In vitro analysis of osteogenic inhibition in non-union spinal fusion caused by nucleus pulposus cells.

Discectomy and spinal fusion is the gold standard for spinal surgery to relieve pain. However, fusion can be hindered for yet unknown reasons that lead to non-fusions with pseudo-arthrosis. Clinical observations indicate that presence of residual intervertebral disc (IVD) tissue might hinder the ossification. We hypothesize that BMP-antagonists are constantly secreted by IVD cells and potentially prevent the ossification process. Furthermore, L51P, the engineered BMP2 variant, stimulates osseo-induction of bone marrow-derived mesenchymal stem cells (MSC) by antagonizing BMP-inhibitors. Human MSCs, primary nucleus pulposus (NPC) and annulus pulposus cells (AFC) were isolated and expanded in monolayer cultures up to passage 3. IVD cells were seeded in 1.2% alginate beads (4Mio/mL) and separated by culture inserts from MSCs. MSCs were kept in 1:control medium, 2:osteogenic medium±alginate beads, 3:osteogenic medium+NPC (±L51P) and 4:osteogenic medium+AFC (±L51P) for 21 days. Relative gene expression of bone-related genes, alkaline phosphatase assay and histological staining were performed. Osteogenesis of MSCs was hindered as shown by reduced alizarin red staining in the presence of NPC. No such inhibition was observed if co-cultured with alginate only or in the presence of AFC. The results were confirmed on the RNA and protein level. Addition of L51Pto the co- cultures, however, induced mineralization of MSCs in presence of NPC. We demonstrated that NPC secrete BMP-antagonists that prevent osteogenesis of MSCs and L51P can antagonize BMP-antagonists and induce bone formation.

Cycling in the nucleus: regulation of RNA 3' processing and nuclear organization of replication-dependent histone genes.

The histones which pack new DNA during the S phase of animal cells are made from mRNAs that are cleaved at their 3' end but not polyadenylated. Some of the factors used in this reaction are unique to it while others are shared with the polyadenylation process that generates all other mRNAs. Recent work has begun to shed light on how the cell manages the assignment of these common components to the two 3' processing systems, and how it achieves their cell cycle-regulation and recruitment to the histone pre-mRNA. Moreover, recent and older findings reveal multiple connections between the nuclear organization of histone genes, their transcription and 3' end processing as well as the control of cell proliferation.

A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement

Nucleus pulposus replacements have been subjected to highly controversial discussions over the last 40 years. Their use has not yet resulted in a positive outcome to treat herniated disc or degenerated disc disease. The main reason is that not a single implant or tissue replacement was able to withstand the loads within an intervertebral disc. Here, we report on the development of a photo-polymerizable poly(ethylene glycol)dimethacrylate nano-fibrillated cellulose composite hydrogel which was tuned according to native tissue properties. Using a customized minimally-invasive medical device to inject and photopolymerize the hydrogel insitu, samples were implanted through an incision of 1 mm into an intervertebral disc of a bovine organ model to evaluate their long-term performance. When implanted into the bovine disc model, the composite hydrogel implant was able to significantly re-establish disc height after surgery (p < 0.0025). The height was maintained after 0.5 million loading cycles (p < 0.025). The mechanical resistance of the novel composite hydrogel material combined with the minimally invasive implantation procedure into a bovine disc resulted in a promising functional orthopedic implant for the replacement of the nucleus pulposus.

Inflammation and Optic Nerve Regeneration

Neuroinflammation has long been studied for its connection to the development and progression of Multiple Sclerosis. In recent years, the field has expanded to look at the role of inflammatory processes in a wide range of neurological conditions and cognitive disorders including stroke, amyotrophic lateral sclerosis, and autism. Researchers have also started to note the beneficial impacts of neuroinflammation in certain diseases. Neuroinflammation: New Insights into Beneficial and Detrimental Functions provides a comprehensive view of both the detriments and benefits of neuroinflammation in human health. Neuroinflammation: New Insights into Beneficial and Detrimental Functions opens with two chapters that look at some fundamental aspects of neuroinflammation in humans and rodents. The remainder of the book is divided into two sections which examine both the detrimental and beneficial aspects of inflammation on the brain, spinal cord and peripheral nerves, on various disease states, and in normal aging. These sections provide a broad picture of the role neuroinflammation plays in the physiology and pathology of various neurological disorders. Providing cross-disciplinary coverage, Neuroinflammation: New Insights into Beneficial and Detrimental Functions will be an essential volume for neuroimmunologists, neurobiologists, neurologists, and others interested in the field.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.

INTRODUCTION Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER NCT01962571.

Effects of subthalamic nucleus stimulation on cognition and mood in Parkinson’s disease (PD)

Objective: To assess the neuropsychological outcome as a safety measure and quality control in patients with subthalamic nucleus (STN) stimulation for PD. Background: Deep brain stimulation (DBS) is considered a relatively safe treatment used in patients with movement disorders. However, neuropsychological alterations have been reported in patients with STN DBS for PD. Cognition and mood are important determinants of quality of life in PD patients and must be assessed for safety control. Methods: Seventeen consecutive patients (8 women) who underwent STN DBS for PD have been assessed before and 4 months after surgery. Besides motor symptoms (UPDRS-III), mood (Beck Depression Inventory, Hamilton Depression Rating Scale) and neuropsychological aspects, mainly executive functions, have been assessed (mini mental state examination, semantic and phonematic verbal fluency, go-no go test, stroop test, trail making test, tests of alertness and attention, digit span, wordlist learning, praxia, Boston naming test, figure drawing, visual perception). Paired t-tests were used for comparisons before and after surgery. Results: Patients were 61.6±7.8 years old at baseline assessment. All surgeries were performed without major adverse events. Motor symptoms ‘‘on’’ medication remained stable whereas they improved in the ‘‘off’’ condition (p<0.001). Mood was not depressed before surgery and remained unchanged at follow-up. All neuropsychological assessment outcome measures remained stable at follow-up with the exception of semantic verbal fluency and wordlist learning. Semantic verbal fluency decreased by 21±16% (p<0.001) and there was a trend to worse phonematic verbal fluency after surgery (p=0.06). Recall of a list of 10 words was worse after surgery only for the third attempt of recall (13%, p<0.005). Conclusions: Verbal fluency decreased in our patients after STN DBS, as previously reported. The procedure was otherwise safe and did not lead to deterioration of mood.