mapping, revealing an approximately 43-kb pair deletion encompassing DUOX2, DUOXA1, and DUOXA2. Thus, in addition to being deficient in DUOXA2, the proband lacks one allele of DUOX2 and DUOXA1 but has two functioning DUOX1 alleles. Conclusion: The transient CH in the presence of only one functional maturation factor allele indicates a high level of functional redundancy in the DUOX/DUOXA system. Copyright © 2011 by The Endocrine Society.

Poddubnyy D.,Charité - Medical University of Berlin | Rudwaleit M.,Endokrinologikum | Haibel H.,Charité - Medical University of Berlin | Listing J.,German Rheumatism Research Center | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objective: To investigate the influence of non-steroidal anti-inflammatory drugs (NSAIDs) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (SpA). Methods: 164 patients with axial SpA (88 with AS and 76 with non-radiographic axial SpA) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake. Spinal radiographs were scored by two trained readers in a concealed randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system. An index of the NSAID intake counting both dose and duration of drug intake was calculated. Results: High NSAIDs intake (NSAID index≥50) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units: OR=0.15, 95% CI 0.02 to 0.96, p=0.045 (adjusted for baseline structural damage, elevated C reactive protein (CRP) and smoking status) in comparison with patients with low NSAIDs intake (NSAID index<50). This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP: mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake, p=0.02. In non-radiographic axial SpA, no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found. Conclusion: A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS. In non-radiographic axial SpA this effect is less evident, probably due to a low grade of new bone formation in the spine at this stage..

Feldtkeller E.,Ankylosing Spondylitis International Federation | Rudwaleit M.,Endokrinologikum | Zeidler H.,Rheumatologikum
Rheumatology (United Kingdom) | Year: 2013

Objectives. Several sets of criteria for the diagnosis of axial SpA (including non-radiographic axial spondyloarthritis) have been proposed in the literature in which scores were attributed to relevant findings and the diagnosis requests a minimal sum of these scores. To quantitatively estimate the probability of axial SpA, multiplying the likelihood ratios of all relevant findings was proposed by Rudwaleit et al. in 2004. The objective of our proposal is to combine the advantages of both, i.e. to estimate the probability by summing up scores instead of multiplying likelihood ratios.Methods. An easy way to estimate the probability of axial spondyloarthritis is to use the logarithms of the likelihood ratios as scores attributed to relevant findings and to use the sum of these scores for the probability estimation.Results. A list of whole-numbered scores for relevant findings is presented, and also threshold sum values necessary for a definite and for a probable diagnosis of axial SpA as well as a threshold below which the diagnosis of axial spondyloarthritis can be excluded. In a diagram, the probability of axial spondyloarthritis is given for sum values between these thresholds.Conclusion. By the method proposed, the advantages of both, the easy summing up of scores and the quantitative calculation of the diagnosis probability, are combined. Our method also makes it easier to estimate which additional tests are necessary to come to a definite diagnosis. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Koetz K.R.,Charité - Medical University of Berlin | Ventz M.,Charité - Medical University of Berlin | Diederich S.,Endokrinologikum | Quinkler M.,Charité - Medical University of Berlin
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis. Objectives: Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women? Design and Patients: We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients. Main Outcome Measures: BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured. Results: PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m 2 (range, 4.9 -19.1) and 15.5 ± 7.8 mg/m 2 (range, 5.7-33.7), respectively. BMD varied within the normal reference range (-2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Ward's region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAIwomentreated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Ward's region compared to non-DHEA-treated women. Conclusions: Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addison's women. Copyright © 2012 by The Endocrine Society.

Koetz K.R.,Charité - Medical University of Berlin | Van Rossum E.F.C.,Erasmus University Rotterdam | Ventz M.,Charité - Medical University of Berlin | Diederich S.,Endokrinologikum | Quinkler M.,Charité - Medical University of Berlin
Clinical Endocrinology | Year: 2013

Context Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD). Objectives To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH. Design and Patients A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured. Results Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum β-CrossLaps (0·37 ± 0·34 μg/l; P < 0·05) and urinary collagen crosslinks (NTX, 68·1 ± 32·4 nmol/g; P < 0·005) despite receiving the lowest average daily hydrocortisone dose of 9·9 ± 3·7 mg/m2 (P < 0·05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6·7, 95% CI = 1·78-25·38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes. Conclusions Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity. © 2012 John Wiley & Sons Ltd.

Feldtkeller E.,Deutsche Vereinigung Morbus Bechterew | Lind-Albrecht G.,Rheumatologie Immunologie Osteologie RHIO | Rudwaleit M.,Endokrinologikum | Rudwaleit M.,Charité - Medical University of Berlin
Rheumatology International | Year: 2013

Advice concerning behaviour and adaptations of living and working environment is considered an unmet need by patients with ankylosing spondylitis (AS). The aim of this study was to develop a core set of recommendations to be given to patients by their rheumatologists. A systematic literature research of scientific and patient-oriented literature revealed 70 raw recommendations. These recommendations were evaluated and ranked at a meeting of the Ankylosing Spondylitis International Federation (ASIF, 26 participants including 19 patients with AS, 5 rheumatologists and 2 physiotherapists from 13 countries) in November 2011. Thereafter, the 59 remaining recommendations were extensively discussed, supplemented, reworded, condensed and voted on during a meeting of local branch leaders of the AS patient organisation in Germany (Deutsche Vereinigung Morbus Bechterew, DVMB) with 80 participants (95 % of whom with AS), 2 rheumatologists and 1 occupational therapist in March 2012. The core set of final recommendations comprises (1) a general statement regarding living with AS which was considered highly important by patients and (2) the following domains: sitting position, walking, sleeping, at work, exercises, sports and recreational activities, diet and lifestyle, sexuality and pregnancy, fall prevention, car driving and advantages of membership in an AS-specific patient organisation. Most recommendations are relevant already in early disease, others concern advanced AS (e.g. fall prevention and car driving). The selected recommendations received high agreements (80-100 %). A first core set of recommendations for the behaviour and environmental adaptations of patients with AS was established under participation of many patients. © 2013 Springer-Verlag Berlin Heidelberg.

Baerlecken N.T.,Leibniz University of Hanover | Nothdorft S.,Leibniz University of Hanover | Stummvoll G.H.,Medical University of Vienna | Sieper J.,Charité - Medical University of Berlin | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA. Methods: Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee ( project number 4928). Results: Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors. Conclusions: Antibodies against CD74 could provide an important additional tool for diagnosis of SpA.

Bobbert T.,Charité - Medical University of Berlin | Mai K.,Charité - Medical University of Berlin | Brechtel L.,Humboldt University of Berlin | Schulte H.M.,Charité - Medical University of Berlin | And 4 more authors.
International Journal of Sports Medicine | Year: 2012

Endurance training may lead to different hormonal alterations e.g., exercised induced hypothalamic ovarian/testicular dysfunction. The aim of this study was to reveal new connections between physical exercise, leptin and hormonal responses. 36 male participants of the Berlin-Marathon had their blood samples taken 2 days before the marathon. Hormones of the hypothalamic-pituitary axis and leptin were correlated with the training status and the achieved marathon time. Leptin correlated with the achieved marathon time after being adjusted for age and BMI (r=0.607, p<0.001) and was lowest in the best trained runners. Additionally, when the group was divided into quartiles of their achieved marathon time, significantly increased cortisol, fT4, cortisol/DHEAS ratio and decreased IGF-1 levels were observed in the slowest group. In the better trained group, a decrease of testosterone/DHT ratio and an increase of testosterone/cortisol ratio were observed. Our study supports the thesis of a linear relationship between physical fitness and leptin variations in the physiological range. We found an increased anabolic hormonal response in well trained marathon runners and hormonal reactions of increased stress in less trained runners. As the stress-induced neuroendocrine adaptations in our study group are associated with more higher leptin values, the pathophysiological role of decreased leptin values seems to be limited to overtrained athletes. © Georg Thieme Verlag KG Stuttgart - New York.

Kulzer B.,Forschungsinstitut Diabetes Akademie | Seitz L.,Novo Nordisk AS | Kern W.,Endokrinologikum
Experimental and Clinical Endocrinology and Diabetes | Year: 2014

Aims: Hypoglycaemia is a common side effect of insulin therapy in diabetes patients, with negative physical and emotional impacts. Despite this, there are few studies investigating the frequency of non-severe hypoglycaemic events from the perspective of patients in the real-world setting. We investigated self-reported NSHE frequency and levels of hypoglycaemia awareness in Germany. Methods: Respondents>15 years with Type 1 or insulin-treated Type 2 diabetes (receiving basal only, basal-bolus or other insulin regimens) were recruited using online panels to complete≤4 questionnaires. Questionnaires collected demographics, non-severe hypoglycaemic event rates and patient-reported level of hypoglycaemia awareness. Non-severe hypoglycaemic event rates are reported as respondent-week records and calculated using data from all respondents completing at least one questionnaire. Results: A total of 1 771 respondent-week records were obtained from 614 participants. Mean non-severe hypoglycaemic event rates per respondent-week were 1.6 for Type 1 and 0.6-0.8 for Type 2, with estimated annual rates of 83 and 31-42 respectively. Two-thirds of Type 1 (65%) and Type 2 (61-72%) respondents reported impaired levels of awareness or unawareness of hypoglycaemic events (inability or impaired ability to recognise the symptoms of hypoglycaemia). Respon ents' self-reported hypoglycaemia- awareness was significantly associated with the proportion of asymptomatic non-severe hypoglycaemic events; respondents classified as being unaware of hypoglycaemia had a higher proportion of asymptomatic non-severe hypoglycaemic events than aware respondents. Conclusion: Non-severe hypoglycaemic events are common in people with Type 1 or insulin-treated Type 2 diabetes in the real-world setting in Germany but may still be underestimated due to an inability to recognise the symptoms of hypoglycaemia. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York.

Jansen T.,Dermatologische Praxis | Janssen O.E.,Endokrinologikum | Plewig G.,Ludwig Maximilians University of Munich
Hautarzt | Year: 2013

Acne is one of the most common skin diseases in the general population, especially among adolescents. Acne tarda (adult acne) is defined as acne that develops (late-onset acne) or continues (persistent acne) after 25 years of age. The disease is more common in women. The clinical features are quite specific: inflammatory acne in the lower facial region or macrocomedones (microcysts) spread over the face. Involvement of the trunk is much more common in men. The etiology of acne tarda is still controversial, as cosmetics, drugs, smoking, stress, diet, and endocrine abnormalities have been implicated. Women with acne tarda and other symptoms of hyperandrogenism have a high probability of endocrine abnormalities such as polycystic ovary syndrome. Treatment is similar to that of acne in adolescence. Long-term treatment over years or decades may be required. © 2013 Springer-Verlag Berlin Heidelberg.

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