Evidence for better response to somatostatin analogue treatment in acromegalic patients treated with metformin

Somatostatin analogues (SSA) constitute the mainstay of pituitary-targeted pharmacological treatment in acromegaly, but half of the patients are resistant to their anti-secretory and tumor shrinking effects. The successful management of acromegaly in addition to targeting biochemical control involves the treatment of the metabolic comorbidities and hypopituitarism that is managed with hormone replacement. The aim of this study was to analyze the impact of the concomitant antidiabetic treatment with metformin and hormone replacement on the response to SSA. Data were collected from 49 acromegalic patients: 45 had transsphenoidal surgery (35 as primary therapy), 36 SSA (octreotide or lanreotide; 11 as primary treatment). All acromegalic patients with diabetes mellitus (25%) received metformin. Hypopituitarism affected 18 patients. Binary logistic regression analysis (SPSS software) showed no correlation between SSA (p=0.71) and transsphenoidal surgery (p=0.541) on the incidence of pituitary insufficiency. Regression analysis showed no correlation between IGF-1 lowering response to SSA and substitution treatment with hydrocorticosterone, testosterone, or L-thyroxin (variance inflation factor \ensuremath{<}}3). Linear regression analysis showed no correlation between age, gender, disease duration, other treatment modalities (hydrocorticosterone, testosterone, or L-thyroxin) and change of IGF-1 levels after SSA treatment. However, the same analysis showed correlation between metformin therapy and IGF-1 levels after SSA treatment (p=0,031; R-square change: 0,135; R-square: 0,321). In a series of in vitro experiments, metformin alone significantly suppressed GH secretion at the 1mM concentration (64{±}13) and similar observations were obtained on the rat GH promoter activity and GH secretion from rat immortalized GH-secreting GH3 cells. In vitro investigation on 7 human acromegalic tumours showed that metformin (500nM) enhances the GH-suppressive effect of octreotide (1nM) (63{±}13% versus 81{±12). These preliminary observations indicate that hormone replacement does not affect SSA response, but metformin treatment improves SSA response in terms of IGF-1 reduction most likely through directly suppressing GH production in somatotroph tumor cells

Neutrino-induced coherent pion production off nuclei reexamined

It is pointed out that so far all theoretical estimates of coherent pion production off nuclei induced by neutrinos rely on the 'local approximation' well known in photonuclear physics. The effects of dropping this approximation are discussed. It is found that in a plane wave approximation for the pion the local approximation overestimates the coherent neutrino-induced pion production on nuclei.Comment: v3: comments on pion FSI added, minor corrections; version as published in Phys. Rev.

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism

Bolometric calibration of a superfluid 3^3He detector for Dark Matter search: direct measurement of the scintillated energy fraction for neutron, electron and muon events

We report on the calibration of a superfluid $^3$He bolometer developed for the search of non-baryonic Dark Matter. Precise thermometry is achieved by the direct measurement of thermal excitations using Vibrating Wire Resonators (VWRs). The heating pulses for calibration were produced by the direct quantum process of quasiparticle generation by other VWRs present. The bolometric calibration factor is analyzed as a function of temperature and excitation level of the sensing VWR. The calibration is compared to bolometric measurements of the nuclear neutron capture reaction and heat depositions by cosmic muons and low energy electrons. The comparison allows a quantitative estimation of the ultra-violet scintillation rate of irradiated helium, demonstrating the possibility of efficient electron recoil event rejection.Comment: 17 pages, submitted to Nuc. Instr. Meth.

Reference Process Flows for Telecommunication Companies - An Extension of the eTOM Model

The telecommunication market is experiencing substantial changes. New business models, innovative services, and technologies require reengineering, transformation, and process standardization. Enterprise Architecture Frameworks support the transformation by specifying methods, procedures, and reference models. With the Enhanced Telecom Operation Map (eTOM), the TM Forum offers an international de facto reference process framework, based on specific features and requirements of the telecommunication industry. However, this reference framework only offers a hierarchical collection of processes on different levels of abstraction; a control view in terms of a sequential ordering of tasks and hence a real process flow as well as an end-to-end view on the customer are missing. In this paper, we extend the eTOM reference model by reference process flows, in which we abstract and generalize the knowledge about processes in telecommunication companies. With reference process flows, we aim to assist companies in achieving a structured and transparent re-structuring and re-design of their processes. We demonstrate the applicability and usefulness of our reference process flows in two case studies, and evaluate them by means of criteria for reference model evaluation. Our reference process flows have been accepted as a standard by the TM Forum and published as part of eTOM version 9. We further elaborate on those components of our approach which can be applied outside the telecommunication industry

Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain

Neurodegeneration is a serious issue of neurodegenerative diseases including epilepsy. Downregulation of the chloride transporter KCC2 in the epileptic tissue may not only affect regulation of the polarity of GABAergic synaptic transmission but also neuronal survival. Here, we addressed the mechanisms of KCC2-dependent neuroprotection by assessing truncated and mutated KCC2 variants in different neurotoxicity models. The results identify a threonine- and tyrosine-phosphorylation-resistant KCC2 variant with increased chloride transport activity, but they also identify the KCC2 N-terminal domain (NTD) as the relevant minimal KCC2 protein domain that is sufficient for neuroprotection. As ectopic expression of the KCC2-NTD works independently of full-length KCC2-dependent regulation of Cl(-) transport or structural KCC2 C-terminus-dependent regulation of synaptogenesis, our study may pave the way for a selective neuroprotective therapeutic strategy that will be applicable to a wide range of neurodegenerative diseases

Disquisition on material parameters and their influence on wear rates at high temperatures

The aim of this work is to find correlations of hard phase content and matrix type with hot hardness and wear rates in the cyclic impact abrasion test at high testing temperatures. Several materials with different matrix types and varying hard phase content have been investigated regarding their wear behaviour as well as their hot hardness up to 800°C. The hot hardness and hard phase content then was correlated to the wear rates using statistical methods. Materials with comparable matrix properties and higher hard phase content always have higher hot hardness and these parameters are statistically dependent so correlation of wear rate with hot hardness is statistically sufficient. It was found, that within the same material the wear rate is correlated to the hot hardness as long as there is no significant change in the wear mechanism. When the matrix of the material changes the hot hardness can not be directly correlated to the wear rate any more. It was also found that among all materials tested those with an austenitic matrix generally have higher wear resistance even if they have the same hot hardness

Parameterization for subgrid-scale motion of ice-shelf calving fronts

A parameterization for the motion of ice-shelf fronts on a Cartesian grid in finite-difference land-ice models is presented. The scheme prevents artificial thinning of the ice shelf at its edge, which occurs due to the finite resolution of the model. The intuitive numerical implementation diminishes numerical dispersion at the ice front and enables the application of physical boundary conditions to improve the calculation of stress and velocity fields throughout the ice-sheet-shelf system. Numerical properties of this subgrid modification are assessed in the Potsdam Parallel Ice Sheet Model (PISM-PIK) for different geometries in one and two horizontal dimensions and are verified against an analytical solution in a flow-line setup