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.

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.

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.

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.

["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.

Thermoelectric cooler concepts and the limit for maximum cooling.

The conventional analysis of a Peltier cooler approximates the material properties as independent of temperature using a constant properties model (CPM). Alternative concepts have been published by Bian and Shakouri (2006 Appl. Phys. Lett. 89 212101), Bian (et al 2007 Phys. Rev. B 75 245208) and Snyder et al (2012 Phys. Rev. B 86 045202). While Snyder's Thomson cooler concept results from a consideration of compatibility, the method of Bian et al focuses on the redistribution of heat. Thus, both approaches are based on different principles. In this paper we compare the new concepts to CPM and we reconsider the limit for maximum cooling. The results provide a new perspective on maximum cooling.

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.

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.

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.

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.

Homocysteine induces cell death of rat astrocytes in vitro.

From several disease states as well as from animal models homocysteine is known to be toxic to the central nervous system. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic, apoptotic, and oxidative injury in vitro and in vivo. Both beneficent and deleterious effects of astrocytes in the pathogenesis of different neurodegenerative disorders have been described. However, data about the neurotoxic effect of homocysteine on astrocytes are lacking. The present study therefore was undertaken to investigate a possible cytotoxic effect of homocysteine on cortical astrocytes in vitro. Exposure to D,L-homocysteine resulted in a time and dose-dependent gliotoxic effect at doses of 2 mM and above (P<0.001). This is comparable to homocysteine toxicity observed in other cell culture models and implies that a participation of astrocytes in homocysteine-induced neurodegeneration may be considered. The results of the present in vitro studies may therefore have implications for understanding the pathogenesis of neurotoxicity linked to neurodegenerative disorders (e.g. Alzheimer's disease, glaucomatous optic neuropathy). This is the first study to report that homocysteine induces cell death of astrocytes. The mechanisms by which homocysteine induces cell death of astrocytes warrant further study.

[Modern carbon fibre orthoses in the management of polio patients--a critical evaluation of the functional aspects]. / Moderne Karbonfaser-Orthetik für Polio-Patienten - Kritische Auswertung nach funktionellen Aspekten -

AIM: Evaluation of practicability and functional benefit with modern carbon fibre knee ankle foot orthoses in polio patients. METHODS: In a retrospective analysis, fifty-five (55) polio patients between the ages of 42 and 80 years who had been provided with a carbon fibre orthoses for a minimum of three months, were asked about their acceptance as well as changes in functional capacity and comfort. RESULTS: Clear improvements were shown in walking, sitting and automobile driving as well as comfort and dressing/undressing of the orthoses. Through the use of these new orthoses, the maximum walking distance increased significantly--at least partially due to less weight (40%). 95% of all treated patients were very satisfied or satisfied. CONCLUSION: The use of carbon fibre material in the orthotic treatment of polio patients seems to be supported by the positive results of our study.

A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection.

OBJECTIVES: To determine whether systemic or deep fungal infections can be prevented, a double-blind, placebo-controlled, phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients. METHODS: HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole (200 mg per day) or matching placebo and followed for 2 years. Development of deep fungal infections, episodes of mucocutaneous candidiasis, change in CD4 count, survival and safety data were collected at each study visit. RESULTS: Three hundred and seventy-four patients received study medication, 187 were given itraconazole and 187 matching placebo. Time to development of deep fungal infection did not differ between groups, in an intention to treat analysis. Low CD4 cell count and prior use of Pneumocystis carinii pneumonia (PCP) prophylaxis were significantly associated with a more rapid development of deep fungal infection (P = 0.044 and 0.017, respectively). Itraconazole treatment significantly reduced the incidence of oral candidosis (25% vs. 48% P < 0.001) and time to development of oral candidosis (508 vs. 413 days, P < 0.001) but not the number of deep fungal infections (11 vs. 13). Survival did not differ significantly between groups (nine vs. 14 deaths). CD4 counts decreased significantly over time in both study arms. Adverse events did not differ between groups; 20% vs. 23% stopped study medication due to an adverse experience. CONCLUSIONS: Although itraconazole prophylaxis significantly reduced the number and time to development of oral candidosis, too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition. Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency.

Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS.

The pharmacokinetics, efficacy, and safety of intravenous (iv) itraconazole (2 days at 400 mg/day, 12 days at 200 mg/day), followed by 12 weeks of oral capsules (400 mg/day) were studied in 31 immunocompromised patients with pulmonary invasive aspergillosis. All patients received iv itraconazole (median duration, 14 days), and 26 then received oral itraconazole (median duration, 78.5 days). After receiving iv itraconazole, concentrations increased rapidly, with trough plasma levels > or =250 ng/mL in 91% of patients and in all patients by day 7. Concentrations > or =500 ng/mL were observed in 64% of patients by day 2. Mean trough concentrations after 2 and 14 days were 670 and 850 ng/mL, respectively. Therapeutic levels were maintained after switching to oral capsules. A complete or partial response was seen at the last on-treatment assessment in 15 (48%) of 31 patients, with 6 (19%) showing stable disease. Itraconazole was well tolerated, with no unexpected effects. Overall iv/oral itraconazole was safe and effective in invasive aspergillosis.

High-performance liquid chromatographic method with electrochemical detection for the analysis of O6-methylguanine.

An improved system consisting of a combination of high-performance liquid chromatographic methods with electrochemical detection for the separation and analysis of the DNA adduct O6-methylguanine (O6MG) has been developed. This adduct is produced by the interaction of methylating agents with DNA and induces mispairing in the DNA of the target cells. A good separation of modified from unmodified bases is first achieved with an HPLC system using a Partisil 10 SCX column and a salt gradient. A second HPLC step with electrochemical detection and a C18 column is used for farther separation and quantitation of O6-methylguanine. This method shows a linear response up to 15 pg of 06MG tested. The lowest amount detected was 0.5 pg of O6MG and is highly reproducible. This method is useful to study DNA damage as a product of cellular metabolism and its effects on the process of carcinogenesis.

Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors.

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881+/-393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.

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.

Curcumin-glutathione interactions and the role of human glutathione S-transferase P1-1.

Curcumin (diferuloylmethane), a yellow pigment of turmeric with antioxidant properties has been shown to be a cancer preventative in animal studies. It contains two electrophilic alpha, beta-unsaturated carbonyl groups, which can react with nucleophilic compounds such as glutathione (GSH), but formation of the GSH-curcumin conjugates has not previously been demonstrated. In the present studies, we investigated the reactions of curcumin with GSH and the effect of recombinant human glutathione S-transferase(GST)P1-1 on reaction kinetics. Glutathionylated products of curcumin identified by FAB-MS and MALDI-MS included mono- and di-glutathionyl-adducts of curcumin as well as cyclic rearrangement products of GSH adducts of feruloylmethylketone (FMK) and feruloylaldehyde (FAL). The presence of GSTP1-1 significantly accelerated the initial rate of GSH-mediated consumption of curcumin in 10 mM potassium phosphate, pH 7.0, and 1 mM GSH. GSTP1-1 kinetics determined using HPLC indicated substrate inhibition (apparent K(m) for curcumin of 25+/-11 microM, and apparent K(i) for curcumin of 8+/-3 microM). GSTP1-1 was also shown to catalyze the reverse reaction leading to the formation of curcumin from GSH adducts of FMK and FAL.

Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B.

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.