Pharmacological inactivation of the prion protein by targeting a folding intermediate.

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases.

Characterization of Physical, Mechanical, and Biological Properties of SilkBridge Nerve Conduit after Enzymatic Hydrolysis.

The degradation profile and the cytotoxicity of the degradation products of a silk fibroin (SF)-based nerve conduit (SilkBridge), with a complex three-layered wall architecture comprising both native and regenerated (electrospun) fibers, are reported. The bacterial protease type XIV from was used as a hydrolytic agent at three different enzyme/substrate ratios (1:8, 1:80, and 1:800 w/w) to account for the different susceptibility to degradation of the native and regenerated components. The incubation time was extended up to 91 days.

Generation, optimization and characterization of novel anti-prion compounds.

Prions are misfolded proteins involved in neurodegenerative diseases of high interest in veterinary and public health. In this work, we report the chemical space exploration around the anti-prion compound BB 0300674 in order to gain an understanding of its Structure Activity Relationships (SARs). A series of 43 novel analogues, based on four different chemical clusters, were synthetized and tested against PrP and mutant PrP toxicity assays.

Restoring global offset and lower limb length with a 3 offset option double-tapered stem.

Background: A proper restoration of hip biomechanics is fundamental to achieve satisfactory outcomes after total hip arthroplasty (THA). A global hip offset (GO) postoperatively reduction of more than 5 mm was known to impair hip functionality after THA. This study aimed to verify the restoration of the GO radiographic parameter after primary THA by the use of a cementless femoral stem available in three different offset options without length changing.

Tibial Tubercle Osteotomy in Total Knee Arthroplasty: Midterm Results Experience of a Monocentric Study.

 Difficult primary total knee arthroplasty (TKA) and revision TKA may be high demanding, especially during joint exposure. Aim of this article is to evaluate the clinical and radiological outcomes of a series of patients, who underwent TKA and revision TKA, where tibial tubercle osteotomy (TTO) was performed.  We retrospectively reviewed a cohort of 79 consecutives TKAs where TTO was performed.

The value of a standardized and reproducible surgical technique in treatment of Vancouver B2 periprosthetic fractures: our experience.

Purpose: To retrospectively review results and complications of our standardized surgical technique addressed exclusively to Vancouver B2 fractures.

Methods: From January 2006 to July 2016, we treated 235 consecutive patients, 47 males and 188 females, mean age at surgery of 71 ± 10 years, with periprosthetic B2 fractures. Exclusion criteria were other kind of periprosthetic fractures and other femoral fractures.

Pharmacological Agents Targeting the Cellular Prion Protein.

Prion diseases are associated with the conversion of the cellular prion protein (PrP), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP) that accumulates in brain tissues of affected individuals. PrP is a self-catalytic protein assembly capable of recruiting native conformers of PrP, and causing their rearrangement into new PrP molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrP, and a number of compounds have shown potent anti-prion effects in experimental models.

Acute Neurotoxicity Models of Prion Disease.

Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP) into disease-associated conformers (PrP) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrP species transmitting disease and/or directly associated with neurotoxicity.

Tibial tubercle osteotomy (TTO) in total knee arthroplasty, is it worth it? A review of the literature.

Introduction: Tibial tubercle osteotomy (TTO) is a well-established extensile approach to improve joint visualization and implant removal. Despite this, TTO is a challenging technique with a long learning curve and potential pitfalls. Complications are not infrequent, even if performing the correct surgical steps.

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein.

Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates.

A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity.

Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrP ) of the cellular prion protein (PrP ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity.

Epidermal RAF prevents allergic skin disease.

The RAS pathway is central to epidermal homeostasis, and its activation in tumors or in Rasopathies correlates with hyperproliferation. Downstream of RAS, RAF kinases are actionable targets regulating keratinocyte turnover; however, chemical RAF inhibitors paradoxically activate the pathway, promoting epidermal proliferation. We generated mice with compound epidermis-restricted BRAF/RAF1 ablation.

Ten-Year Results of Primary and Revision Condylar-Constrained Total Knee Arthroplasty in Patients with Severe Coronal Plane Instability.

Objective: To retrospectively review the results at minimum ten years after surgery of a consecutive series of total knee arthroplasties (TKAs) performed using a constrained condylar implant in patients with severe coronal plane instability.

Materials And Methods: The series comprised of 44 patients (45 knees) who received primary (19 knees) or revision (26 knees) TKA with a constrained condylar implant between 2001 and 2003 at a single institution.

Results: There were no revisions or any other surgery related complications at a mean implantation time of 11.

Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury.

Excitotoxicity following cerebral ischemia elicits a molecular cascade, which leads to neuronal death. c-Jun-N-terminal kinase (JNK) has a key role in excitotoxic cell death. We have previously shown that JNK inhibition by a specific cell-permeable peptide significantly reduces infarct size and neuronal death in an in vivo model of cerebral ischemia.

Synchronous occurrence of pulmonary adenocarcinoma and pleural diffuse malignant mesothelioma.

We report a rare case of diffuse malignant pleural mesothelioma synchronous with a localized adenocarcinoma of lung in a 68-year old man with a suspicious history of asbestos exposure. Computed tomography revealed a sub-pleural mass in the lower lobe and an irregular dense area of medium lobe of right lung with thickening of pleura encasing the lung parenchyma and homolateral pleural effusion 1 cm thick. The patient underwent surgery and a right medium and lower lobectomy was performed.

Correlation between HRCT and pulmonary functional tests in cystic fibrosis.

Purpose: To compare the HRCT score by Oikonomou and air trapping in expiratory scans with pulmonary functional tests and evaluate which radiological criteria are more useful to predict clinical impairment.

Materials And Methods: From January to September 2003, pulmonary HRCT study was performed in 37 patients (23 males), aged between 7 and 41 years, with cystic fibrosis. In the same day of CT examination they also received a complete functional evaluation.

Incision of AP sites in lung cancer patients: a pilot study.

DNA base excision repair (BER) removes frequent DNA lesions of either endogenous or exogenous origin. Some indications point to BER defects in lung cancer patients. We have investigated the ability of ten lung cancer patients to repair natural AP sites, the most frequent genetic lesion, using an in vitro assay in which peripheral blood lymphocytes (PBL) extracts incise randomly depurinated plasmid DNA.

[Clinico-diagnostic aspects and therapeutic considerations of the combined surgical and radiotherapeutic approach in 2 cases of sacrococcygeal chordoma: our experience].

Chordomas are rare tumours arising from embryonic notochord tissue remnants. The commonest affected segment is the sacrum. This localization may present diagnostic and therapeutic problems.