Osteoarthritis: From upcoming treatments to treatments yet to come

Osteoarthritis affects hundreds of millions of people worldwide, and its prevalence is constantly increasing. While there is currently no treatment that can alter the course of the disease, promising therapeutic strategies and novel targets are being investigated. Innovative cell therapies are already reaching clinical trials, and recent progress in our understanding of the disease is opening new routes for gene therapy. In the long term, the development of new biofabrication tools, such as 3D bioprinting, may pave the way for personalized mini-joint models that could be used to screen drugs and to personalize treatments. This review provides an overview of the most promising therapeutic approaches in the field of osteoarthritis, from upcoming treatments to those that are yet to be discovered.     

Methicillin-resistant Staphylococcus aureus in surgical patients: identification of high-risk populations for the development of targeted screening programmes

INTRODUCTION

Methicillin-resistant Staphylococcus aureus (MRSA)-related hospital-acquired infection (HAI) in surgical patients is associated with high morbidity, mortality and financial cost. The identification and characterisation of populations of patients who are at high risk of developing MRSA infection or colonisation could inform the design of more effective strategies to prevent HAIs and reduce transmission of MRSA.

PATIENTS AND METHODS

An analysis of historical discharge data for the whole of 2005 (7145 surgical in-patients) was performed, for all patients admitted to general surgery at the Royal Infirmary of Edinburgh. Analysis specifically focused on MRSA laboratory data and coding data for patient demographics, medical co-morbidities, and progress of in-patient stay.

RESULTS

A total of 134 (1.88%) individual patients with colonisation or infection by MRSA were identified from indicated laboratory testing. Univariate analysis identified a significant association of concurrent MRSA-positive status with patients aged over 60 years (P < 0.01), a duration of inpatient stay > 7 days (P < 0.01), presence of a malignant neoplasm (P < 0.01), circulatory disease (P < 0.01), respiratory disease (P < 0.01), central nervous system disease (P < 0.01), renal failure (P < 0.01), and concurrent admission to ITU/HDU (P < 0.01). Multivariate analysis suggested MRSA colonisation or infection was strongest in those with co-morbid malignancy (P < 0.0001) or admission to ITU/HDU (P < 0.0001).

CONCLUSIONS

This large observational study has identified cancer patients as a UK surgical patient subpopulation which is at significantly higher risk of colonisation by MRSA. These data could inform the development of focused hospital in-patient screening protocols and provide a means to stratify patient risk.     

Interleukin-17: A new bone acting cytokine in vitro.

Interleukin-17 (IL-17) is a recently cloned cytokine that is exclusively produced by activated T cells, but its receptor has been found on several cells and tissues. Like other proinflammatory cytokines produced by activated T cells, IL-17 may affect osteoclastic resorption and thereby mediate bone destruction accompanying some inflammatory diseases. In the present study, we investigated whether osteogenic cells possess the receptor for IL-17 (IL-17R) and whether IL-17 affects osteoclastic resorption. We found that IL-17R mRNA is expressed both in mouse MC3T3-E1 osteoblastic cells and fetal mouse long bones, suggesting that osteogenic cells may be responsive to IL-17. In fetal mouse long bones, IL-17 had no effect on basal and IL-1beta-stimulated osteoclastic bone resorption, but when given together with tumor necrosis factor-alpha (TNF-alpha) it increased bone resorption dose dependently in serum-free conditions. In addition, IL-17 increased TNF-alpha-induced IL-1alpha, IL-1beta, and IL-6 mRNA expression in fetal mouse metatarsals and IL-1alpha and IL-6 mRNA expression in MC3T3-E1 cells. In conclusion, IL-17R mRNA was expressed by mouse osteoblastic cells and fetal mouse long bones, and IL-17 in combination with TNF-alpha, but not IL-1beta, increased osteoclastic resorption in vitro. IL-17 may therefore affect bone metabolism in pathological conditions characterized by the presence of activated T cells and TNF-alpha production such as rheumatoid arthritis and loosening of bone implants.     

B-cell targeted treatments for lupus: The journey counts as much as the destination

Obstacles facing therapeutic trials in systemic lupus erythematosus (SLE) include the low incidence, seriousness, complexity, and clinical polymorphism of the disease. A large-scale multicenter design has been required in most cases. Over the last few years, several biologics have been evaluated as treatments for lupus nephritis or for the skin and joint manifestations of SLE. The central role for the B-cell in SLE, together with improved knowledge of the targets on the B-cell surface, has prompted efforts to develop monoclonal antibodies as treatments for SLE. The two available monoclonal antibodies are rituximab (anti-CD20 antibody) and belimumab (anti-BlyS antibody). The results obtained with belimumab were used to develop a new measurement tool, the SLE Responder Index (SRI), and prompted an application for a license to use belimumab in SLE. Other targets identified on the B-cell surface are being evaluated.     

Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND: A number of genetic polymorphisms have been shown to regulate the production and secretion of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interferon (IFN)-gamma, interleukin (IL)-6, and IL-10. Several of these genetic polymorphisms have been shown to be associated with either acute or chronic rejection of kidney, liver, and heart allografts and with development of allograft fibrosis after lung transplantation. The aim of this study was to assess the effect of these genetic polymorphisms on the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Genetic polymorphisms were detected by means of polymerase chain reaction in 93 lung allograft recipients for functional polymorphisms in the TNF-alpha (-308), TGF-beta1 (+869 and +915), IL-6 (-174), IFN-gamma (+874), and IL-10 (-1082, -819, and -592) genes. Then, a correlation between BOS development and the presence of these cytokine genotypes was determined using Kaplan-Meier actuarial analysis. RESULTS: A significant correlation was detected between the presence of high-expression polymorphisms of the IL-6 and IFN-gamma genes and BOS development after lung transplantation (P =0.045 and 0.039, respectively). Also, patients with high-expression polymorphisms in both genes developed BOS significantly earlier than patients with low-expression polymorphisms in one or both genes, suggesting a synergistic effect of the alleles during BOS pathogenesis (P =0.016). No correlation was detected between polymorphisms of the TNF-alpha, TGF-beta1, and IL-10 genes and development of BOS after lung transplantation. CONCLUSIONS: The presence of high-expression polymorphisms at position -174 of the IL-6 gene and position +874 of the IFN-gamma gene significantly increases the risk for BOS development after lung transplantation.     

From renal amyloid deposits to the identification of the culprit genes

Hereditary amyloidoses with renal involvement are classified in two groups. The first group is a growing family of autoinflammatory disorders characterized by recurrent fever attacks. Amyloidosis is caused by the deposition of amyloid A (AA) protein, which is a degradation product of a normal serum acute-phase protein: serum amyloid A (SAA). The prototype is familial Mediterranean fever (FMF). TNF Receptor Associated Periodic Syndrome (TRAPS) is a recently recognized periodic fever syndrome, differing from FMF in several characteristics: autosomal-dominant transmission, longer duration of attacks, and lack of response to colchicine prophylaxis. The second group comprises a variety of disorders, each characterized by the deposition of a specific mutant protein. The prototype is transthyretin amyloidosis (TTR). Identification of the form of amyloidosis has clinical implications. Therefore, in a patient with a history of recurrent fever attacks and AA amyloidosis, a diagnosis of FMF or TRAPS dictates appropriate genetic counseling and management. In patients with renal amyloidosis without a history of fever, identification of the mutant protein is therapeutically crucial; therefore, when the cell type that produces the precursor is (exclusively or mainly) the hepatocyte, a liver transplantation is to be considered.     

Interleukin-6 in the pathogenesis of rheumatoid arthritis

Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed.     

Lack of Knowledge: Breast Cancer and the Soluble Interleukin-6 Receptor

Zusammenfassung

Hintergrund

In der Krebstherapie stellen Zytokine therapeutische Angriffsziele, sogenannte Targets, dar. Beim Mammakarzinom ist ein hoher Interleukin (IL)-6-Gehalt mit verschiedenen Tumorcharakteristika wie z.B. Metastasierung, bestimmten Stadien und vermindertem Überleben assoziiert. In der Zwischenzeit hat sich herausgestellt, dass die Signalweiterleitung über den löslichen IL-6-Rezeptor (sIL-6R) (“Transsignaling”) von großer Bedeutung innerhalb des IL-6-Geschehens ist.

