Die Bewertung von Vorräten

Ziel der Bachelorarbeit ist es, einen Einblick in die Welt des österreichischen Unternehmens- und Steuerrechtes zu geben und über die wichtigsten Punkte bei der Bewertung der Vorräte aufzuklären. Neben der Erläuterung der einzelnen Vorratsarten sollen vor allem die anzuwendenden Bewertungsmethoden näher betrachtet werden. Besonderes Augenmerk gilt den Abweichungen zwischen den unternehmensrechtlichen und den steuerrechtlichen Vorschriften, die für die Bewertung der Vorräte anzuwenden ist. Sämtliche angeführte Rechtsquellen beziehen sich auf geltendes österreichisches Recht, soweit nicht anders angeführt

DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson’s disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease

Probable multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 75: 924–925

Abstract: Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing. © 2006 Movement Disorder Society Key words: Parkinson's disease; genetics; LRRK2; mutation Parkinson's disease (PD) is the second most common neurodegenerative disorder. Clinical features of PD include resting tremor, rigidity, bradykinesia, and postural instability. Although quite variable, the average age of onset is 60 years. In addition, there is a slight preponderance of affected men. Pathologically, PD is characterized by the presence of Lewy bodies and progressive degeneration of neurons in the substantia nigra, pars compacta, and other brain regions. In our ongoing effort to identify additional PD susceptibility genes, we have recruited a large cohort of PD families. The control sample was collected through three sources and provided appropriate written informed consent. One sample of controls (n ϭ 52) was ascertained in Indiana, and all control subjects were examined by a single Parkinson Study Group movement disorder specialist. These control subjects completed the identical clinical evaluation as the PD sample. Individuals were considered controls if they met the following criteria: did not have a diagnosis or symptoms of PD, Alzheimer's disease (AD), stroke, or other neurological disorder; no tremor; no other first-degree family members reported to be diagnosed with PD; and no history of polio. The average age at examination of these first control subjects was 68.3 years, with a range of 55 to 82 years. All individuals were non-Hispanic Caucasians. A second control sample (n ϭ 40) was obtained from the National Cell Repository for Alzheimer's Disease. The subjects were recruited as part of an ongoing genetic initiative to make available to the research community a sample of rigorously evaluated individuals without any evidence of neurological disease. All control subjects were evaluated, and there was no evidence for either PD or dementia. The average age at examination of the second control cohort was 76.9 years, with a range of 58 to 91 years. As was the case with the first control set, all subjects from the second control set were non-Hispanic Caucasians. DNA was prepared from peripheral blood samples collected from the PD families and control subjects. The third control sample (n ϭ 276) is composed of three neurologically normal Caucasian control panels (NDPT002, NDPT006, NDPT009) obtained from the NINDS Human Genetics Resource Center at the Coriell Institute Coriell Cell Repositories (Camden, NJ). This third control sample contains 132 males and 144 females. The average age at examination of the subjects was 69.7 years, with a range of 55 to 88 years. In total, 368 neurologically normal control samples were evaluated. The guanine to adenine substitution at nucleotide 4541 of the LRRK2 cDNA that results in the R1514Q Lrrk2 (dardarin) protein variant was screened for using a newly developed TaqMan allelic-discrimination assay (Applied Biosystems). The assay was performed with 30 ng of genomic DNA from each PD subject and control individual using conditions recommended by the manufacturer and an Applied Biosystems 7300 Real Time PCR System. Of 954 affected individuals from 12 different families, 16 (1.8%) were shown to be heterozygous carriers of the R1514Q variant. In addition, 5 (1.4%) of 368 control subjects were also found to be heterozygous for the same variant similar to the frequency observed by Zimprich and associates. Discordance for the mutation among affected individuals was observed in 10 of the 13 families in which the variant was segregating. Of the 28 affected individuals in these 12 families for whom DNA was available for study, 12 of them do not carry the R1514Q variant. This finding suggests that the R1514Q variant is not segregating with PD in these families. No statistically significant difference between the R1514Q carrier group (16) and the noncarrier group (938) was detected in our analyses of numerous parameters, including age of disease onset (61.75 years in R1514Q carriers vs. 60.9 years in noncarriers), disease duration (7.18 years carriers vs. 9.53 years noncarriers), Mini-Mental State Examination score (25.62 carriers vs. 26.48 noncarriers), Blessed Functional Activity Scale (3.66 carriers vs. 4.41 noncarriers), Hoehn & Yahr (2.2 carriers vs. 2.48 noncarriers), and ethnicity. Taken together, these data suggest that the R1514Q variant is likely a nonpathogenic variant in Lrrk2 that does not contribute to the development of Parkinson disease, confirming the report of Zimprich and coworkers

