Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised

The use of a combined bipedicled axial perforator based fasciocutaneous flap for the treatment of a traumatic diabetic foot wound: a case report

The axial and perforator vascularised fasciocutaneous flaps are reliable and effective treatment methods for covering lower limb post-traumatic, septic, Charcot, and diabetic foot wounds. The authors describe the unique utilisation of a hybrid flap as an axial-perforator flap combination for the treatment of a traumatic diabetic foot wound

Bone metabolism in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disease of not well-defined etiology that involves immune cell activation and frequently affects the skeleton. Bone involvement in LCH usually presents in the form of osteolytic lesions along with low bone mineral density. Various molecules involved in bone metabolism are implicated in the pathogenesis of LCH or may be affected during the course of the disease, including interleukins (ILs), tumor necrosis factor α, receptor activator of NF-κB (RANK) and its soluble ligand RANKL, osteoprotegerin (OPG), periostin and sclerostin. Among them IL-17A, periostin and RANKL have been proposed as potential serum biomarkers for LCH, particularly as the interaction between RANK, RANKL and OPG not only regulates bone homeostasis through its effects on the osteoclasts but also affects the activation and survival of immune cells. Significant changes in circulating and lesional RANKL levels have been observed in LCH patients irrespective of bone involvement. Standard LCH management includes local or systematic administration of corticosteroids and chemotherapy. Given the implication of RANK, RANKL and OPG in the pathogenesis of the disease and the osteolytic nature of bone lesions, agents aiming at inhibiting the RANKL pathway and/or osteoclastic activation, such as bisphosphonates and denosumab, may have a role in the therapeutic approach of LCH although further clinical investigation is warranted

A systematic approach to the failed plastic surgical reconstruction of the diabetic foot

Plastic reconstruction for diabetic foot wounds must be approached carefully and follow sound micro-surgical principles as it relates to the anatomy of the designated flap chosen for coverage. First, the surgeon always needs to evaluate the local and general conditions of the presenting pathology and patient, respectively when considering a flap for reconstruction. The flap that is chosen is based on the vascularity, location, and size of the defect. Salvage of the failed flap and revisional reconstructive procedures are very challenging. Often, adjunctive therapies such as hyperbaric oxygen, negative pressure wound therapy, vasodilators, and/or vascular surgery is required. In certain case scenarios, such as patients with poor general health and compromised local vascularity in which revisional flap coverage cannot be performed, the above mentioned adjunctive therapies could be used as a primary treatment to potentially salvage a failing flap

High Strength Bolts for Bridges

DTFH61-85-C-00174An extensive experimental program was conducted to evaluate the performance of both black and galvanized high strength bolts for bridges. Seventy two a325 black bolts, 145 hot dip galvanized a325 bolts, 85 mechanically galvanized a325 bolts, and 83 black a490 bolts from several different suppliers, were tested under direct and torqued tension in order to evaluate the current installation practices and astm standard requirements for high strength bolts and to develop guidelines which will ensure proper installation and satisfactory performance of these bolts. An important parameter in the test program was the thread conditions of the bolts and nuts. Four thread conditions were examined: as received, cleaned, weathered and lubricated. Several types of lubricants were considered in the course of the experimental program. The results indicate that a great deal of the problems associated with the performance of high strength bolts lies in the vagueness of the current astm standards and the failure of the bolt suppliers to follow the requirements stated in these standards. A major recommendation in this study is to establish a unified standard which will cover the performance of fastener assemblages (bolt nut washer) under the responsibility of one committee. Guidelines for proper installation of high strength bolts are also given

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals