Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood-Onset Hypophosphatasia

Hypophosphatasia is an inherited disease characterized by reduced alkaline phosphatase activity, extracellular accumulation of inorganic pyrophosphate, and impaired bone mineralization. Asfotase alfa (AA) is a recombinant human alkaline phosphatase therapy approved for treatment of pediatric-onset hypophosphatasia. Studies show promising outcome in AA-treated children with hypophosphatasia; however, data on adults with pediatric-onset hypophosphatasia are scarce. We report on a 59-year-old woman with childhood- onset hypophosphatasia and a history of multiple fractures and orthopedic procedures. Owing to renal failure (histological diagnosis: focal segmental glomerulosclerosis), hemodialysis was started in 2013. By the end of 2015, the patient was unable to walk, could only stand for 30 seconds, and was completely dependent on help for activities of daily living. After 13 months of AA therapy, the patient showed a dramatic increase in quality of life (increased mobility), reduction in pain medication, and a significant improvement in bone mineralization throughout the skeleton, including consolidation of existing fractures and no occurrence of new fractures. This case report demonstrates a relevant therapeutic success of AA treatment in an adult hemodialysis patient with childhood onset of hypophosphatasia

Empirical essays on tax planning and transfer pricing

This dissertation consists of three empirical studies contributing to the literature on tax planning and transfer pricing. The first study investigates the impact of U.S. state taxation on the geographical allocation of the intra-U.S. trademark ownership of large U.S. multinationals. The study documents that the U.S. State of Delaware has a leading position as a trademark holding location and that the major-ity of trademarks are registered there. Moreover, it contains an analysis of the effectiveness of group consolidation (combined reporting) and provides evidence that combined reporting signifi-cantly reduces the share of trademarks allocated to Delaware. Nevertheless, the identified effects indicate that Delaware-based trademark strategies have not been entirely abandoned. The second study examines the use of information technologies in a firm’s transfer pricing system. In particular, it investigates the role of firms’ information environment in mitigating the conflict of managerial and tax objectives in transfer pricing. The study provides empirical evi-dence that if firms facing conflicting objectives make intensive use of information technologies, they are more profitable, report lower effective tax rates, and face lower tax risk. The third study analyzes whether the strictness of transfer pricing regulations and their en-forcement affect intrafirm trade of U.S. multinational firms. In particular, the results suggest that stricter transfer pricing in a country decrease the tax rate sensitivity of bilateral U.S. intrafirm trade. Thus, the possibilities of U.S. multinationals to engage in transfer pricing related tax plan-ning schemes are effectively reduced

Проблеми побудови відкритої та гнучкої методичної системи навчання математичних методів фізики у педагогічних університетах

(uk) Розглядаються тенденції розвитку фундаментальної фізико-математичної освіти, зближення природничо-наукового та гуманітарного, що уможливлюють розв’язання проблеми побудови відкритої та гнучкої науково-обґрунтованої методичної системи навчання математичних методів фізики у педагогічних університетах.(en) The article examines progressive trends of fundamental physical and mathematical education, rapprochement of naturally scientific and humanitarian, that makes possible to solve the problem of constructing the open and flexible scientifically reasonable methodical systeme of mathematical methods of physics teaching inpedagogical universities

Glucagonoma-induced acute heart failure

Neuroendocrine tumours (NETs) represent a broad spectrum of tumours, of which the serotonin-producing carcinoid is the most common and has been shown to cause right ventricular heart failure. However, an association between heart failure and NETs other than carcinoid has not been established so far. In this case report, we describe a 51-year-old patient with a glucagon-producing NET of the pancreas who developed acute heart failure and even cardiogenic shock despite therapy. Heart failure eventually regressed after initialising i.v. treatment with the somatostatin analogue octreotide. Chromogranin A as a tumour marker was shown to be significantly elevated, and it decreased with clinical improvement of the patient. The effects of long-time stimulation of glucagon on the myocardium have not been studied yet; however, sarcoplasmic reticulum calcium leak can be discussed as a possible mechanism for glucagon-induced heart failure

Apparent mineralocorticoid excess syndrome: an overview

Apparent mineralocorticoid excess (AME) syndrome results from defective 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and converts cortisol (F) to its inactive metabolite cortisone (E). Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension. Mutations in the gene encoding 11beta-HSD2 account for the inherited form, but a similar clinical picture to AME occurs following the ingestion of bioflavonoids, licorice and carbenoxolone, which are competitive inhibitors of 11beta-HSD2. Reduced 11beta-HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease and liver cirrhosis. Relative deficiency of 11beta-HSD2 activity can occur in Cushing's syndrome due to saturation of the enzyme and explains the mineralocorticoid excess state that characterizes ectopic ACTH syndrome. Reduced placental 11beta-HSD2 expression might explain the link between reduced birth weight and adult hypertension. Polymorphic variability in the HSD11B2 gene in part determines salt sensitivity, a forerunner for adult hypertension onset. AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2; although AME is a genetic disorder, several exogenous compounds can bring about the symptoms by inhibiting 11beta-HSD2 enzyme. Substrate excess as seen in Cushing's syndrome and ACTH ectopic production can overwhelm the capacity of 11beta-HSD2 to convert F to E, leading up to an acquired form of AME

Functional consequences of seven novel mutations in the CYP11B1 Gene: four mutations associated with nonclassic and three mutations causing classic 11 -Hydroxylase Deficiency

Context: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. Objective: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. Methods: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. Results: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11β-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. Conclusion: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling i

Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy

CONTEXT Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. OBJECTIVE The aim of this study was to analyze long-term clinical and biochemical outcome of unilateral adrenalectomy versus bilateral adrenalectomy in patients with PBMAH in comparison to outcome of cortisol-producing adenoma (CPA) treated by unilateral adrenalectomy. DESIGN Retrospective observational study in three German and one Italian academic tertiary care center. PATIENTS AND METHODS 25 PBMAH patients after unilateral adrenalectomy (unilat-ADX-PBMAH), 9 patients with PBMAH and bilateral adrenalectomy (bilat-ADX-PBMAH) and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. RESULTS Baseline clinical and biochemical parameters were comparable in unilat-ADX-PBMAH, bilat-ADX-PBMAH and unilat-ADX-CPA. Directly after surgery, 84% of the unilat-ADX-PBMAH patients experienced initial remission of Cushing's syndrome. In contrast, at last follow-up (median 50 months) 32% of the unilat-ADX-PBMAH patients were biochemically controlled compared to nearly all patients in the other two groups (p=0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initially unilat-ADX-PBMAH patients. 3 of 20 unilat-ADX-PBMAH patients (15%) died during follow-up presumably of Cushing's syndrome related causes whereas no deaths occurred in the other two groups (p=0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX. CONCLUSIONS Our data suggest that unilateral adrenalectomy of PBMAH patients leads to clinical remission and a lower incidence of adrenal crisis, but less sufficient biochemical control of hypercortisolism potentially provoking a higher mortality

Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5Gy*cm(2) (0.3-3181) and FT 18 min (0.3-184). The calculated ED was 6.4 mSv (0.1-636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm(2), FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusion: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure

Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study

Background: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome