Human osteoblast growth and maturation in response to metformin and the thienopyridone, A769662

Metformin (Met) is a biguanide drug widely used in the treatment and management of non insulin-dependent diabetes mellitus. In recent years it has emerged that Met, by stimulating adenosine monophosphate-activated protein kinase (AMPK), can promote the maturation of osteoblasts, albeit cells sourced from rodent and murine calvaria. Finding novel uses for existing drugs is especially appealing, primarily from the fiscal and time constraints posed in developing new products. Identifying agents capable of supporting human osteoblast growth and differentiation are attractive in a bone regenerative context. Since studies using Met are invariably restricted to rodent and murine osteoblasts we sought to investigate whether this biguanide might have a positive influence upon human osteoblast growth and maturation. To this end we examined the effect of Met on two osteoblast-like cell lines, MG63 and Saos-2, and compared the responses to primary human osteoblasts and their bone marrow-derived stem cell progeny. Furthermore we examined the effect of a cell permeable Met surrogate, A769662, which is a potent and far more selective activator of AMPK. Herein we report that Met is without influence on cell growth. Furthermore the application of Met, albeit in the millimolar range, actually inhibited osteoblast maturation. Conversely A769662 was toxic to the osteosarcoma-derived cell lines, MG63 and Saos-2, but without effect on the growth of primary cells or their stem cell progenitors. Since the cell lines are known to be p53 deficient we propose that activation of AMPK by A769662 could form part of the arsenal in the fight against osteosarcoma

The effects of three quarter and full length foot orthoses on knee mechanics in healthy subjects and patellofemoral pain patients when walking and descending stairs

Background An increased load of the patellofemoral joint is often attributed to foot function in patients with patellofemoral pain. Foot orthoses are commonly prescribed for this condition; however the mechanisms by which they work are poorly understood. The aim of this study was to investigate the kinematics and kinetics of the knee between patellofemoral pain patients and a group of healthy subjects when using a standardised foot orthosis prescription during walking and step descent. Method Fifteen healthy subjects and fifteen patients diagnosed with PFP with a foot posture index greater than 6, had foot orthoses moulded to their feet. They were asked to walk at a self-selected pace and complete a 20 cm step descent using customised orthoses with ¾ and full length wedges. Kinematic and Kinetic data were collected and modelled using Calibrated Anatomical System Technique. Results Significant differences were seen in both the kinematics and kinetics between the healthy group and the PFP patients at the knee. A significant reduction in the knee coronal plane moment was found during the forward continuum phase of step descent when wearing the foot orthoses; this was attributed to a change in the ground reaction force as there were no changes reported in the kinematics of the knee with the orthoses. Conclusions This study identified potentially clinically important differences in the knee mechanics between the PFP patients and the healthy group during walking and step descent. The foot orthoses reduced the coronal plane knee moment in the PFP patients to a value similar to that of the healthy subjects with no intervention

Children with lesbian parents: A community study

Existing research on children with lesbian parents is limited by reliance on volunteer or convenience samples. The present study examined the quality of parent-child relationships and the socio-emotional and gender development of a community sample of 7-year-old children with lesbian parents. Families were recruited through the Avon Longitudinal Study of Parents and Children, a geographic population study of 14,000 mothers and their children. Thirty-nine lesbian-mother families, 74 two-parent heterosexual families, and 60 families headed by single heterosexual mothers were compared on standardized interview and questionnaire measures administered to mothers, co-mothers/fathers, children, and teachers. Findings are in line with those of earlier investigations showing positive mother-child relationships and well-adjusted children

Differences in structural and pain phenotypes in the sodium monoiodoacetate and meniscal transection models of osteoarthritis

This study was funded by Arthritis Research UK Grant number 18769.Peer reviewedPublisher PD

A Role for Antimicrobial Stewardship in Clinical Sepsis Pathways: A Prospective Interventional Study

© 2017 by The Society for Healthcare Epidemiology of America. All rights reserved. OBJECTIVE To evaluate the impact of early infectious diseases (ID) antimicrobial stewardship (AMS) intervention on inpatient sepsis antibiotic management. DESIGN Interventional, nonrandomized, controlled study. SETTING Tertiary-care referral hospital, Sydney, Australia. PATIENTS Consecutive, adult, non-intensive care unit (non-ICU) inpatients triggering an institutional clinical sepsis pathway from May to August 2015. INTERVENTION All patients reviewed by an ID Fellow within 24 hours of sepsis pathway trigger underwent case review and clinic file documentation of recommendations. Those not reviewed by an ID Fellow were considered controls and received standard sepsis pathway care. The primary outcome was antibiotic appropriateness 48 hours after sepsis trigger. RESULTS In total, 164 patients triggered the sepsis pathway: 6 patients were excluded (previous sepsis trigger); 158 patients were eligible; 106 had ID intervention; and 52 were control cases. Of these 158 patients, 91 (58%) had sepsis, and 15 of these 158 (9.5%) had severe sepsis. Initial antibiotic appropriateness, assessable in 152 of 158 patients, was appropriate in 80 (53%) of these 152 patients and inappropriate in 72 (47%) of these patients. In the intervention arm, 93% of ID Fellow recommendations were followed or partially followed, including 53% of cases in which antibiotics were de-escalated. ID Fellow intervention improved antibiotic appropriateness at 48 hours by 24% (adjusted risk ratio, 1.24; 95% confidence interval, 1.04-1.47; P=.035). The appropriateness agreement among 3 blinded ID staff opinions was 95%. Differences in intervention and control group mortality (13% vs 17%) and median length of stay (13 vs 17.5 days) were not statistically significant. CONCLUSION Sepsis overdiagnosis and delayed antibiotic optimization may reduce sepsis pathway effectiveness. Early ID AMS improved antibiotic management of non-ICU inpatients with suspected sepsis, predominantly by de-escalation. Further studies are needed to evaluate clinical outcomes. Infect Control Hosp Epidemiol 2017;38:1032-1038

Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis

© 2020, The Author(s). Introduction: Osteoarthritis (OA) is the most common form of joint disease, causing pain and disability. Previous studies have demonstrated the role of lipid mediators in OA pathogenesis. Objectives: To explore potential alterations in the plasma lipidomic profile in an established mouse model of OA, with a view to identification of potential biomarkers of pain and/or pathology. Methods: Pain behaviour was assessed following destabilisation of the medial meniscus (DMM) model of OA (n = 8 mice) and compared to sham controls (n = 7). Plasma and knee joints were collected at 16weeks post-surgery. Plasma samples were analysed using ultra-high performance liquid chromatography accurate mass high resolution mass spectrometry (UHPLC-HR-MS) to identify potential differences in the lipidome, using multivariate and univariate statistical analyses. Correlations between pain behaviour, joint pathology and levels of lipids were investigated. Results: 24 lipids, predominantly from the lipid classes of cholesterol esters (CE), fatty acids (FA), phosphatidylcholines (PC), N-acylethanolamines (NAE) and sphingomyelins (SM), were differentially expressed in DMM plasma compared to sham plasma. Six of these lipids which were increased in the DMM model were identified as CE(18:2), CE(20:4), CE(22:6), PC(18:0/18:2), PC(38:7) and SM(d34:1). CEs were positively correlated with pain behaviour and all six lipid species were positively correlated with cartilage damage. Pathways shown to be involved in altered lipid homeostasis in OA were steroid biosynthesis and sphingolipid metabolism. Conclusion: We identify plasma lipid species associated with pain and/or pathology in a DMM model of OA

Therapeutic benefit for late, but not early, passage mesenchymal stem cells on pain behaviour in an animal model of osteoarthritis

Background: Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods: Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5×106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5×106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL), 1.5×106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results: Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion: Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain