Steroid Hormone Production in Patients with Aldosterone Producing Adenomas.

Primary aldosteronism encompasses 2 major underlying causes: (1) aldosterone producing adenoma and (2) bilateral adrenal hyperplasia. In addition to the aldosterone excess, increased production of other compounds of the steroidogenic pathways may be involved. Until recently, most studies examined the production of steroids other than aldosterone in tumor tissue, urine, or peripheral plasma samples, but several new studies have also addressed steroid levels in adrenal venous blood samples using liquid chromatography tandem mass spectrometry. Plasma and tissue levels of several precursors of aldosterone with mineralocorticoid activity are higher in patients with aldosterone producing adenomas than in those with bilateral hyperplasia. These include corticosterone, deoxycorticosterone, and their 18-hydroxylated metabolites. Similarly, urinary, peripheral, and adrenal venous concentrations of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol are higher in patients with aldosterone producing adenomas than in bilateral hyperplasia. Differences in the pathophysiology and in clinical and biochemical phenotypes caused by aldosterone producing adenomas and bilateral adrenal hyperplasia may be related to the differential expression of steroidogenic enzymes, and associated to specific underlying somatic mutations. Correct appreciation of differences in steroid profiling between aldosterone producing adenomas and bilateral adrenal hyperplasia may not only contribute to a better understanding of the pathogenesis of primary aldosteronism but may also be helpful for future subtyping of primary aldosteronism.

Local inhomogeneities resolved by scanning probe techniques and their impact on local 2DEG formation in oxide heterostructures.

Lateral inhomogeneities in the formation of two-dimensional electron gases (2DEG) directly influence their electronic properties. Understanding their origin is an important factor for fundamental interpretations, as well as high quality devices. Here, we studied the local formation of the buried 2DEG at LaAlO3/SrTiO3 (LAO/STO) interfaces grown on STO (100) single crystals with partial TiO2 termination, utilizing in situ conductive atomic force microscopy (c-AFM) and scattering-type scanning near-field optical microscopy (s-SNOM). Using substrates with different degrees of chemical surface termination, we can link the resulting interface chemistry to an inhomogeneous 2DEG formation. In conductivity maps recorded by c-AFM, a significant lack of conductivity is observed at topographic features, indicative of a local SrO/AlO2 interface stacking order, while significant local conductivity can be probed in regions showing TiO2/LaO interface stacking order. These results could be corroborated by s-SNOM, showing a similar contrast distribution in the optical signal which can be linked to the local electronic properties of the material. The results are further complemented by low-temperature conductivity measurements, which show an increasing residual resistance at 5 K with increasing portion of insulating SrO-terminated areas. Therefore, we can correlate the macroscopic electrical behavior of our samples to their nanoscopic structure. Using proper parameters, 2DEG mapping can be carried out without any visible alteration of sample properties, proving c-AFM and s-SNOM to be viable and destruction-free techniques for the identification of local 2DEG formation. Furthermore, applying c-AFM and s-SNOM in this manner opens the exciting prospect to link macroscopic low-temperature transport to its nanoscopic origin.

Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells.

Alternative splicing of pre-mRNA increases proteomic diversity, a crucial mechanism in defining tissue identity. We demonstrate differentially spliced interleukin (IL)-7 in distinct anatomic areas in the adult, in developing human brains and in normal human neuronal progenitor (NHNP) cells. IL-7c (c, the canonical form spanning all six exons) or its variants IL-7 delta 5, delta 4 or delta 4/5 were cloned and expressed as recombinant proteins. IL-7 and splice variants were able to shift the differentiation of NHNP cells as compared with the diluent control (P<0.01) defined by anti-beta (III)-tubulin and glial fibrillary acidic protein expression, with different degrees (IL-7c>delta 4/5>IL-7 delta 5); IL-7 delta 4 exhibited a significantly weaker potency. Differentiation was confirmed by transcriptome analysis of IL-7c-stimulated neural NHNP cells, resulting in 58 differentially expressed genes; some of these are involved in neural differentiation, for example, the developmentally regulated transcription factor krüppel-like factor 12, musashi 2, a translational regulator of cell fate or the sonic hedgehog receptor patch 1. This suggests that IL-7 influences neural development at a molecular level by participating in human brain architecture through glia cell formation: a paradigm that alternative splicing in cytokines, for example, for IL-7, has a physiological role in human organ development and progenitor cell differentiation.

A role for complement receptor-like molecules in iron acquisition by Candida albicans.

Candida albicans, an opportunistic fungal pathogen of humans, is dependent upon iron for growth. Consequently, human serum inhibits C. albicans growth due to the presence of high affinity iron-binding proteins that sequester serum iron, making it unavailable for use by the organism. We report that in the inhibitory environment of human serum, the growth of C. albicans can be restored by the addition of exogenous hemoglobin or heme, but not by protoporphyrin IX, the heme precursor that does not contain iron. We further report that C. albicans can utilize cell surface proteins that are homologues of the mammalian complement receptors (CR) to rosette complement-coated red blood cells (RBC) and obtain RBC-derived iron for growth. The ability of Candida to acquire RBC-derived iron under these conditions is dependent upon Candida-RBC rosetting mediated by CR-like molecules. Unopsonized RBC do not support Candida growth in serum, and restoration of Candida growth in serum by complement-opsonized RBC is inhibited by monoclonal antibodies to the human CR type 3 (CR3). In addition, activation of the human alternative pathway of complement by Candida leads to "bystander" deposition of C3 fragments on the surface of autologous, unopsonized RBC, generating the ligands necessary for Candida-RBC rosetting. These results suggest that C. albicans has evolved a unique strategy for acquiring iron from the host, which exploits the host complement system, and which may contribute to the pathogenic potential of the organism.

C2H2 interaction with Ni nanocrystals: towards a better understanding of carbon nanotubes nucleation in CVD synthesis.

We present a study of the early stages of carbon nanotubes nucleation in CVD synthesis by combining field ion/electron emission microscopy (FIM/FEM) and atom-probe investigation (AP) of the nickel-carbon interaction. Acetylene decomposition on Ni tips at 873K is observed to induce additional step formation on an initially facetted (polyhedral) crystal. Carbon-enriched steps are then observed to act as preferential nucleation centers of graphene sheets formation. Atom-probe experiments reveal C(2) and C(3) species and frequency dependent studies demonstrate that the origin of these species is different from C(1). Experiments provide clear evidence for the crucial role of carbon-enriched steps as nucleation sites of graphene sheets on the Ni surface.

Surface segregation of Au-Pd alloys in UHV and reactive environments: quantification by a catalytic atom probe.

The surface composition of an Au-62at%Pd alloy has been studied by means of a catalytic atom probe (CAP) before and after exposures to nitric oxide (NO) at temperatures ranging from 300 to 573K for 20min. Subsequent CAP analysis at 100K revealed a considerable surface enrichment in Pd (to approximately 80at%) after exposure at 573K. This is correlated with the occurrence of NO dissociation, and the formation of strong Pd-O bonds at the surface. Blank experiments in ultra-high vacuum reflect the surface composition of the bulk material, in excellent agreement with electron microprobe analysis. At 573K, no detectable surface segregation occurs in the absence of NO adsorption for the times and temperatures studied. However, classical Metropolis Monte-Carlo simulations performed with a semi-empirical potential on the Au(40)Pd(60) (111), (110) and (100) systems show surface enrichment of gold at equilibrium. This suggests that the temperatures of the clean surface segregation experiments are too low to reach equilibrium within times of the order of hours.

Resistive switching in optoelectronic III-V materials based on deep traps.

Resistive switching random access memories (ReRAM) are promising candidates for energy efficient, fast, and non-volatile universal memories that unite the advantages of RAM and hard drives. Unfortunately, the current ReRAM materials are incompatible with optical interconnects and wires. Optical signal transmission is, however, inevitable for next generation memories in order to overcome the capacity-bandwidth trade-off. Thus, we present here a proof-of-concept of a new type of resistive switching realized in III-V semiconductors, which meet all requirements for the implementation of optoelectronic circuits. This resistive switching effect is based on controlling the spatial positions of vacancy-induced deep traps by stimulated migration, opening and closing a conduction channel through a semi-insulating compensated surface layer. The mechanism is widely applicable to opto-electronically usable III-V compound semiconductors.

Vulnerability and revictimization: Victim characteristics in a Dutch assault center.

Sexual and family violence are highly prevalent problems with numerous negative health consequences. Assault centres, such as the Centre for Sexual and Family Violence (CSFV) in the Netherlands, have been set up to provide optimal care to victims. We wanted to gain insight into characteristics of the population that presented to the Centre in order to customize care to their needs. File analysis was conducted of victims who attended the CSFV between 2013 and 2016. Data were analyzed in SPSS. A total of 121 victims entered the Centre, 93% of them being female. Forty-two per cent were adult victims of sexual violence, 28% minor victims of sexual violence and 30% adult victims of family violence. One-third of sexual and two-third of family violence victims had experienced prior abuse. Current use of psychosocial services and psychiatric medication was high, and a cognitive disability was present in 18% of the sexual violence victims. Half the victims reported, but when the perpetrator was a recent contact, e.g., someone met at a party, reporting rates went down. Sexual and family violence victims share characteristics that indicate vulnerability, suggesting that care for both groups might best be combined in one single assault centre. In this way, victims can make use of the same services and knowledge of gender-based violence. One of the major aims of assault centres is to provide psychosocial follow-up care and facilities for reporting. The victims' needs in these matters deserve further research.

Interface-driven formation of a two-dimensional dodecagonal fullerene quasicrystal.

Since their discovery, quasicrystals have attracted continuous research interest due to their unique structural and physical properties. Recently, it was demonstrated that dodecagonal quasicrystals could be used as bandgap materials in next-generation photonic devices. However, a full understanding of the formation mechanism of quasicrystals is necessary to control their physical properties. Here we report the formation of a two-dimensional dodecagonal fullerene quasicrystal on a Pt3Ti(111) surface, which can be described in terms of a square-triangle tiling. Employing density functional theory calculations, we identify the complex adsorption energy landscape of the Pt-terminated Pt3Ti surface that is responsible for the quasicrystal formation. We demonstrate the presence of quasicrystal-specific phason strain, which provides the degree of freedom required to accommodate the quasicrystalline structure on the periodic substrate. Our results reveal detailed insight into an interface-driven formation mechanism and open the way to the creation of tailored fullerene quasicrystals with specific physical properties.

Tuning the surface electronic structure of a Pt3Ti(111) electro catalyst.

Increasing the efficiency and stability of bimetallic electro catalysts is particularly important for future clean energy technologies. However, the relationship between the surface termination of these alloys and their catalytic activity is poorly understood. Therefore, we report on fundamental UHV-SPM, LEED, and DFT calculations of the Pt3Ti(111) single crystal surface. Using voltage dependent imaging the surface termination of Pt3Ti(111) was studied with atomic resolution. Combining these images with simulated STM maps based on ab initio DFT calculations allowed us to identify the three upper layers of the Pt3Ti(111) single crystal and their influence upon the surface electronic structure. Our results show that small changes in the composition of the second and third atomic layer are of significant influence upon the surface electronic structure of the Pt3Ti electro catalyst. Furthermore, we provide relevant insights into the dependence of the surface termination on the preparation conditions.

Proteasome-mediated regulation of interleukin-1beta turnover and export in human monocytes.

Interleukin-1beta is a secreted protein that accumulates in the cytosol as an inactive precursor (pIL-1beta) before processing and release of biologically active protein. To understand the impact of this property on IL-1beta production, we examined the intracellular stability of pIL-1beta in lipopolysaccharide (LPS)-stimulated human monocytes. Precursor IL-1beta was degraded with a relatively short half-life of 2.5 h in the promonocytic cell line, THP-1, and in primary monocytes. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal) stabilized pIL-1beta levels in THP-1 cells, suggesting that degradation was proteasome-mediated, but this inhibitor was toxic for primary monocytes, causing release of pIL-1beta as well as the cytoplasmic enzyme, lactate dehydrogenase (LDH) into supernatants. In contrast, clasto-lactacystin beta-lactone, a specific inhibitor of the proteasome, caused a dose-dependent stabilization of intracellular pIL-1beta, and this led to a corresponding increase in mIL-1beta and pIL-1beta but not LDH release into culture supernatants. Therefore, by regulating intracellular levels of precursor IL-1beta, the proteasome plays an important and previously unrecognized role in controlling the amount of biologically active IL-1beta that is exported by activated monocytes.

Altered macrophage antigen-presenting cell function following Friend leukemia virus infection.

To investigate the mechanism by which Friend leukemia virus (FV) causes immunosuppression, the ability of peritoneal macrophages to mediate antigen-specific T-cell activation following FV infection was examined. Decreased IL-2 production was observed when antigen-primed T cells were cultured with antigen-pulsed macrophages from mice infected with FV, compared to T cells cultured with macrophages from control mice. Macrophages from FV-infected mice demonstrated decreased phagocytic and pinocytic activity, suggesting that antigen uptake may be impaired in these cells. In addition, FV-infected mice had decreased numbers of MHC class II positive macrophages compared to uninfected controls, as measured by immunofluorescence. The alterations in antigen uptake and class II expression observed in macrophages from FV-infected mice may be the result of infection of these cells by FV, which was demonstrated by in situ hybridization using a FV-specific probe. The ability of FV to infect and modulate the functions of macrophages may account, at least in part, for the immunosuppression observed in FV-infected mice.

AC impedance measurements on high copper dental amalgams.

In recent years alloys with a high copper content were developed to improve the corrosion resistance of dental amalgam by elimination of the gamma 2 (Sn-Hg) phase. The purpose of the present investigation was to compare the electrochemical behaviour of high copper amalgams obtained from single composition amalgam alloys (Indiloy; Shofu, Dental Corp., Menlo Park, USA) with those that used the additive mode of copper alloying (Dispersalloy; Johnson & Johnson, East Windsor, USA).

Knowledge-based system for the automated solid-phase extraction of basic drugs from plasma coupled with their liquid chromatographic determination. Application to the biodetermination of beta-receptor blocking agents.

Techniques for the preparation of biological samples are often based nowadays on solid-phase extraction (SPE). The different SPE steps can be performed automatically on disposable extraction cartridges (DECs) by means of a sample processor. A knowledge-based system was developed to facilitate the development of fully automated methods for the solid-phase extraction of relatively hydrophobic basic drugs from plasma, coupled with their determination by high-performance liquid chromatography (HPLC). The DEC filled with 50 mg of cyanopropyl-bonded silica phase is first conditioned with methanol and buffer solution (pH 7.4). After sample application, the DEC sorbent is washed with the same buffer. The analytes are then desorbed with an appropriate eluent and the eluate is finally diluted with the same buffer as used in the HPLC mobile phase before injection. Under these conditions, only three variables are still to be optimized: the composition and volume of the elution solvent and the volume of buffer to be added to the eluate. On the basis of this general strategy, a decision tree providing information about suggested starting conditions and guidelines for the optimization of the three variables was developed and implemented by use of a hypermedia software. This didactic expert system was evaluated using several beta-receptor blocking agents as model compounds and the operating conditions obtained for the automated SPE of these compounds are presented. A method for the determination of propranolol in plasma using the SPE conditions deduced from the knowledge-based system was validated. The absolute recovery of propranolol is ca. 93% and the limit of detection is 1.3 ng ml-1. The mean within-day and between-day reproducibilities are 2.3 and 3.6%, respectively.

Evaluation of solid-phase extraction of basic drugs from human milk.

This article evaluates the use of commercially available cyanopropyl and octadecyl sorbents for the extraction of basic drugs from breast milk. Twenty drugs were selected from different pharmacological groups (beta-blocking agents, antidepressants, anxiolytic sedatives and neuroleptics, antihistamines, alkaloids and an anthelmintic) and subjected to a general solid-phase extraction (SPE) procedure described earlier for plasma samples. This SPE method was developed on a cyanopropyl cartridge and consisted of a conditioning step with methanol and water, the adsorption of the deproteinized matrix, washing with water and/or methanol, and finally the elution of the basic compounds with 0.1% propylamine in methanol. The extracts were further analysed by reversed-phase liquid chromatography (RP-LC). The application of SPE to human milk samples utilized cyanopropyl and octadecyl cartridges. The latter can be applied more generally because it better retains the basic compounds. For 14 out of 17 drugs extracted from breast milk, recoveries of greater than 70% were obtained. Standard deviations were, with the exception of three drugs, in the same range as those observed for plasma samples, i.e. 2-8%. The development of a strategy for SPE of drugs from human milk was difficult. For a number of drugs, in particular those present in human milk at low concentrations and/or detected in a non-selective way, matrix compounds interfered with the subsequent LC analysis. Therefore, SPE on CN or C18-sorbent for the analysis of basic compounds in breast milk was found to be useful as one of the steps in an extraction procedure, but not as a single technique. A major drawback of SPE is the batch-to-batch variation of the sorbents.

Simultaneous determination of levodopa, carbidopa, 3-O-methyldopa and dopamine in plasma using high-performance liquid chromatography with electrochemical detection.

An analytical method is described which allows a fast, reliable and precise determination of levodopa and its metabolises 3-O-methyldopa and dopamine, as well as the peripheral aromatic amino acid decarboxylase inhibitor carbidopa, in a single 1 ml plasma sample of Parkinsonian patients. The compounds are quantitatively isolated on small Sephadex G-10 columns and determined by HPLC with electrochemical detection. Dihydroxybenzylamine or alpha-methyldopa are used as the internal standard. An example of therapeutic drug monitoring in a patient with fluctuations in motor performances is given. It is confirmed that interference with absorption of levodopa from the stomach by food can be partly responsible for these observed fluctuations.

Solid-phase extraction of small drugs on apolar and ion-exchanging silica bonded phases: towards the development of a general strategy.

In connection with the development of a general strategy for solid-phase extraction (SPE) of drugs, the use of the apolar octadecyl silica bonded phase and ion-exchanging phases with a benzene sulphonic acid or quaternary amine bonded functionality is investigated for the SPE of small polar drugs. This investigation was performed on a set of 15 drugs, belonging to varying pharmacological groups and with varying structures. For each analyte, its adsorption on the C18 and the ion-exchanging phase was controlled for an aqueous solution and for a spiked plasma sample. For those analytes retained on the sorbent, different elution solvents were compared. Although SPE methods could successfully be developed for some drugs, no general solution can be proposed and no solution was found for a few drugs. The main problems are that for these few drugs no sufficient retention is obtained on any SPE phase investigated or the selectivity is too low.

A scanning electron microscopic and tensile bond strength evaluation of Gluma dentin bond application, as a function of dentinal pretreatment.

Scanning Electron Micrographs (SEM) and Tensile Bond Strength (TBS) measurements were used to evaluate the influence of three different dentinal pretreatments. A new testing device was developed for the TBS measurements. Human tooth roots were ground with a diamond bur. Tap water, Gluma Cleanser, and Neo-Sabenyl-Tubulicid were used to clean the surfaces before SEM inspection. The adhesion between root dentin and Lumifor Composite restorations was mediated by Gluma Bond. SEM observations revealed that a 30-second application of Gluma Cleanser removes the smear layer totally. Neo-Sabenyl-Tubulicid produced a very smooth surface. Application of Gluma Bond did not alter this appearance. Mean TBS values for surfaces sprayed with tap water, Gluma Cleanser, and Neo-Sabenyl-Tubulicid were 10 MPa, 7.3 MPa, and 10 MPa, respectively. There was a significant difference between group 2 (Gluma Cleanser) and the other groups. From this in vitro study, it is concluded that total removal of the smear layer with opening of the dentinal tubules (e.g., by means of Gluma Cleanser) reduces the TBS of Gluma Dentin Bond-Lumifor restorations to ground root dentin.

[The fiscal position of medical specialists]. / De fiscale positie van medisch specialisten.

Independent medical specialists in the Netherlands are treated as entrepreneurs for tax purposes and therefore enjoy tax benefits. A change in the legal relationship between medical specialists and hospitals is foreseen in 2015. Independent medical specialists will then no longer be considered to be entrepreneurs. This could negatively affect their tax position. The Dutch government has adopted a policy aimed at controlling expenses arising from medical specialists' fees. According to this policy, the formation of regional practices or mega-practices of specialists will be discouraged. In contrast, the current fiscal legislation encourages medical specialists to incorporate their practice into regional practices or mega-practices or to become shareholders of their hospitals. It has been proposed that fiscal benefits be linked to certain aspects of entrepreneurship, such as investing in medical equipment or employing medical personnel.