n-type Ge/Si antennas for THz sensing.

Ge-on-Si plasmonics holds the promise for compact and low-cost solutions in the manipulation of THz radiation. We discuss here the plasmonic properties of doped Ge bow-tie antennas made with a low-point cost CMOS mainstream technology. These antennas display resonances between 500 and 700 GHz, probed by THz time domain spectroscopy. We show surface functionalization of the antennas with a thin layer of α-lipoic acid that red-shifts the antenna resonances by about 20 GHz. Moreover, we show that antennas protected with a silicon nitride cap layer exhibit a comparable red-shift when covered with the biolayer. This suggests that the electromagnetic fields at the hotspot extend well beyond the cap layer, enabling the possibility to use the antennas with an improved protection of the plasmonic material in conjunction with microfluidics.

["Be right" vs. "get one's rights" : Practice-oriented recommendations from a legal viewpoint]. / "Recht haben" vs. "Recht bekommen" : Praxisnahe Empfehlungen aus juristischer Sicht.

OBJECTIVE: When is off-label use permitted by law in the statutory health insurance? Which approach is recommended for medical professionals to avoid recourse? RESULTS: The statutory health insurance in Germany is characterized among others by the precepts of efficiency and quality. Thus medicinal products may only be prescribed after an examination of quality, safety and efficacy. For using medicinal products off label, i. e. without applicable authorization or outside the authorized indications, these requirements are slightly reduced. Prerequisites for an off-label use are 1) a severe disease, 2) the absence of approved treatment alternatives and 3) scientific data that makes treatment success sufficiently probable. The clinical trials must be: placebo-controlled, randomized and double blind. Indications of lower evidential value are sufficient for life-threatening diseases. CONCLUSION: For an off-label use reference is often made to scientifically insufficient studies; however, it is always important to have the most careful possible reasoning for the specific case, especially for the absence of an approved treatment alternative. This also includes having an answer to all possible objections from critics.

Novel mutations of the PRKAR1A gene in patients with acrodysostosis.

Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation. This assumption is supported by the de novo origin of these mutations. Apart from typical radiological abnormalities of the hand bones, elevated thyroid stimulating hormone and parathyroid hormone values as well as short stature are the most common findings. Less frequent features are characteristic facial dysmorphisms, sensorineural hearing loss and mild intellectual disability. These results lead to the conclusion that mutations of PKRAR1A are the major molecular cause for acrodysostosis with endocrinological abnormalities. In addition, in our cohort of 44 patients affected with brachydactyly type E (BDE) we detected only one sequence variant of PRKAR1A (p.Asp227Asn) with an unclear effect on protein function. Thus, we conclude that PRKAR1A mutations may play no major role in the pathogenesis of BDE.

Experts' Perceived Patient Burden and Outcomes of Knee-ankle-foot-orthoses (Kafos) Vs. Microprocessor-stance-and-swing-phase-controlled-knee-ankle-foot Orthoses (Mp-sscos).

BACKGROUND: Patients with neuromuscular knee-instability assisted with orthotic devices experience problems including pain, falls, mobility issues and limited engagement in daily activities. OBJECTIVES: The aim of this study was to analyse current real-life burden, needs and orthotic device outcomes in patients in need for advanced orthotic knee-ankle-foot-orthoses (KAFOs). METHODOLOGY: An observer-based semi-structured telephone interview with orthotic care experts in Germany was applied. Interviews were transcribed and content-analysed. Quantitative questions were analysed descriptively. FINDINGS: Clinical experts from eight centres which delivered an average of 49.9 KAFOs per year and 13.3 microprocessor-stance-and-swing-phase-controlled-knee-ankle-foot orthoses (MP-SSCOs) since product availability participated. Reported underlying conditions comprised incomplete paraplegia (18%), peripheral nerve lesions (20%), poliomyelitis (41%), post-traumatic lesions (8%) and other disorders (13%). The leading observed patient burdens were "restriction of mobility" (n=6), followed by "emotional strain" (n=5) and "impaired gait pattern" (n=4). Corresponding results for potential patient benefits were seen in "improved quality-of-life" (n=8) as well as "improved gait pattern" (n=8) followed by "high reliability of the orthosis" (n=7). In total, experts reported falls occurring in 71.5% of patients at a combined annual frequency of 7.0 fall events per year when using KAFOs or stance control orthoses (SCOs). In contrast, falls were observed in only 7.2 % of MPSSCO users. CONCLUSION: Advanced orthotic technology might contribute to better quality of life of patients, improved gait pattern and perceived reliability of orthosis. In terms of safety a substantial decrease in frequency of falls was observed when comparing KAFO and MP-SSCO users.

