Gene Therapy for Parkinson's Disease Associated with GBA1 Mutations.

Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson's disease. Among the lysosomal genes involved, GBA1 has the largest impact on Parkinson's disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many clinical aspects of Parkinson's disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia.

Randomized, Placebo Controlled Trial of NPT088, A Phage-Derived, Amyloid-Targeted Treatment for Alzheimer's Disease.

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced β-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease.

Extra-abdominal desmoid tumours - further evidence for the watchful waiting policy.

Purpose: Extra-abdominal desmoid tumours are benign and rare, and lead to a persistent treatment dilemma because of their high recurrence rate and their heterogeneous behaviour. The goal of this retrospective study was to evaluate the results of different treatment modalities for extra-abdominal desmoid tumours at four sarcoma treatment centres.

Methods: The mean follow-up time for the 96 patients included in the study (63.

Pharmacology of nerve growth factor and discovery of tanezumab, an anti-nerve growth factor antibody and pain therapeutic.

The pharmacology of Nerve Growth Factor (NGF) and the discovery and development of tanezumab, a monoclonal anti-NGF antibody for the treatment of pain illustrate the complex and unpredictable nature of modern drug development. Initial efforts attempted to use NGF agonistically for Alzheimer's disease and neuropathies. Most unexpectedly, clinical studies unmasked hyperalgesic effects.

First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain.

Introduction: The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology.

Objectives: Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain.

Methods: In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design.

An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging.

Soluble amyloid β oligomers (AβOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer's disease (AD). One of the profound downstream consequences of AβO-triggered events is dysregulation of cytosolic calcium concentration ([Ca]), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AβO-blocking candidates by measuring AβO-induced real-time changes in [Ca].

Impact of Single Center Treatment on Ewing Sarcoma 10-Year Long Term Survival Rates.

PURPOSE OF THE STUDY Ewing sarcomas (ES) are the second most common solid malignant bone tumors in both, children and adolescents, and systemic chemotherapy protocols were established during the last 3 decades which proved to be a successful approach in addition to local treatment. The purpose of the present study is (i) to provide survival rates and prognostic factors for patients with ES which received treatment in a single center and (ii) to compare data with results of multicenter studies. MATERIALS AND METHODS Patients (n = 38) were treated by the same surgeon whereas surgery was combined with radiotherapy in 55.

Non-vascularised fibula grafts for reconstruction of segmental and hemicortical bone defects following meta- /diaphyseal tumour resection at the extremities.

Background: The reconstruction of meta-/diaphyseal bone defects following bone tumour resection is challenging, and biological treatment options should be applied whenever possible, especially in benign lesions and early stage sarcomas. We aimed to evaluate the results of segmental (SR) and hemicortical reconstructions (HR) at the extremities using non-vascularised fibula grafts.

Methods: We retrospectively enrolled 36 patients who were treated with non-vascularised fibula reconstructions (15 SR, 21 HR) after bone tumour resection (15 malignant, 21 benign).

Treatment of shepherd's crook deformity in patients with polyostotic fibrous dysplasia using a new type of custom made retrograde intramedullary nail: a technical note.

Aims: The severe form of coxa vara, the 'shepherd's crook deformity', is always a consequence of a locally extensive form of polyostotic fibrous dysplasia (or McCune-Albright syndrome). Treatment of this deformity is a challenge. The soft bone does not tolerate any implant that depends on the stability of the cortical bone (like plates or external fixators).

Conformation as the Therapeutic Target for Neurodegenerative Diseases.

Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies.

[Acetabuloplasty - The Dega and Pemberton technique].

Background: Hip dysplasia is the most common congenital deformity requiring surgical correction osteotomy in order to prevent early onset of secondary hip arthrosis. The shape of the acetabulum can be modified by Dega or Pemberton osteotomy and is indicated for hip dysplasia and luxation with irregularities of the socket for children aged between 2 and 12 when the y‑physis is still open.

Method: We will describe indication, contra-indication, preoperative planning as well as details of the Pemberton technique.

Growth guidance of angular lower limb deformities using a one-third two-hole tubular plate.

Purpose: The eight-plate system for angular deformity correction is well known, reliable and effective at any age during growth. Due to high implant costs, we sought to evaluate the effectiveness and safety of a less expensive alternative.

Methods: Between 2006 and 2011, 41 children with angular deformities were managed using a two-hole one-third tubular plate in cases where an eight plate would normally be indicated.

Pathogenesis and biomechanics of adolescent idiopathic scoliosis (AIS).

Adolescent idiopathic scoliosis is defined as a scoliosis that starts after the age of ten and has no clear underlying disease as a reason for its development. There is, however, a disparity between the growth of the vertebral bodies anteriorly and that of the posterior elements. The vertebral bodies grow faster than the posterior elements, resulting primarily in a lordosis.

Do malignant bone tumors of the foot have a different biological behavior than sarcomas at other skeletal sites?

We analyze the delay in diagnosis and tumor size of malignant bone tumors of the foot in a retrospective study. We compared the oncological and surgical long-term results with identical tumor at other anatomical sites in order to analyze the biological behavior of sarcomas that are found in the foot. Thirty-two patients with a histologically proven malignant bone tumor (fifteen chondrosarcomas, nine osteosarcomas, and eight Ewing sarcomas) between the years 1969 and 2008 were included.

The case for soluble Aβ oligomers as a drug target in Alzheimer's disease.

Soluble Aβ oligomers are now widely recognized as key pathogenic structures in Alzheimer's disease. They inhibit synaptic function, leading to early memory deficits and synaptic degeneration, and they trigger the downstream neuronal signaling responsible for phospho-tau Alzheimer's pathology. The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques.

Virtual reconstruction of pelvic tumor defects based on a gender-specific statistical shape model.

Tumors in the pelvic region cause deformation and destruction of bony structures. Because the original pelvic anatomy cannot be adequately assessed at the tumor site, reconstruction with patient-specific implants is required. A widely used strategy for the reconstructive planning is mirroring of the contralateral side.