Showing papers by "Andreas Bender published in 2013"

TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease.

Abstract: Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson’s disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

Early cranioplasty may improve outcome in neurological patients with decompressive craniectomy.

Abstract: Primary objective: Decompressive craniectomy is an effective therapy to relieve intractable intracranial hypertension following acute brain injury. However, little is known about the optimal timing for cranioplasties in the sub-acute phase. The objective of the present study was to analyse the effect of cranioplasty timing on neurological outcomes.Research design: Single-centre observational study.Methods and procedures: One hundred and forty-seven consecutive patients with decompressive craniectomy and cranioplasty during the course of inpatient neurorehabilitation were identified by means of a retrospective hospital database search. This database contains the following prospectively-entered weekly scores: Barthel-Index (BI), Functional Independence Measure (FIM) and Coma Remission Scale (CRS). Additional clinical data were taken retrospectively from patient charts. Regression analysis was used to identify factors that influenced the end-of-rehabilitation outcome.Main outcomes and results: Patien...

Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms

Abstract: Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA deletions than cytochrome c oxidase-positive cells (60.38±3.92% versus 45.18±2.83%). Survival of dopaminergic neurons in POLGD257A mice was associated with increased mitochondrial DNA copy number, enhanced mitochondrial cristae network, improved mitochondrial respiration, decreased exacerbation of mitochondria-derived reactive oxygen species, greater striatal dopamine levels and resistance to parkinsonian mitochondrial neurotoxins. These results indicate that primary accumulation of mitochondrial DNA deletions within substantia nigra pars compacta dopaminergic neurons, at an extent similar to that observed in patients with Parkinson's disease, do not kill dopaminergic neurons but trigger neuroprotective compensatory mechanisms at a mitochondrial level that may account for the high pathogenic threshold of mitochondrial DNA deletions in these cells.

Long-term outcome in patients with Guillain-Barré syndrome requiring mechanical ventilation.

Abstract: We aimed to determine long-term disability and quality of life in patients with Guillain-Barre syndrome (GBS) who required mechanical ventilation (MV) in the acute phase. Our retrospective cohort study included 110 GBS patients admitted to an intensive care unit and requiring MV (01/1999-08/2010) in nine German tertiary academic medical centers. Outcome was determined 1 year or longer after hospital admission using the GBS disability scale, Barthel index (BI), EuroQuol-5D (EQ-5D) and Fatigue Severity Scale. Linear/multivariate regression analysis was used to analyze predicting factors for outcome. Mean time to follow up was 52.6 months. Hospital mortality was 5.5 % and long-term mortality 13.6 %. Overall 53.8 % had a favorable outcome (GBS disability score 0-1) and 73.7 % of survivors had no or mild disability (BI 90-100). In the five dimensions of the EQ-5D "mobility", "self-care", "usual activities", "pain" and "anxiety/depression" no impairments were stated by 50.6, 58.4, 36.4, 36.4 and 50.6 % of patients, respectively. A severe fatigue syndrome was present in 30.4 % of patients. Outcome was statistically significantly correlated with age, type of therapy and number of immunoglobulin courses. In GBS-patients requiring MV in the acute phase in-hospital, and long-term mortality are lower than that in previous studies, while long-term quality of life is compromised in a large fraction of patients, foremost by immobility and chronic pain. Efforts towards improved treatment approaches should address autonomic dysfunction to further reduce hospital mortality while improved rehabilitation concepts might ameliorate long-term disability.

Rehabilitation outcome of unconscious traumatic brain injury patients.

Abstract: Outcome prediction of traumatic brain injury (TBI) patients with severe disorders of consciousness (DOC) at the end of their time in an intensive care setting is important for clinical decision making and counseling of relatives, and constitutes a major challenge. Even the question of what constitutes an improved outcome is controversially discussed. We have conducted a retrospective cohort study for the rehabilitation dynamics and outcome of TBI patients with DOC. Out of 188 patients, 37.2% emerged from a minimally conscious state (MCS) and 16.5% achieved at least partial functional independence after a mean observation period of 107 days (range 1–399 days). This reflects that emergence from MCS is much easier to achieve than functional independence. Logistic regression analysis identified age and level of consciousness upon admission to neurorehabilitation as independent prognostic factors for both outcomes. The group who reached at least partial functional independence started to improve signi...

Iterative reconstruction of high-dimensional Gaussian Graphical Models based on a new method to estimate partial correlations under constraints.

Abstract: In the context of Gaussian Graphical Models (GGMs) with high-dimensional small sample data, we present a simple procedure, called PACOSE – standing for PArtial COrrelation SElection – to estimate partial correlations under the constraint that some of them are strictly zero. This method can also be extended to covariance selection. If the goal is to estimate a GGM, our new procedure can be applied to re-estimate the partial correlations after a first graph has been estimated in the hope to improve the estimation of non-zero coefficients. This iterated version of PACOSE is called iPACOSE. In a simulation study, we compare PACOSE to existing methods and show that the re-estimated partial correlation coefficients may be closer to the real values in important cases. Plus, we show on simulated and real data that iPACOSE shows very interesting properties with regards to sensitivity, positive predictive value and stability.

Climate parameters and the influence on the foot pad health status of fattening turkeys B.U.T. 6 during the early rearing phase

Abstract: Online first: 22.04.2013 http://vetline.de/zeitschriften/bmtw/ open_access.htm Lehrstuhl für Tierschutz, Verhaltenskunde, Tierhygiene und Tierhaltung, Veterinärwissenschaftliches Department, Ludwig-Maximilians-Universität München1 Klinik für Vögel und Reptilien, Veterinärmedizinische Fakultät, Universität Leipzig2 Statistisches Beratungslabor, Institut für Statistik, Ludwig-Maximilians-Universität München3

Effects of the housing climate on the foot pad health of fattening turkeys of British United Turkeys 6 origin during the early rearing phase

Abstract: The climate in the stables during the turkeys' first weeks of life is a crucial factor for a successful rearing and the following fattening period. The present study has examined the influence of climate parameters on the foot pad health status of 2681 fattened turkeys from twelve farms during the early rearing phase. In addition to wide-ranging collections of data concerning livestock husbandry and management an examination of the foot pads of 60 animals has been carried out respectively on day 3-5, as well as on day 22-35, shortly before relocation into another stable. For assessing the foot pads a scheme of five categories has been used (ranging from category 0 = no alteration to category 4 = deep lesion). Solely beak trimmed turkeys of the British United Turkeys (BUT) 6 strain, male and female, were examined. In twelve farms air temperature and humidity have been recorded continuously, ammonia and dust concentration were registered on each day of the examination. When assessing the foot pads, the first alterations could already be noted at the age of 3-5 days. On the second period of exzmination 55.6% of the turkeys showed category 2 or category 3. Examinations of the climate parameters showed strong differences concerning temperature, humidity and ammonia concentration among all farms. Using the Fisher's Exact Test, significant dependency of foot pad health on starting temperature (p < 0.001), on temperature measured one week before the second examination (p = 0.004), on humidity (p < 0.001), and on air ammonia concentration (p < 0.001) could be indicated.