Quantitative and qualitative tremor evaluation after MR-guided focused ultrasound thalamotomy

Introduction: Tremor syndromes are common neurological disorders, usually distinguished by clinical examination. Ordinal rating scales are widely used to rate tremor severity but are limited by subjective observation, interrater reliability, ceiling effects and lack of knowledge about sensitivity to change emphasizing the relevance of quantitative methods. Methods: To assess tremor characteristics in essential tremor (ET) and Parkinson’s disease tremor (PT) quantitatively, we used a wearable triaxial accelerometer in comparison to a common clinical rating scale. Furthermore, different activation conditions and changes after treatment with MR-guided focused ultrasound (MRgFUS) were examined concomitantly. Patients with disabling, medication-refractory ET (n = 35) or PT (n = 21) undergoing unilateral MRgFUS thalamotomy were assessed before, 1, 6 and 12 months after MRgFUS treatment. Clinical assessments included the Clinical Rating Scale for Tremor (CRST) and accelerometric recordings at rest, posture and kinetic movement. Peak frequencies (fp), frequency width at half maximum (FWHM), tremor stability index (TSI), and half-width power (HWP) were extracted from the power spectrum of acceleration and compared to the CRST. Results: We observed moderate to strong correlations between CRST subscores and log-transformed HWP, whereas significant correlations were only evident in ET when groups were evaluated separately. Fp, FWHM and TSI showed no differences between groups and conditions. Further, repeated measurements after MRgFUS treatment revealed significant changes of tremor severity in both, clinical rating and accelerometric recordings. Discussion: Tremor assessment using accelerometric recordings provided a fast and investigator independent method for tremor characterization and quantitative assessment, which were sensitive to changes after therapeutic interventions

Generating Aptamers by Cell-SELEX for Applications in Molecular Medicine

Aptamers are single-stranded oligonucleotides of DNA or RNA that bind to target molecules with high affinity and specificity. Typically, aptamers are generated by an iterative selection process, called systematic evolution of ligands by exponential enrichment (SELEX). Recent advancements in SELEX technology have extended aptamer selection from comparatively simple mixtures of purified proteins to whole living cells, and now cell-based SELEX (or cell-SELEX) can isolate aptamers that bind to specific target cells. Combined with nanotechnology, microchips, microfluidic devices, RNAi and other advanced technologies, cell-SELEX represents an integrated platform providing ultrasensitive and highly specific tools for clinical medicine. In this review, we describe the recent progress made in the application of cell-SELEX for diagnosis, therapy and biomarker discovery

Peptide-Pulsed Dendritic Cells Induce the Hepatitis C Viral Epitope-Specific Responses of Naïve Human T Cells

Hepatitis C virus (HCV) is a major cause of liver disease. Spontaneous resolution of infection is associated with broad, MHC class I- (CD8+) and class II-restricted (CD4+) T cell responses to multiple viral epitopes. Only 20% of patients clear infection spontaneously, however, most develop chronic disease. The response to chemotherapy varies; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success in clinical trials. Vector-mediated vaccination with multi-epitope-expressing DNA constructs provides an improved approach. Highly-conserved, HLA-A2-restricted HCV epitopes and HLA-DRB1-restricted immunogenic consensus sequences (ICS, each composed of multiple overlapping and highly conserved epitopes) were predicted using bioinformatics tools and synthesized as peptides. HLA binding activity was determined in competitive binding assays. Immunogenicity and the ability of each peptide to stimulate naïve human T cell recognition and IFN-γ production were assessed in cultures of total PBMCs and in co-cultures composed of peptide-pulsed dendritic cells (DCs) and purified T lymphocytes, cell populations derived from normal blood donors. Essentially all predicted HLA-A2-restricted epitopes and HLA-DRB1-restricted ICS exhibited HLA binding activity and the ability to elicit immune recognition and IFN-γ production by naïve human T cells. The ability of DCs pulsed with these highly-conserved HLA-A2- and -DRB1-restricted peptides to induce naïve human T cell reactivity and IFN-γ production ex vivo demonstrates the potential efficacy of a multi-epitope-based HCV vaccine targeted to dendritic cells

Physical characterixation and in vitro biological impact of highly aggregated antibodies separated into size-enriched populations by fluorescence-activated cell sorting

An IgG2 monoclonal antibody (mAb) solution was subjected to stirring, generating high concentrations of nanometer and subvisible particles, which were then successfully size enriched into different size bins by low speed centrifugation or a combination of gravitational sedimentation and Fluorescence-Activated Cell Sorting (FACS). The size-fractionated mAb particles were assessed for their ability to elicit the release of cytokines from a population of donor-derived human peripheral blood mononuclear cells (PBMC) at two phases of the immune response. Fractions enriched in nanometer-sized particles showed a lower response than those enriched in micron-sized particles in this assay. Particles of 5–10 μm in size displayed elevated cytokine release profiles compared to other size ranges. Stir-stressed mAb particles had amorphous morphology, contained protein with partially altered secondary structure, elevated surface hydrophobicity (compared to controls), and trace levels of elemental fluorine. FACS size-enriched the mAb particle samples, yet did not notably alter the overall morphology or composition of particles as measured by Microflow imaging, Transmission Electron Microscopy, and Scanning Electron Microscopy-Energy Dispersive X-ray Spectroscopy. The utility and limitations of FACS for size separation of mAb particles and potential of in-vitro PBMC studies to rank order the immunogenic potential of various types of mAb particles is discussed

Clinical Problems in the Hospitalized Parkinson's Disease Patient: Systematic Review

The problems Parkinson's disease (PD) patients encounter when admitted to a hospital, are known to be numerous and serious. These problems have been inventoried through a systematic review of literature on reasons for emergency and hospital admissions in PD patients, problems encountered during hospitalization, and possible solutions for the encountered problems using the Pubmed database. PD patients are hospitalized in frequencies ranging from 7 to 28% per year. PD/parkinsonism patients are approximately one and a half times more frequently and generally 2 to 14 days longer hospitalized than non-PD patients. Acute events occurring during hospitalization were mainly urinary infection, confusion, and pressure ulcers. Medication errors were also frequent adverse events. During and after surgery PD patients had an increased incidence of infections, confusion, falls, and decubitus, and 31% of patients was dissatisfied in the way their PD was managed. There are only two studies on medication continuation during surgery and one analyzing the effect of an early postoperative neurologic consultation, and numerous case reports, and opinionated views and reviews including other substitutes for dopaminergic medication intraoperatively. In conclusion, most studies were retrospective on small numbers of patients. The major clinical problems are injuries, infections, poor control of PD, and complications of PD treatment. There are many (un-researched) proposals for improvement. A substantial number of PD patients' admissions might be prevented. There should be guidelines concerning the hospitalized PD patients, with accent on early neurological consultation and team work between different specialities, and incorporating nonoral dopaminergic replacement therapy when necessary. © 2011 Movement Disorder Societ

Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus

Kainate receptors are a class of ionotropic glutamate receptors that have a role in the modulation of glutamate release and synaptic plasticity in the hippocampal formation. Previous studies have implicated corticosteroids in the regulation of these receptors and recent clinical work has shown that polymorphisms in kainate receptor subunit genes are associated with susceptibility to major depression and response to anti-depressant treatment. In the present study we sought to examine the effects of chronic stress and corticosteroid treatments upon the expression of the mRNA of kainate receptor subunits GluR5-7 and KA1-2. Our results show that, after 7 days, adrenalectomy results in increased expression of hippocampal KA1, GluR6 and GluR7 mRNAs, an effect which is reversed by treatment with corticosterone in the case of KA1 and GluR7 and by aldosterone treatment in the case of GluR6. 21 days of chronic restraint stress (CRS) elevated the expression of the KA1 subunit, but had no effect on the expression of the other subunits. Similarly, 21 days of treatment with a moderate dose of corticosterone also increased KA1 mRNA in the dentate gyrus, whereas a high corticosterone dose has no effect. Our results suggest an interaction between hippocampal kainate receptor composition and the hypothalamic-pituitary-adrenal (HPA) axis and show a selective chronic stress induced modulation of the KA1 subunit in the dentate gyrus and CA3 that has implications for stress-induced adaptive structural plasticity

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics