Prevention of Wear Particle-Induced Osteolysis by a Novel V-ATPase Inhibitor Saliphenylhalamide through Inhibition of Osteoclast Bone Resorption

Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis

Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy

Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders

Periprosthetic osteolysis after total hip replacement: molecular pathology and clinical management

Periprosthetic osteolysis is a serious complication of total hip replacement (THR) in the medium to long term. Although often asymptomatic, osteolysis can lead to prosthesis loosening and periprosthetic fracture. These complications cause significant morbidity and require complex revision surgery. Here, we review advances in our understanding of the cell and tissue response to particles produced by wear of the articular and non-articular surfaces of prostheses. We discuss the molecular and cellular regulators of osteoclast formation and bone resorptive activity, a better understanding of which may lead to pharmacological treatments for periprosthetic osteolysis. We describe the development of imaging techniques for the detection and measurement of osteolysis around THR prostheses, which enable improved clinical management of patients, provide a means of evaluating outcomes of non-surgical treatments for periprosthetic osteolysis, and assist in pre-operative planning for revision surgery. Finally, there have been advances in the materials used for bearing surfaces to minimise wear, and we review the literature regarding the performance of these new materials to date.Donald W. Howie, Susan D. Neale, David R. Haynes, Oksana T. Holubowycz, Margaret A. McGee, Lucian B. Solomon, Stuart A. Callary, Gerald J. Atkins, David M. Findla

Development of an advanced, continuous mild gasification process for the production of co-products (Task 4. 7), Volume 3

The focus of this task is the preparation of (1) preliminary piping and instrument diagrams (P IDs) and single line electrical diagrams for a site-specific conceptual design and (2) a factored cost estimate for a 24 ton/day (tpd) capacity mild gasification process development unit (PDU) and an associated form coke preparation PDU. The intended site for this facility is the Illinois Coal Development Park at Carterville, Illinois, which is operated by Southern Illinois University at Carbondale. (VC

Biomimetic hydroxyapatite coating on glass coverslips for the assay of osteoclast activity in vitro

The osteoclast (OC) is the cell type responsible for the resorption of bone. The activity of this cell is important in the aetiology of a large number of skeletal pathologies, and also for the biocompatibility and osseointegration of orthopaedic implant materials. OC mediated acid hydrolysis of calcium phosphate from the bone matrix offers a prime means of studying the biology and activity of this cell type. We have developed a method of coating glass coverslips with a hydroxyapatite (HA)-like mineral, using a biomimetic approach. Hydroxylation followed by formation of a self assembled monolayer (SAM) using the surfactant triethoxysilylpropyl succinic anhydride (TESPSA), allowed biomimetic deposition of HA-like mineral from a simulated body fluid (SBF). The biocompatibility of the TESPSA SAM-HA coated glass coverslips was tested by culturing human mature OC present in samples of giant cell tumour of bone (GCT). Parameters of OC activity were assayed, including F-actin ring formation, release of calcium and formation of osteoclastic resorption pits, confirming that OC were able to attach to and resorb the coated surface. This approach for the preparation of HA coatings on glass coverslips could have wide applicability for the study of osteoclast behaviour in vitro.Asiri K. A. R. Wijenayak, Christopher B. Colby, Gerald J. Atkins and Peter Majewsk