Head-to-Head Linked Isoprenoid Hydrocarbons in Petroleum.

A series of petroleum isoprenoid hydrocarbons possessing an unusual head-to-head linkage is present as an important component in petroleum. The entire series appears to be produced by diagenesis or catagenesis from precursors containing 40 carbon atoms. A suitable precursor compound has been reported in one type of living organism, thermoacidophile bacteria.

Performance of a recombinant fusion protein linking coagulation factor IX with recombinant albumin in one-stage clotting assays.

Essentials Performance of the one-stage clotting (OSC) assay varies with the clotting activator used. Recombinant FIX-albumin fusion protein (rIX-FP) was reliably monitored with most OSC reagents. rIX-FP shows comparable reagent-dependent variability to other rFIX products in the OSC assay. Actin® FS and kaolin-based reagents underestimated rIX-FP activity by around 50% in the OSC assay. SUMMARY: Background Measuring factor IX activity (FIX:C) with one-stage clotting (OSC) assays, based on the activated partial thromboplastin time (APTT), is the current mainstay of diagnostic techniques for hemophilia B. Assessing the performance of new recombinant FIX (rFIX) products in OSC assays is essential, as APTT reagents from different manufacturers yield different potency estimates for rFIX. Objectives To evaluate the extent to which choice of reagent composition influences rFIX potency measurements of recombinant FIX-albumin fusion protein (rIX-FP, IDELVION) activity in OSC assays. Methods rIX-FP was added to FIX-deficient plasma, and FIX:C was assessed centrally and locally in a multicenter international field study with a variety of commercial OSC APTT reagents. Paired sample analysis of clinical samples was performed to compare values of FIX:C from local and central laboratories. In-house bioanalytical investigations with spiked samples were conducted to compare the APTT-reagent dependent variability of rIX-FP with unmodified rFIX and rFIX Fc fusion protein (rFIXFc). Results Central and local assessments of FIX:C from 10 countries and 21 participating centers showed comparable results to those from the central laboratory across the majority of 18 different APTT reagents from both clinical and spiked samples. There was a consistent underestimation of rIX-FP activity of ≈ 50% with OSC assays using Actin FS or kaolin-based APTT reagents. In the bioanalytical study, rIX-FP showed comparable variability in OSC assays to unmodified rFIX and rFIXFc. Conclusions rIX-FP activity can be accurately measured by the use of OSC assays with the majority of commercial reagents. Actin FS or kaolin-based reagents will probably lead to a 50% underestimation of activity.

A giant exoplanet orbiting a very-low-mass star challenges planet formation models.

Surveys have shown that super-Earth and Neptune-mass exoplanets are more frequent than gas giants around low-mass stars, as predicted by the core accretion theory of planet formation. We report the discovery of a giant planet around the very-low-mass star GJ 3512, as determined by optical and near-infrared radial-velocity observations. The planet has a minimum mass of 0.46 Jupiter masses, very high for such a small host star, and an eccentric 204-day orbit. Dynamical models show that the high eccentricity is most likely due to planet-planet interactions. We use simulations to demonstrate that the GJ 3512 planetary system challenges generally accepted formation theories, and that it puts constraints on the planet accretion and migration rates. Disk instabilities may be more efficient in forming planets than previously thought.

EBIC and luminescence studies of defects in solar cells.

Electron beam-induced current (EBIC) can be used to detect electronic irregularities in solar cells, such as shunts and precipitates, and to perform physical characterization of defects by, e.g. measuring the temperature dependence of their recombination activity. Recently also luminescence methods such as electroluminescence (EL) and photoluminescence (PL) have been shown to provide useful information on crystal defects in solar cells. In this contribution it will be shown that the combined application of EBIC, EL and PL may deliver useful information on the presence and on the physical properties of crystal defects in silicon solar cells. Also pre-breakdown sites in multicrystalline cells can be investigated by reverse-bias EL and by microplasma-type EBIC, in comparison with lock-in thermography investigations.

Regular dislocation networks in silicon as a tool for nanostructure devices used in optics, biology, and electronics.

