Proteombasierte diagnostische und prognostische Biomarker beim Prostatakarzinom

Background

Due to comprehensive PSA screening, the incidence for prostate cancer (PCa) is rising. Therefore, there is an urgent need for improved PCa diagnostics and prognostic tools to differentiate between insignificant and aggressive, fast growing tumors.

Methods

With the proteome-based method presented here, we were able to distinguish PCa from BPH, chronic prostatitis and healthy controls with 83?% sensitivity and 67?% specificity. Furthermore, the methods discerned advanced PCa from local, organ-confined PCa in a group of patients with gleason score 7 (80?% sensitivity, 82?% specificity).

Results

Our proteomic approach is based on the analysis of low molecular weight polypeptides, identified as the endpoint of the naturally occuring liquefaction cascade in seminal plasma. For the first time using seminal plasma as a source, we analysed a complex network of interacting proteases and specific inhibitors, reflecting tumor biology specificity. Our diagnostic and prognostic tool is robust and easy to handle, and therefore it is well suitable for the laboratory and medical practice.     

Infection of orthopedic implants and the use of antibiotic-loaded bone cements: A review

Infections by bacteria are a serious complication following orthopedic implant surgery, that can usually only be cured by removing the implant, since the biofilm mode of growth of infecting bacteria on an implant surface protects the organisms from the host immune system and antibiotic therapy. Over the past few decades, attempts have been made to prevent and cure orthopedic implant infections by incorporating antibiotics in polymethylmethacrylate bone cements, in primary and revision surgery. However, the clinical efficacy of antibiotic-releasing bone cements is not accepted by all and the long-term exposure to low doses from antibiotic-releasing bone cements in patients is strongly related to the emerging threat of antibiotic resistance in medicine today. In this article, we start by reviewing the mechanisms governing the formation of an infectious biofilm on orthopedic implant materials, the release mechanisms and properties of clinically-used, antibiotic-loaded bone cements. The clinical efficacy of antibiotic-loaded bone cements is evaluated analyzing separatedly the prophylactic and therapeutic uses of these products.     

Calretinin inputs are confined to motoneurons for upward eye movements in monkey

Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g., isolated up‐/downgaze palsy or up‐/downbeat nystagmus, indicates that up‐ and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium‐binding protein calretinin (CR). With combined tract‐tracing and immunofluorescence, the motoneurons of vertically pulling eye muscles in monkey were investigated for the presence of CR‐positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double‐immunofluorescence labeling revealed that CR‐positive terminals lacked the γ‐aminobutyric acid (GABA)‐synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR‐containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo‐ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain. J. Comp. Neurol. 521:3154–3166, 2013. © 2013 Wiley Periodicals, Inc.     

Adrenoleukodystrophy in Norway: High Rate of De Novo Mutations and Age-Dependent Penetrance

To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients.     

Subthalamic deep brain stimulation for refractory Gilles de la Tourette’s syndrome: clinical outcome and functional connectivity

Background

Deep brain stimulation (DBS) is a promising novel approach for managing refractory Gilles de la Tourette’s syndrome (GTS). The subthalamic nucleus (STN) is the most common DBS target for treating movement disorders, and smaller case studies have reported the efficacy of bilateral STN-DBS treatment for relieving tic symptoms. However, management of GTS and treatment mechanism of STN-DBS in GTS remain to be elucidated.

Methods

Ten patients undergoing STN-DBS were included. Tics severity was evaluated using the Yale Global Tic Severity Scale. The severities of comorbid psychiatric symptoms of obsessive–compulsive behavior (OCB), attention-deficit/hyperactivity disorder, anxiety, and depression; social and occupational functioning; and quality of life were assessed. Volumes of tissue activated were used as seed points for functional connectivity analysis performed using a control dataset.

Results

The overall tics severity significantly reduced, with 62.9% ± 26.2% and 58.8% ± 27.2% improvements at the 6- and 12-months follow-up, respectively. All three patients with comorbid OCB showed improvement in their OCB symptoms at both the follow-ups. STN-DBS treatment was reasonably well tolerated by the patients with GTS. The most commonly reported side effect was light dysarthria. The stimulation effect of STN-DBS might regulate these symptoms through functional connectivity with the thalamus, pallidum, substantia nigra pars reticulata, putamen, insula, and anterior cingulate cortices.

Conclusions

STN-DBS was associated with symptomatic improvement in severe and refractory GTS without significant adverse events. The STN is a promising DBS target by stimulating both sensorimotor and limbic subregions, and specific brain area doses affect treatment outcomes.

     

Groningen orthopaedic exit strategy: Validation of a support program after total hip or knee arthroplasty

OBJECTIVE: Validation of the program theory of the Groningen orthopaedic exit strategy (GOES), a theory-driven program aiming to improve the rehabilitation of total hip and knee arthroplasty patients after shortened hospital stay. First part of the program theory is the action theory, hypothesising that the GOES treatment positively influences the mediating variables (self-efficacy, social support, pain-coping). The second part, the conceptual theory, hypothesis a positive relationship between these variables and the outcome variables (ADL functioning, physical activity behaviour, quality of life). METHODS: Patients were randomly assigned to the GOES or control groups. Questionnaires were used to assess mediating and outcome variables in 103 patients (50 GOES, 53 controls) pre-operatively, and 6 and 26 weeks post-operatively. RESULTS: No difference was seen between the two groups in terms of changes between pre-operative and post-operative mediating variables (action theory). Moderate-to-large correlations explaining reasonable amount of variance (22%, 25%, 56%) were found between the mediating and outcome variables (conceptual theory). CONCLUSION: The conceptual theory is supported; however, as the treatment did not influence the mediating variables (action theory), it has no added value in its current form. PRACTICE IMPLICATIONS: The treatment needs to be adjusted; it is discussed that individualised treatment could be more effective.     

Bioinformatic integration of biomechanics makes HLA sequencing universally applicable

Sequencing provides the most reliable and accurate information of the sequence of a gene and is therefore of particular interest for fully characterizing the genetic complexity and allelic diversity of human leukocyte antigens (HLA) genes. This complexity makes sequencing the method of choice for HLA low- and high-resolution typing. However, sequencing is considered a complex process, which requires the management of an overwhelming amount of data. However, only sequencing can be used as a sole typing technique without the need of supplementation by other typing techniques; it offers additional advantages by providing results in electronic formats and by being fully automatable. This makes sequencing the best candidate for bioinformatic and biomechanic integration to maintain the benefits and discard the drawbacks. We have, therefore, developed robotic platforms and a bioinformatic tool allowing complete documentation, interpretation and processing of all amplification and sequencing steps as well as the full integration of all instruments involved. It was shown that this integrative approach allows sequencing to run fully automated for low- and high-resolution typing on each throughput level desired. This integration of robotics and software secures the traceability of each specimen at each step of the process and minimizes the risk of contamination and sample mix-up.