SARS-CoV-2 Vaccination in Kidney Transplant Recipients-Stratified Analysis of the Humoral Immune Response.

Kidney transplant recipients are at increased risk of SARS-CoV-2 infection and a more severe course of COVID-19. Methods: We conducted a quantitative serologic testing of antibodies specific for the wild type of SARS-CoV-2 and the Omicron variant of concern before and after a third-dose vaccination, either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) in a cohort of 103 stable kidney transplant recipients (median [range] age, 58 [22-84] y, 57 men [55.3%]). Results: Third-dose vaccination increased the seroconversion rate from 57.3% to 71.8%. However, despite a marked rise of the antibody concentrations after the booster, 55.4% and 11.6% only formed neutralizing antibodies against the SARS-CoV-2 wild type and Omicron, respectively. Treatment with mycophenolic acid/mycophenolate mofetil (in strata of the dose quartiles), advanced age, and' above all' impaired renal function (eGFR <60 mL/min) adversely influenced the humoral immunity regarding seroconversion and inhibition of the wild type of SARS-CoV-2. Conclusions: Apart from immunosuppressive therapy, the humoral vaccination response is largely affected by nonmodifiable factors in kidney transplant recipients. With the currently leading and clinically easier Omicron variant, this puts into perspective the strategy to significantly enhance the protective efficacy of the available vaccines by reducing or temporarily stopping proliferation inhibitors, not least considering the inherent rejection risk with a possible deterioration of graft function.

Heterologous immunization with BNT162b2 followed by mRNA-1273 in dialysis patients: seroconversion and presence of neutralizing antibodies.

INTRODUCTION: The vital renal replacement therapy makes it impossible for dialysis patients to distance themselves socially. This results in a high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and developing coronavuris disease 2019, with excess mortality due to disease burden and immunosuppression. We determined the efficacy of a 100-µg booster of mRNA-1273 (Moderna, Cambridge, MA, USA) 6 months after two doses of BNT162b2 (BioNTech/Pfizer, Mainz, Germany/New York, USA) in 194 SARS-CoV-2-naïve dialysis patients. METHODS: Anti-SARS-CoV-2 spike antibodies were measured with the Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics, Mannheim, Germany) 4 and 10-12 weeks after two doses of BNT162b2 as well as 4 weeks after the mRNA-1273 booster. The presence of neutralizing antibodies was measured by the SARS-CoV-2 Surrogate Virus Neutralization Test (GenScript Biotech, Piscataway, NJ, USA). Two different cut-offs for positivity were used, one according to the manufacturer's specifications and one correlating with positivity in a plaque reduction neutralization test (PRNT). Receiver operating characteristics analyses were performed to match the anti-SARS-CoV-2 spike antibody cut-offs with the cut-offs in the surrogate neutralization assay accordingly. RESULTS: Any level of immunoreactivity determined by the anti-SARS-CoV-2 spike antibody assay was found in 87.3% (n = 144/165) and 90.6% (n = 164/181) of patients 4 and 10-12 weeks, respectively, after two doses of BNT162b2. This was reduced to 68.5% or 60.6% 4 weeks and 51.7% or 35.4% 10-12 weeks, respectively, when using the ROC cut-offs for neutralizing antibodies in the surrogate neutralization test (manufacturer's cut-off ≥103 U/mL and cut-off correlating with PRNT ≥196 U/mL). Four weeks after the mRNA-1273 booster, the concentration of anti-SARS-CoV-2 spike antibodies increased to 23 119.9 U/mL and to 97.3% for both cut-offs of neutralizing antibodies. CONCLUSION: Two doses of BNT162b2 followed by one dose of mRNA-1273 within 6 months in patients receiving maintenance dialysis resulted in significant titres of SARS-CoV-2 spike antibodies. While two doses of mRNA vaccine achieved adequate humoral immunity in a minority, the third vaccination boosts the development of virus-neutralizing quantities of SARS-CoV-2 spike antibodies (against wild-type SARS-CoV-2) in almost all patients.

Surrogate scores of advanced fibrosis in NAFLD/NASH do not predict mortality in patients with medium-to-high cardiovascular risk.

Untreated non-alcoholic fatty liver disease (NAFLD) may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver-related but also cardiovascular mortality. However, almost nothing is known about coexisting NAFLD in patients with coronary artery disease (CAD). We investigated the impact of surrogate scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography. Modeling the common NALFD and fibrosis scores, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as splines revealed significant associations with all-cause and cardiovascular mortality when Cox regression models were only adjusted for cardiovascular risk factors that were not already included in the calculation of the scores. Stratifying the scores into quartiles yielded hazard ratios [95% confidence interval (CI)] for all-cause and cardiovascular mortality for the 4th quartile versus the 1st quartile of 2.28 (1.90-2.75) and 2.11 (1.67-2.67) for FIB-4 and of 3.21 (2.61-3.94) and 3.12 (2.41-4.04) for NFS. However, we did not observe an independent association of FIB-4 or NFS with overall or cardiovascular mortality in our prospective CAD cohort after full adjustment for all cardiovascular risk factors [all-cause mortality: HR 1.13 (0.904-1.41) and 1.17 (0.903-1.52); cardiovascular mortality: HR 1.06 (0.8-1.41) and 1.02 (0.738-1.41)]. Thus, neither FIB-4 nor NFS, as surrogate markers for NAFLD/NASH, were independent risk factors for overall or cardiovascular mortality in patients with CAD. Our data show that surrogate risk scores for NAFLD-related fibrosis do not add information in assessing the CVD events in patients with CAD proven by angiography.NEW & NOTEWORTHY We investigated the impact of NAFLD surrogate markers in a large cohort of patients that had been referred to coronary angiography. In contrast to a repeatedly demonstrated increased link of cardiovascular events in patients with NALFD, we demonstrated that NAFLD surrogate markers were not independent risk factors for overall or cardiovascular mortality in patients with CAD. Thus, these markers may not be useful for primary prevention of cardiovascular events in patients with CAD.

[Postoperative hypocalcemia - the most common complication of endocrine head and neck surgery: acute management]. / Postoperative Hypokalzämie ­ die häufigste Komplikation der endokrinen Chirurgie der Halsregion: Akutes Management.

BACKGROUND: In Germany, 8000 patients are affected by postoperative hypoparathyroidism per year following surgery of the thyroid gland, parathyroidal glands and the larynx. Patients do not only suffer from paresthesia in the acute phase of this complication, but are also adversely affected by the fear of loss of control following episodes of tetany even years after the first episode. OBJECTIVES: Discussion of a diagnostic pathway and presentation of a management pathway for postoperative hypocalcemia. METHODS: Narrative review, analysis and discussion of current literature and expert recommendations. RESULTS: Early determination of calcium and parathyroid hormone allows timely diagnosis and treatment of postoperative hypoparathyroidism. Active vitamin D is pivotal for the resorption of calcium. Only the combined treatment with active vitamin D and calcium can mitigate or prevent the postoperative drop of calcium levels. CONCLUSIONS: A standard operating procedure (SOP) for postoperative hypoparathyroidism should be implemented in every surgical department. An SOP for diagnosis and treatment of postoperative hypoparathyroidism is proposed for institutional individualization and implementation.

Bile Acids in Patients with Uncontrolled Type 2 Diabetes Mellitus - The Effect of Two Days of Oatmeal Treatment.

BACKGROUND: Beta-glucans are effective in binding bile acids (BA) thereby lowering cholesterol concentration. This might contribute to the beneficial effects of the consumption of ß-glucan-rich foods like oatmeal on glucose homeostasis. OBJECTIVE: We measured BA serum concentrations in patients with uncontrolled type 2 diabetes (T2DM) to investigate the effect of two days of oatmeal treatment on BA concentration as compared to a conventional T2DM-adapted diet. METHODS: The OatMeal And Insulin Resistance study was performed as a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients in an inpatient clinical setting. Bile acids were measured by high-resolution mass spectrometry. For statistical analysis, the differences in the concentration of serum BA and laboratory parameters between the fifth day and the third day of each inpatient stay were calculated and the effect compared between both phases by using the Wilcoxon test. RESULTS: Whereas there was a mean decrease in total BA following oatmeal treatment (-0.82±1.14 µmol/l), there was no decrease following the control treatment. Glycocholic acid was lower after oatmeal treatment but higher following control treatment (-0.09±0.17 vs. 0.05±0.11 µmol/l). The reduction in total BA was directly correlated with a decrease in proinsulin during the oatmeal phase. Decreases in blood lipids or apolipoproteins were mostly greater after oatmeal treatment, but these differences were not statistically significant. CONCLUSION: Two days of oatmeal diet led to significant reductions in total BA as compared to a diabetes-adapted control diet. The magnitude of BA reduction was directly correlated with a decrease in proinsulin.

Neuro-Endocrine Recovery After Pituitary Apoplexy: Prolactin as a Predictive Factor.

OBJECTIVE: Pituitary apoplexy is a serious medical complication of a pre-existing pituitary adenoma characterized by a variety of clinical symptoms ranging from mild headache to neurologically impaired and finally comatose patients. Management options are surgery or conservative treatment (e. g., with dexamethasone). Surgery is commonly performed in case of severe acute neurological and visual symptoms. However, prospective studies demonstrating a benefit of surgery over conservative treatment in terms of visual, neurological and even endocrine outcomes are lacking. Decision making is still controversial, and recommendations for surgery are based on low evidence grades and focus on visual impairment. Endocrine function and especially markers identifying patients with potential for pituitary recovery after surgery are not well described in the literature. PATIENTS AND DESIGN: We analysed data from 24 patients (m:f/16:8) with a median age of 64 yrs (38 to 83yrs) that underwent surgery for pituitary apoplexy regardless of time from symptom onset. Apoplexies were necrotic in 14 cases and haemorrhagic in 10 cases. RESULTS: Preoperatively, 7 patients (29.2%) showed complete anterior pituitary insufficiency, 16 patients (66.6%) had partial anterior pituitary insufficiency and one patient (4.17%) had normal pituitary functions. Persistent panhypopituitarism was found in 7 patients (29.2%), whereas an overall improvement of pituitary function was noted in 13 (57.1%) patients. Preoperative prolactin (PRL) levels were significantly associated with recovery of endocrine functions, whereas specifically all patients with preoperative PRL levels of at least 8.8 ng/ml recovered partially or fully. Time to surgery (0-7 days vs. 1-4 weeks vs.>4 weeks) was not significantly associated with outcome. CONCLUSIONS: Our data emphasize that normal and high preoperative PRL levels are associated with better endocrine outcome after surgery. We conclude that patients benefit from surgical intervention even after delayed diagnosis with the serum PRL levels is being a valid biomarker for clinical decision making.

Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary Adenomas and Carcinomas-A German Survey.

CONTEXT: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. OBJECTIVE: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. DESIGN AND SUBJECTS: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. RESULTS: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. CONCLUSION: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.

Poor risk factor control in outpatients with diabetes mellitus type 2 in Germany: The DIAbetes COhoRtE (DIACORE) study.

INTRODUCTION: Patients with diabetes mellitus type 2 (DM2) are at high risk for micro- and macrovascular disease. Here, we explore the degree of traditional risk factor control in the baseline visit of a cohort of DM2 outpatients. METHODS: DIACORE (DIAbetes COhoRtE) is a prospective cohort study of 3000 adult DM2 outpatients. Here, we present results from the baseline visit. Sociodemographic and anthropometric variables, cardiovascular risk factors, comorbidities and medication were assessed by interview and medical exams. Serum-creatinine based estimated glomerular filtration rate (eGFRcrea) and urinary albumin-creatinine ratio (UACR) were determined for classification of chronic kidney disease (CKD). The proportion of patients with adequate control of traditional risk factors (blood pressure<140/90mmHg, HbA1c<7.5%, LDL<100mg/dl) was calculated in 2892 patients with non-missing data in 9 relevant variables within each KDIGO 2012 CKD class. RESULTS: In the analyzed baseline data (n = 2892, 60.2% men), mean (standard deviation) values for age, DM2 duration and HbA1c were 65.3 (9.3) years, 10.3 (8.4) years and 6.9% (1.1) respectively. Of these 2892 patients, 18.7% had CKD stage 3 or higher, 25.7% had UACR≥30mg/g. Adequate blood pressure, HbA1c and LDL control was achieved in 55.7%, 78.5% and 34.4%, respectively. In 16.4% of patients (473), all three risk factors were below recommended targets. The proportion of adequate risk factor control was similar across KDIGO eGFRcrea classes. Adequate blood pressure and HbA1c control were significantly associated with lower UACR category without and with controlling for other risk factors (p<0.0001, p = 0.0002, respectively). CONCLUSION: In our study of patients with diabetes mellitus type 2, we observed a low level of risk factor control indicating potential for risk reduction.

Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy.

This study assessed if serum carnosinase (CNDP1) activity and concentration in patients with type 2 diabetes mellitus (T2D) with diabetic nephropathy (DN) differs from those without nephropathy. In a cross-sectional design 127 patients with T2D with DN ((CTG)5 homozygous patients n = 45) and 145 patients with T2D without nephropathy ((CTG)5 homozygous patients n = 47) were recruited. Univariate and multivariate regression analyses were performed to predict factors relevant for serum CNDP1 concentration. CNDP1 (CTG)5 homozygous patients with T2D with DN had significantly lower CNDP1 concentrations (30.4 ± 18.3 vs 51.2 ± 17.6 µg/ml, p < 0.05) and activity (1.25 ± 0.5 vs 2.53 ± 1.1 µmol/ml/h, p < 0.05) than those without nephropathy. This applied for patients with DN on the whole, irrespective of (CTG)5 homozygosity. In the multivariate regression analyses, lower serum CNDP1 concentrations correlated with impaired renal function and to a lesser extend with the CNDP1 genotype (95% CI of regression coefficients: eGFR: 0.10-1.94 (p = 0.001); genotype: - 0.05 to 5.79 (p = 0.055)). Our study demonstrates that serum CNDP1 concentrations associate with CNDP1 genotype and renal function in patients with T2D. Our data warrant further studies using large cohorts to confirm these findings and to delineate the correlation between low serum CNDP1 concentrations and renal function deterioration in patients with T2D.

Dietary Intervention with Oatmeal in Patients with uncontrolled Type 2 Diabetes Mellitus - A Crossover Study.

BACKGROUND: In a pilot study, we evaluated the efficacy of two days of oatmeal on insulin resistance and glucose metabolism and found a marked decrease of insulin requirements. The most important shortcoming of that study was that the interventions were not isocaloric (diabetes adapted diet: 1500 kcal/d vs. oatmeal 1100 kcal/d). To address these drawbacks we designed the OatMeal And Insulin Resistance (OMA-IR) study. METHODS: The study was a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients with uncontrolled type 2 diabetes. The intervention comprised two days of oatmeal on days 3 and 4 of a 5 days hospital stay. During the control period, patients received a diabetes mellitus adapted diet only. The primary endpoint was the daily insulin requirement and glycemic control. RESULTS: Upon oatmeal treatment, the required insulin dose could be significantly reduced on the third and fourth day as compared to the second day of inpatient stay (82.0±30.3 and 69.9±29.9IU versus 112±36.2IU;P<0.001). During control treatment, insulin requirement did not change. There were no significant differences in the changes of mean blood glucose or fasting glucose between both treatments. HbA1c was lower four weeks after the oatmeal intervention. CONCLUSION: In this crossover study, two days of oatmeal intervention allowed a highly significant reduction of required daily insulin doses while maintaining adequate metabolic control as compared to a diabetes adapted diet only. The beneficial effects of the intervention might last for several weeks as shown by the lower HbA1c four weeks after the intervention.

[Intraoperative Indocyanine Green Fluorescence to Assure Vital Parathyroids in Thyroid Resections]. / Intraoperative Indocyaningrün-Fluoreszenzbildgebung zur Sicherung vitaler Nebenschilddrüsen bei Schilddrüsenresektionen.

INTRODUCTION: Total thyreoidectomy is associated with high rates of temporary or permanent hypoparathyroidism. During surgery, ICG fluorescence angiography can be used to detect and preserve well vascularised parathyroid glands; this technique has been recently introduced in retrospective and prospective trials as an intraoperative technical support to avoid postoperative hypoparathyroidism. MATERIALS UND METHODS: 27 patients undergoing total thyreoidectomy were prospectively enrolled in our study. The vascularisation of the parathyroid glands was analysed intraoperatively using ICG tissue angiography. 5 mg indocyanine green were intravenously administered. Fluorescence angiography was evaluated in real time using the PinPoint (Novadaq, Canada) imaging system. The study was approved by the local ethics committee. RESULTS: ICG fluorescence angiography was performed uneventfully in all cases. There was no case of postoperative hypoparathyroidism when at least one parathyroid gland with high fluorescence intensity was preserved. In 4 cases, only low fluorescence intensity was detected in the remaining parathyroid glands after completing the resection. All 4 patients received activated vitamin D3 prophylactically. Two of 4 developed symptomatic hypocalcaemia due to temporary hypoparathyroidism. CONCLUSION: Implementation of ICG fluorescence angiography can help in predicting and therefore preventing postoperative hypoparathyreoidism after total thyreoidectomy. If a well vascularised parathyroid gland with high ICG fluorescence intensity can be secured, calcium substitution and postoperative prophylaxis of hypoparathyreoidism may become obsolete in the future.

The CNDP1 (CTG)5 Polymorphism Is Associated with Biopsy-Proven Diabetic Nephropathy, Time on Hemodialysis, and Diabetes Duration.

Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study.

Retinopathy in an obesity WHO III cohort: prevalence and risk factors.

OBJECTIVE: To assess retinopathy and its risk factors in an obesity WHO III cohort. METHODS: In the Mannheim Obesity Study, 277 subjects with obesity WHO III aged 18-64 years were examined in a cross-sectional approach. Screening for retinopathy was performed using 3-field retinal photography. Endothelial function was assessed using arteriole-to-venule ratio and flicker light analysis. Subjects with and without retinopathy were analysed for anthropometry, metabolic, vascular and renal parameters. RESULTS: Retinopathy was found in 18 of the 277 subjects (6.5%). Prevalence of retinopathy was 16.7% in subjects with and 3.4% in subjects without diabetes mellitus. Between subjects with and without retinopathy there were significant differences in diabetes prevalence (61.1% vs 21.7%, p<0.001), systolic blood pressure (145.56 vs 131.73 mm Hg, p=0.005), intima-media thickness (0.7 vs 0.59 mm, p=0.034), dilatation of retinal veins in response to flicker light (2.24% vs 4.28%, p=0.004) and creatinine (0.92 vs 0.83 mg/dL, p=0.011). Stepwise logistic regression analysis revealed that the presence of diabetes mellitus led to an 8.3-fold increased risk for retinopathy (OR 8.3, p=0.049, 95% CI 1.01 to 67.49), whereas risk for retinopathy decreased by nearly 50% (OR 0.54, p=0.032, 95% CI 0.30 to 0.95) with each percentage increase in venous dilatation in response to flicker light. CONCLUSIONS: Retinopathy prevalence in our obesity WHO III cohort is low. Presence of diabetes mellitus is the most important risk factor for retinopathy. Preserved venular function indicates protection from retinopathy. TRIAL REGISTRATION NUMBER: NCT00770276, Results.

Renal Denervation in Patients with Resistant Hypertension-Assessment by 3T Renal 23Na-MRI: Preliminary Results.

BACKGROUND/AIM: Renal denervation (RDN) has been considered a promising therapy option for patients suffering from therapy-resistant hypertension. Besides, in blood-pressure regularization, the kidneys play a fundamental role in sodium ((23)Na) homeostasis. This study assesses the effect of RDN on renal (23)Na concentration using (23)Na magnetic resonance imaging (MRI). PATIENTS AND METHODS: Two patients with therapy-resistant hypertension underwent RDN. (23)Na-MRI, (1)H-MRI, including diffusion weighted imaging (DWI), as well as endothelial dysfunction assessment, were performed 1 day prior, as well as 1, 30 and 90 days after RDN. RESULTS: The renal corticomedullary (23)Na gradient did not change after RDN for all time points. Additionally, functional imaging and retinal vessel parameters were not influenced by RDN. Results regarding blood pressure changes and arterial stiffness, as well as patients' clinical outcome, were heterogeneous. CONCLUSION: RDN does not seem to alter renal (23)Na concentration gradients, as measured by MRI.

Minoxidil for Treatment of Resistant Hypertension in Chronic Kidney Disease--A Retrospective Cohort Analysis.

Resistant hypertension is still a challenge and reserve antihypertensive agents are often necessary to achieve blood pressure control. One reserve antihypertensive is minoxidil, a direct vasodilator that is known for its strong blood pressure-lowering effect, but contemporary studies are sparse. The authors retrospectively analyzed 54 inpatients with uncontrolled hypertension despite the combined use of current antihypertensive agents. To investigate the effect of minoxidil when added to other antihypertensive agents, blood pressure was evaluated at the time minoxidil treatment was initiated and at discharge. Minoxidil treatment was associated with a significant reduction in blood pressure from 162.4±15.1/83.2±12.7 mm Hg to 135.8±12.2/72.8±6.9 mm Hg (P<.0001). This effect was sustained across all analyzed subgroups. Although the well-known adverse events of minoxidil limit its widespread use, these data show that minoxidil as a reserve antihypertensive agent still has a niche indication in the particular subgroup of patients with treatment-resistant or uncontrolled hypertension.

Performance of the 1 mg dexamethasone suppression test in patients with severe obesity.

OBJECTIVE: To analyze the performance of the 1 mg dexamethasone suppression test (DST) in patients with obesity. Special attention was paid to the influence of interfering medication on DST. METHODS: In this prospective cohort study (Mannheim Obesity Study), patients with obesity were evaluated before bariatric surgery. For evaluation of hypercortisolism, a 1 mg dexamethasone-suppression test (DST) in all subjects was performed. Medication was assessed for possible interference. RESULTS: Two hundred seventy-eight patients with a mean age of 42.3 years (68.8% women) and a mean BMI of 47.9 ± 8.4 kg/m(2) were screened. Insufficient suppression of cortisol after DST was found in 24 patients (8.6%). In two patients hypercortisolism was confirmed. The specificity for DST was calculated at 92.0%. Only CYP3A4 inducers (n = 22, 7.9%) and estrogen therapy (n = 17, 6.1%) were significantly associated with falsely elevated cortisol after DST. Regression analysis excluded any interrelation between DST and anthropometry. CONCLUSIONS: Low prevalence of hypercortisolism (0.7 or <1.8%) was found. Specificity of DST in this cohort typically screened for hypercortisolism was 92.0% (≤ 50 nmol/L). DST should be avoided in patients taking CYP3A4 inducers or estrogen therapy, due to their significant interaction. In summary, the 1 mg DST is an adequate test for screening for hypercortisolism even in patients with extreme obesity.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study.

CONTEXT: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

3T renal (23)Na-MRI: effects of desmopressin in patients with central diabetes insipidus.

PURPOSE: The purpose of this prospective study was to assess physiologic changes in the renal corticomedullary (23)Na-concentration ([(23)Na]) gradient with (23)Na-MRI at 3.0T in patients with central diabetes insipidus (CDI) before and after intranasal administration of 20 µg desmopressin (DDAVP). METHODS AND MATERIALS: Four patients with CDI (all male, mean age 60.2 years) were included in this IRB-approved study. For (23)Na-imaging, a 3D density adapted, radial GRE-sequence (TE = 0.55 ms; TR = 120 ms; projections = 8,000; spatial resolution = 5 × 5 × 5 mm(3)) was used in combination with a dedicated (23)Na-coil and reference phantoms. The corticomedullary [(23)Na] gradient (in mmol/L/mm) was calculated pixel-by-pixel along a linear region-of-interest (ROI) spanning from the renal cortex in the direction of the medulla. Mean ± SDs of [(23)Na] were calculated for each patient as well as for the entire group. RESULTS: Mean [(23)Na] increased along the corticomedullary gradient from the cortex (pre-DDAVP 38.0 ± 6.3 mmol/L vs. post-DDAVP 30.7 ± 3.5 mmol/L) to the medulla (pre-DDAVP 71.6 ± 14.8 mmol/L vs. post-DDAVP 59.7 ± 10.8 mmol/L). The overall mean decrease of [(23)Na] after DDAVP administration was 17.1 ± 1.1 %. CONCLUSION: (23)Na-MRI with state-of-the-art techniques at 3T depicts the physiologic renal response to the administration of desmopressin in patients with central diabetes insipidus.

Adipokines and endothelial dysfunction in obesity WHO°III.

Obesity is closely associated with the metabolic syndrome (MetS) and subsequent low-grade inflammation links to endothelial dysfunction (ED) and cardiovascular disease. The impact of adipokines on retinal ED is not fully understood, in particular not in severe obesity. The aim of the study was to identify the association of the MetS and prespecified adipokines on retinal ED in obesity WHO°III. 92 obese patients (obesity WHO°III) were assessed for the MetS (IDF), neck circumference, adipokines and inflammatory markers (hsCRP, TNFα, Il-6, MCP-1, sICAM, sVCAM, IGF-BP3, RBP 4 and adiponectin). Retinal ED as determined by the arterio-venous-ratio (AVR) and retinal vessel diameters (CRAE, CRVE) was measured using retinal photographs. Obese subjects with MetS (MetS+ group) differed from the MetS- by neck circumference, fasting plasma glucose, insulin, HOMA-IR, triglycerides and HDL-C. Importantly, IL-6, sICAM and adiponectin were significantly different between groups, while measures of retinal ED showed no differences. Univariate linear regression revealed a significant association between neck circumference and ED for patients with MetS, and a significant association between adiponectin and CRAE for patients without MetS. This study shows that ED in obesity WHO°III is independent of MetS or inflammation and that neck circumference has an impact on ED in obesity WHO°III.

Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2.

BACKGROUND: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). METHODS: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro- and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e.g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. DISCUSSION: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.