Well-controlled fabrication of dislocation networks in Si using direct wafer bonding opens broad possibilities for nanotechnology applications. Concepts of dislocation-network-based light emitters, manipulators of biomolecules, gettering and insulating layers, and three-dimensional buried conductive channels are presented and discussed. A prototype of a Si-based light emitter working at a wavelength of about 1.5 microm with an efficiency potential estimated at 1% is demonstrated.

Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome.

Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.

Exciton fine structure splitting in InP quantum dots in GaInP.

We have investigated the electronic structure of excitons in InP quantum dots in GaInP. The exciton is theoretically expected to have four states. Two of the states are allowed to optically decay to the ground (vacuum) state in the dipole approximation. We see these two lines in photoluminescence (PL) experiments and find that the splitting between the lines (the fine structure splitting) is 150(± 30) µeV. The lines were perpendicularly polarized. We verified that the lines arise from neutral excitons by using correlation spectroscopy. The theoretical calculations show that the polarization of the emission lines are along and perpendicular to the major axis of elongated dots. The fine structure splitting depends on the degree of elongation of the dots and is close to zero for dots of cylindrical symmetry, despite the influence of the piezoelectric polarization, which is included in the calculation.

Calcium ions induce glutamate transport into rat brain membrane vesicles in the absence of sodium and chloride. Evidence for a novel uptake site?

Evidence is presented that glutamate binding to rat brain synaptic plasma membranes measured in Cl(-)- and Na+-free but Ca2+-supplemented buffers is partly due to uptake of glutamate into resealed membrane vesicles. An intravesicular volume of 7.9 microliter/mg protein was measured. Ca2+-induced glutamate binding to synaptic plasma membranes was found to be sensitive to low temperatures as well as to an increase in osmolarity and was abolished by short pulses of ultrasonication. None of several glutamate receptor agonists tested discriminated between basal and Ca2+-induced binding, but 4 out of 5 glutamate uptake inhibitors did. The Ca2+-induced increase in glutamate binding was the same irrespective of whether calcium acetate, calcium sulfate or calcium gluconate in either Tris-acetate of Tris-citrate buffer was used.

Late effects of intraoperative radiation therapy in anastomotic rat colon.

PURPOSE: to determine whether intraoperative radiotherapy causes long-term negative effects on the healing of colonic anastomoses in the rat. METHODS AND MATERIALS: 175 rats were divided into seven equal groups. One group served as sham-irradiated control group. In the others, following a colonic resection, 1 or 2 cm of the distal bowel limb was irradiated with a single dose of 10, 15, or 20 Gy (groups 10/1, 15/1, 20/1, 10/2, 15/2, and 20/2, respectively). Subsequently, an anastomosis was constructed. The animals were killed after 6 (n = 10 in each group) or 12 (n = 15) months. The abdomen was inspected for abnormalities and the colonic diameter was measured. The anastomotic segment was analyzed biochemically (hydroxyproline) and histologically. RESULTS: During the experimental period, 1 rat (group 15/1) died because of anastomotic leakage and 3 others died from unknown causes. There was no difference in colonic diameter between groups. Altogether 17 rats developed an adenocarcinoma in the irradiated area: 11 of these had received a dose of 20 Gy. Histological observation indicated that fibrosis was present only in a limited number of animals, mostly after irradiation with a dose of 15 or 20 Gy. All anastomoses were functional and showed normal histology. The hydroxyproline content of the anastomotic segment was increased--with respect to the control group--only in the 20/2 group after 6 months. After 12 months, the hydroxyproline concentration in the (irradiated) segment distal to the anastomosis proper was higher in the 10/1 and 15/1 groups than in the control group. Otherwise, there were no differences between groups. CONCLUSION: Intraoperative irradiation with a single dose of 10-20 Gy, delivered to the distal limb used for anastomotic construction, does not appear to constitute a threat to anastomotic integrity. Dose-related changes included formation of adenocarcinomas and fibrosis, but function and histology of the anastomosis proper remained unaffected.

Biopterin synthesis defects: problems in diagnosis.

Hyperphenylalaninemia due to a biopterin synthesis defect was detected in an infant with decreased biopterin and increased neopterin levels in plasma and urine. Tetrahydrobiopterin (BH4) administration normalized plasma phenylalanine levels. CSF biopterin and neurotransmitter metabolite levels were normal and with the infant's normal growth and development suggest that the defect in biopterin synthesis did not affect CNS biopterin metabolism. Comparison of plasma and urine pterin levels from this patient with levels reported in patients who have neurologic complications fails to reveal differences that would distinguish patients at risk for neurologic problems. CSF pterin and neurotransmitter levels may correlate with neurologic function in these patients. CSF pterin and neurotransmitter determinations should be performed prior to initiation of neurotransmitter precursor and BH4 replacement therapies in patients who were determined to have biopterin synthesis defect(s).

Mass-spectrometric analysis of naturally processed peptides recognized by ovarian tumor-associated CD8(+) CTL.

Antigens recognized by cytotoxic T cells (CTL) are expressed as peptides presented by MHC class I molecules. To isolate peptides from the MHC molecule HLA-A2.1 and identify epitopes that define the activity profile of ovarian CD8(+) CTL, peptides were separated by reverse-phase high-pressure liquid chromatography (HPLC), and analyzed by electrospray ionization-tandem mass spectrometry (ES-MS). HLA-A2.1-bound peptides were extracted from the ovarian tumor line SKOV3 transfected with the HLA-A2.1 (clone 1E4) and C1R.A2 cells transfected with HCA-A2.1 and HER-2 (clone HER-2.J) by immunoaffinity chromatography. At least five peaks of distinct retention times (termed 1, 2A, 2B, 2C, and 3) were recognized by an ovarian HER-2(high) (HER-2(hi)) tumor-associated HLA-A2(+), CD8(+) CTL line. ES-MS analysis was performed for peak 2B peptides from both types of cells. In the four consecutive fractions of peak 2B, at least 27 and 16 ion species of mass-to-charge (m/z) ratio between 760-1300 were detected in 1E4 and HER-2.J cells, respectively. The abundance of four 1E4 and six HER-2.J ions believed to be peptides in four consecutive HPLC fractions in this peak matched the CTL activity profile. Of these, two ions with actual m/z ratios 497.3-498.4 and 792.8-793.2, were found in the peak 2B from both types of cells. Since little is known about the tumor Ag recognized in human cancers, characterization of these ions may lead to identification of novel tumor Ag in breast and ovarian cancers. This may also be useful in developing quantitative approaches to the identification of tumor Ag and the determination of epitope density on tumor and normal cells. This may help characterize the relationship between tumor immunity and epitope tolerance in human epithelial cancers.

Serum iron and serum bilirubin after administration of Gd-DTPA-dimeglumine. A pharmacologic study in healthy volunteers.

Gadolinium (Gd)-DTPA-dimeglumine is an extracellular contrast agent (0.5 mol/L) for magnetic resonance imaging. At a dose of 0.1 mmol/kg body weight occasional slight transient elevations of serum iron and bilirubin were observed. To verify these findings, to determine time course, and to assess probability of drug relationship, a single-blind, randomized cross-over study in 12 healthy male volunteers was conducted. Either 0.25 mmol Gd-DTPA/kg body weight or the corresponding volume control 0.5 ml 0.9% saline/kg body weight were injected intravenously with an interval of one week. No relevant clinical side effects were reported or observed. Differences between the two treatments were found for serum iron, total bilirubin, and indirect bilirubin. An increase of serum iron and total bilirubin is observed at 3 to 4 hours postinjection, with a maximum at 6 to 12 hours. At 24 hours after injection all values were back to baseline range. This is a predictable side effect of no recognizable clinical consequence. The unchanged values of the intraerythrocytic enzymes and of haptoglobin indicate the minor nature of this phenomenon. Current experiences with the clinical application of Gd-DTPA at a dose of 0.1 mmol/kg body weight suggest that serum iron and bilirubin increases with that dose are less frequent and less marked than increases shown in this study at a dose of 0.25 mmol/kg body weight.

Out-diffusion and precipitation of copper in silicon: An electrostatic model

Concentrations of mobile interstitial copper and precipitated copper in silicon were studied after a high temperature intentional contamination and quench to room temperature. It was found that below a critical contamination the copper predominantly diffuses out to the surface, while for higher initial copper concentrations it mainly precipitates in the bulk. The critical copper contamination equals the acceptor concentration plus 10(16) cm (-3). This behavior can be explained by the electrostatic interaction between the positively charged interstitial copper and the forming copper precipitates.

Intra-operative irradiation prolongs the presence of matrix metalloproteinase activity in large bowel anastomoses of the rat.