Methoden und Ergebnisse

In diesem Mini-Review stellen wir fest, dass das publizierte Wissen über den Serumgehalt an sIL-6R bei Mammakarzinompatienten lückenhaft ist. Des Weiteren zeigen publizierte In-vitro-Daten lediglich die Tatsache, dass Tumorzellen selber den sIL-6R produzieren.

Schlussfolgerungen

Aus diesem Grunde erscheint es uns notwendig herauszufinden, welche Bedeutung der sIL-6R, und damit einhergehend der Transsignaling-Prozess, beim Mammakarzinom hat. Ein breiteres Wissen über den sIL-6R beim Brustkrebs könnte seine Rolle als eventueller Marker des aktiven Tumorgeschehens beleuchten und eine neue therapeutische Möglichkeit darstellen, zumindest für diejenigen Patienten, deren Serumgehalte an IL-6 und/oder sIL-6R erhöht sind.     

From QOL to QALYs: Comparing nononcologic outcomes in prostate cancer survivors across treatments

Objective

We aim to highlight the progression from the early definition of nononcologic outcomes in prostate cancer (PC) to measurement and use of preferences to ensure appropriate treatment decisions in men with localized disease.

Pig-to-baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments

Galactosyl transferase knock-out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti-inflammatory enzymes and self-recognition receptors, and knock-down of the β4Gal xenoantigen were tested in various combinations. Transient life-supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n = 15), hTBM (n = 4), or hEPCR.hTFPI (n = 11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24 h. Co-expression of hEPCR and hTBM (n = 11) and additionally blocking multiple pro-inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1 day, with one recipient surviving for 31 days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life-supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.     

Analysis of Interleukin-6 and Interleukin-8 in Lung Transplantation: Correlation With Nitric Oxide Administration

Introduction and Objectives

Primary graft dysfunction (PGD) following lung transplantation (LT) is associated with an activation of the inflammatory cascade and release of cytokines. Inhaled nitric oxide (iNO) provides specific pulmonary vasodilatation and improves oxygenation. Our objective was to verify whether administering iNO to LT patients modified the blood and bronchoalveolar lavage (BAL) interleukin (IL)-6 and -8 levels in the event of PGD.

Materials and Methods

Thirty-two LT patients were randomized to the iNO treatment or the control group. Patients in the first group were given 10 ppm of iNO from the start of LT until 48 hours afterward. BAL and peripheral arterial blood samples were taken preimplantation as well as 12, 24, as and 48 hours postreperfusion.

Results

The iNO treatment group showed a lower incidence of PGD (29%) in comparison with the control group (40%). Significant differences (P < .05) were observed in the iNO group, with lower IL-6 levels at 12 hours in blood and BAL. A lower percentage of IL-8 was also detected in the iNO group at 24 hours in BAL and at 12 hours in blood and BAL.

Conclusions

Lung transplant recipients develop an inflammatory response following implantation with systemic elevation of IL-6 and significant local elevation of IL-8 within the first few hours, especially in the event of PGD. In our series, iNO appeared to modulate the inflammatory response by reducing IL concentrations found immediately after reimplantation, and this reduction was related to a lower incidence of PGD.     

Interleukin-6 in CAPD patients without peritonitis: relationship to the intrinsic permeability of the peritoneal membrane.

We investigated whether day to day changes in the transport characteristics of the peritoneal membrane to macromolecules in patients treated with CAPD, were related to the levels of interleukin-6 (IL-6) in the effluent of an overnight dwell. Four stable CAPD patients without peritonitis collected all "nightbags" on consecutive days during 2 months for the determination of peritoneal IgG clearance. Serum samples were obtained weekly. IL-6 was determined in the effluent on all occasions where the IgG clearance was less than mean - SD or greater than mean + SD. On these days clearances of beta 2-microglobulin, albumin and alpha 2-macroglobulin were determined as well, to calculate the peritoneal restriction coefficient, i.e. the slope of the power relationship between protein clearances and their free diffusion coefficient in water. This coefficient was used as a parameter of the intrinsic permeability of the membrane. IL-6 was measured by a sensitive and specific bioassay, using the B13.29, subclone 9.9 hybridoma cell assay. Dialysate IL-6 was measured on 43 occasions when IgG clearance was high and on 37 occasions when IgG clearance was low. In all 4 patients indirect evidence was found for local production of IL-6 within the peritoneal cavity: mean dialysate/serum ratios were 15 to 452 times higher than could be expected when IL-6 would enter the dialysate by diffusion only. The patient with the highest dialysate/serum ratio showed higher clearances of albumin, IgG and alpha 2-macroglobulin than the other 3 patients (p less than 0.001) and a lower restriction coefficient (p less than 0.001), indicating a high intrinsic permeability.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment

Serum concentrations of interleukin-6 (IL-6), IL-6-soluble receptor (sIL-6R), IL-6 gp130-soluble receptor (sgp130), ligand of receptor activator of nuclear factor (NF)-kappaB (RANKL), and osteoprotegerin (OPG) were determined in 42 patients with polyostotic Paget's disease of bone (PDB) and acquired resistance to clodronate (M/F ratio 23:19; mean age 58.5 +/- 9.4 years) in acute phase of disease and after oral risedronate treatment (30 mg/day for 8 weeks). At baseline, pagetic patients showed higher levels of OPG, sIL-6R, and IL-6 with lower levels of sgp130 compared to 24 age- and sex-matched controls (respectively, 4.69 +/- 1.27 vs. 2.87 +/- 0.54 pmol/L; 40.89 +/- 8.61 vs. 30.98 +/- 4.24 ng/ml; 3.59 +/- 0.97 vs. 1.8 +/- 0.9 pg/ml; 327.34 +/- 43.41 vs. 411.7 +/- 79.5 ng/ml). Response to treatment is related to a significant increase of OPG levels in all patients (from 4.69 +/- 1.27 to 5.48 +/- 1.31 pmol/L). The disease remission, that is, total alkaline phosphatase (tALP) levels within the normal range after therapy, was associated with a simultaneous increase in OPG and sgp130 levels. In patients with tALP higher than the normal range after therapy, the OPG increase was associated with a parallel increase in RANKL levels. Our data suggest that serum levels of components of RANKL/OPG and IL-6 systems, before and after treatment, may be used to better define a therapeutical strategy in pagetic patients.     

The lumbar intervertebral disc: From embryonic development to degeneration

Lumbar intervertebral discs (IVDs) are prone to degeneration upon skeletal maturity. In fact, this process could explain approximately 40% of the cases of low back pain in humans. Despite the efficiency of pain-relieving treatments, the scientific community seeks to develop innovative therapeutic approaches that might limit the use of invasive surgical procedures (e.g., spine fusion and arthroplasty). As a prerequisite to the development of these strategies, we must improve our fundamental knowledge regarding IVD pathophysiology. Recently, several studies have demonstrated that there is a singular phenotype associated with Nucleus pulposus (NP) cells, which is distinct from that of articular chondrocytes. In parallel, recent studies concerning the origin and development of NP cells, as well as their role in intervertebral tissue homeostasis, have yielded new insights into the complex mechanisms involved in disc degeneration. This review summarizes our current understanding of IVD physiology and the complex cell-mediated processes that contribute to IVD degeneration. Collectively, these recent advances could inspire the scientific community to explore new biotherapeutic strategies.     

From collection to museum: the development of the Geoffrey Kaye Museum of Anaesthetic History

Located at the Australian and New Zealand College of Anaesthetists (ANZCA) headquarters in Melbourne, Victoria, this internationally significant collection was founded in 1935 by renowned Australian anaesthetist Dr Geoffrey Kaye (1903 to 1986). Although it has always been referred to as a museum, it lacked the necessary management structure and infrastructure to meet museum standards. In March 2003, the first full-time professionally trained Museum Curator Ms Elizabeth Triarico, was employed by ANZCA to work with the Honorary Curator Dr Rod Westhorpe, and the Honorary Assistant Curator; Dr Christine Ball, to build on past achievements and to develop the collection into an accessible and relevant modern museum. Ms Triarico has extensive museum management experience with emphasis on management of major projects, collection management, strategic planning, marketing, interpretation and exhibition development. This paper outlines the management issues and innovative strategies involved in developing this important collection into a professionally managed museum based on best practice standards. It illustrates the benefits of introducing a clear vision and an agreed longterm management plan based on Museums Australia (Victoria) Museum Accreditation Program guidelines.