There exists a growing interest in intra-operative radiation therapy as a treatment modality for large bowel cancer. In a previous experimental study we showed that high-dose intra-operative irradiation delays the healing of colonic anastomoses. However, the contribution of proteases is unknown. In the present study, the gelatinolytic and collagenolytic activity in the healing anastomoses is investigated. After a resection of a 1-cm length of colon (uninjured colon), the rats were irradiated with a single dose of 25 Gy, either to the proximal limb, referred to as the proximal group, or to both proximal and distal limbs of the bowel, referred to as the combined group, before anastomotic construction. Both groups were compared to a control group with anastomoses which were sham-irradiated. The animals were killed 1, 3 or 7 days after operation. The gelatinolytic activity in uninjured and anastomotic tissue was quantified by gelatin zymography and the collagenolytic activity by an assay using a fibrillar rat collagen substrate. Compared with resected uninjured colon, most of the gelatinolytic activities were markedly increased in anastomotic tissue of all groups during the first postoperative week, and new additional activities were detected. The additional metalloproteinases (the 95-kDa family) of both irradiated groups were significantly elevated compared to the anastomoses of the sham-irradiated control group at 7 days after operation. In anastomotic tissue of all groups, the collagenolytic activity of the tissue was also significantly increased at 1 and 3 days after construction with respect to the resected, uninjured colon. After 7 days this effect had disappeared for the sham-irradiated anastomoses, but the activity in the anastomoses in both the proximal and combined groups remained significantly elevated. The findings provide evidence that intra-operative irradiation prolongs the presence of elevated gelatinolytic and collagenolytic activities in colon anastomoses. It may contribute to a reduced or delayed accumulation of collagen and other matrix proteins that supply anastomotic strength.

Moderate doses of intraoperative radiation severely suppress early strength of anastomoses in the rat colon.

Intraoperative irradiation appears to be a valuable addition to the modalities available to treat patients with large bowel cancer. However, its potential effect on healing of anastomoses has not been investigated extensively. For this purpose, male Wistar rats underwent colonic resection. Subsequently, 1 cm of each bowel end was irradiated with doses of 10, 15, 20 or 25 Gy and intestinal continuity was restored. After 3 or 7 days, animals were killed and the anastomoses were analyzed for bursting pressure (intraluminal force), breaking strength (longitudinal force) and hydroxyproline content. Intraoperative irradiation led to a massive (40-70%) and significant (P < 0.025) reduction in bursting pressure 3 days after operation compared to the control group for every dose used. After 7 days, the bursting site was outside the area of the anastomosis in all groups. The breaking strength at day 3 was also reduced, even after 10 Gy. At day 7, when tearing still occurred in the wound area, the breaking strength was still significantly lower in the 15- and 25-Gy groups than in the control group. The hydroxyproline content of the anastomoses was significantly reduced only after irradiation with the higher doses. Thus intraoperative irradiation constitutes a threat to early strength of anastomoses in the rat colon, and even at moderate doses it may threaten the integrity of the anastomosis.

A semiquantitative histological analysis of repair of anastomoses in the rat colon after combined preoperative irradiation and local hyperthermia.

Hyperthermia is a promising method for increasing the efficacy of radiation therapy of colorectal cancer. To study the histological aspects of healing of an anastomosis in the colon, after combined preoperative (sham) irradiation and (sham) hyperthermia treatment, 48 male Wistar rats were divided randomly into four groups. In each animal, a segment of the colon was treated successively by (sham) irradiation (single dose of 25 Gy X rays) and/or (sham) hyperthermia (44 degrees C, 30 min). After 5 days, a resection of the colon was performed by construction of an anastomosis: The distal limb consisted of (sham-) irradiated and/or (sham-) hyperthermia-treated bowel. Rats were killed 3 or 7 days after the surgical procedure. Evaluation of healing of the anastomosis was made by: (1) histological analysis of sections stained with hematoxylin and eosin, (2) semiquantitative measurement of collagen in the area of the anastomosis and (3) semiquantitative analysis of the number of macrophages by immunocytochemistry. Healing of the anastomoses in animals receiving irradiation or hyperthermia alone and in control animals was relatively uneventful. There were no differences between groups in formation of collagen or infiltration by macrophages in the area of the anastomosis. Animals treated with both radiation and hyperthermia showed marked necrosis, infiltration by polymorphonuclear leukocytes and rupture of the anastomosis. It is concluded that preoperative irradiation with a single dose of 25 Gy in combination with local hyperthermia at 44 degrees C for 30 min leads to disturbed repair of anastomoses.