Allogeneic mesenchymal stromal cells for cartilage regeneration: A review of in vitro evaluation, clinical experience, and translational opportunities

The paracrine signaling, immunogenic properties and possible applications of mesenchymal stromal cells (MSCs) for cartilage tissue engineering and regenerative medicine therapies have been investigated through numerous in vitro, animal model and clinical studies. The emerging knowledge largely supports the concept of MSCs as signaling and modulatory cells, exerting their influence through trophic and immune mediation rather than as a cell replacement therapy. The virtues of allogeneic cells as a ready-to-use product with well-defined characteristics of cell surface marker expression, proliferative ability, and differentiation capacity are well established. With clinical applications in mind, a greater focus on allogeneic cell sources is evident, and this review summarizes the latest published and upcoming clinical trials focused on cartilage regeneration adopting allogeneic and autologous cell sources. Moreover, we review the current understanding of immune modulatory mechanisms and the role of trophic factors in articular chondrocyte-MSC interactions that offer feasible targets for evaluating MSC activity in vivo within the intra-articular environment. Furthermore, bringing labeling and tracking techniques to the clinical setting, while inherently challenging, will be extremely informative as clinicians and researchers seek to bolster the case for the safety and efficacy of allogeneic MSCs. We therefore review multiple promising approaches for cell tracking and labeling, including both chimerism studies and imaging-based techniques, that have been widely explored in vitro and in animal models. Understanding the distribution and persistence of transplanted MSCs is necessary to fully realize their potential in cartilage regeneration techniques and tissue engineering applications.fals

A survey of people with foot problems related to rheumatoid arthritis and their educational needs

Background Up to 50% of people with rheumatoid arthritis (RA) have foot symptoms at diagnosis, hence early foot health intervention is recommended and this should include patient education. This study identifies, for the first time, the foot health education (FHE) needs of people with RA. Methods An online survey of people with RA (n = 543) captured quantitative data in relation to the aims, methods of delivery, content, timing and accessibility of FHE. Results The majority concurred about the aims of FHE. Verbal delivery and websites were the most common methods. Written and verbal FHE were perceived to be the most effective methods. The point of diagnosis was the preferred time to receive it. Lack of access to FHE included minimal focus on foot health during consultations by both health practitioners and patients with RA. Participant gender, age, disease duration and living situation had a statistically significant influence on the results. Conclusion Foot health education is rarely considered within the medical consultation. There is a lack of patient and/or health professional awareness of this need with a detrimental impact on foot health. Patients require health professionals to identify their foot education health needs. Tailored foot health education should begin at initial diagnosis

Absence of Fas-L aggravates renal injury in acute Trypanosoma cruzi infection

Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.Instituto Oswaldo Cruz-Fiocruz Laboratório de Biologia CelularUniversidade Federal do Rio de Janeiro Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal Fluminense Instituto Biomédico Departamento de Fisiologia e FarmacologiaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Disciplina de NefrologiaCentro de Criação de Animais de Laboratório Departamento de Controle de Qualidade AnimalUNIFESP, EPM, Disciplina de NefrologiaSciEL

How do cemented short Exeter stems perform compared with standard-length Exeter stems? The experience of the New Zealand National Joint Registry

Background: The standard Exeter (Stryker) cemented stem is 150 mm long with standard offsets ranging from 37.5 mm to 56 mm. Exeter short stems of 125 mm are also available in the offsets of 37.5 mm, 44 mm, and 50 mm. In addition, smaller (125 mm or shorter) Exeter cemented stems with offsets of 35.5 mm or less are available. The aim of this study was to examine the New Zealand Joint Registry (NZJR) comparing medium-term survival rates and functional outcomes of standard-length stems with Exeter short stems of various offsets in patients undergoing primary total hip replacement. Methods: Using the NZJR, we compared the results of 3 separate groups of patients with Exeter stems. Patients with standard 150 mm length Exeter stems (Standard) were compared with patients with Exeter 125 mm stems with regular 37.5 mm, 44 mm, and 50 mm offsets (Short 37+) and Exeter 125 mm stems with offsets of 35.5 mm and below (Short 37−). Demographic data, preoperative diagnosis, patient-reported outcome measures, and reasons for revision were compared between groups. Kaplan-Meier survival analysis and Cox multivariate regression analysis were used to examine implant survival and the influence of stem group on revision rates adjusting for gender, age, diagnosis, and surgical approach. Results: There were 43,427 Exeter cemented stems in the NZJR between January 1, 1999 and 31, May 2018; 41,629 Standard, 657 Short 37+, and 1501 Short 37−. In all 3 groups, the posterior surgical approach was preferred (Standard, 76.1%; Short 37+, 94.6%; Short 37−, 76.6%; P < .001). In the Short 37− group, 94.1% were female, while in the other 2 groups, there was an equal gender ratio (P < .001). The Short 37- group was also significantly younger than the other 2 groups with 41.6% younger than 65 years compared with Short 37+ (37.2%) and Standard groups (36.9%) (P < .01). There was no difference in American Society of Anesthesiologists grade between groups. Body mass index (BMI) was significantly higher in both the Short 37− and Short 37 + groups compared with the Standard group (Standard BMI, 28.71; SD 5.72; Short 37+ BMI, 29.69; SD, 6.67; Short 37− BMI, 29.09; SD 7.07; P < .001). The all-cause revision rate for standard stems was 0.55/100 component years (cy) (95% CI: 0.52 to 0.58). The Short 37− group had a higher rate of revision compared with the Standard group (hazard ratio 1.6; 95% CI: 1.3 to 1.98; P < .001), while the Short 37+ group had a hazard ratio of 0.84 (95% CI: 0.38 to 1.88; P = .674) compared with the Standard group. Cox regression analysis controlling for age, gender, diagnosis of OA, and surgical approach did not affect these findings. However, no clinically meaningful difference between Oxford hip scores was observed. Conclusions: There was a significant difference in revision rates for aseptic loosening with standard-length Exeter stems having a lower revision rate than short Exeter stems with offsets 35.5 mm or less. The Short 37+ groups, despite comprising relatively small numbers, performed similarly to the Standard stem group.fals

Antimicrobial resistance (AMR) nanomachines: mechanisms for fluoroquinolone and glycopeptide recognition, efflux and/or deactivation

In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics—the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins. Expression of efflux systems is regulated by GntR-like (S. aureus NorG), MarR-like (MgrA, MepR) regulators or a two-component signal transduction system (TCS) (S. aureus ArlSR). Resistance to the glycopeptide antibiotic teicoplanin occurs via efflux regulated by the TcaR regulator in S. aureus. Resistance to vancomycin occurs through modification of the D-Ala-D-Ala target in the cell wall peptidoglycan and removal of high affinity precursors, or by target protection via cell wall thickening. Of the six Van resistance types (VanA-E, VanG), the VanA resistance type is considered in this review, including its regulation by the VanSR TCS. We describe the recent application of biophysical approaches such as the hydrodynamic technique of analytical ultracentrifugation and circular dichroism spectroscopy to identify the possible molecular effector of the VanS receptor that activates expression of the Van resistance genes; both approaches demonstrated that vancomycin interacts with VanS, suggesting that vancomycin itself (or vancomycin with an accessory factor) may be an effector of vancomycin resistance. With 16 and 19 proteins or protein complexes involved in fluoroquinolone and glycopeptide resistances, respectively, and the complexities of bacterial sensing mechanisms that trigger and regulate a wide variety of possible resistance mechanisms, we propose that these antimicrobial resistance mechanisms might be considered complex ‘nanomachines’ that drive survival of bacterial cells in antibiotic environments

Methanobactin and the Link Between Copper and Bacterial Methane Oxidation

Methanobactins (mbs) are low-molecular-mass (<1,200 Da) copper-binding peptides, or chalkophores, produced by many methane-oxidizing bacteria (methanotrophs). These molecules exhibit similarities to certain iron-binding siderophores but are expressed and secreted in response to copper limitation. Structurally, mbs are characterized by a pair of heterocyclic rings with associated thioamide groups that form the copper coordination site. One of the rings is always an oxazolone and the second ring an oxazolone, an imidazolone, or a pyrazinedione moiety. The mb molecule originates from a peptide precursor that undergoes a series of posttranslational modifications, including (i) ring formation, (ii) cleavage of a leader peptide sequence, and (iii) in some cases, addition of a sulfate group. Functionally, mbs represent the extracellular component of a copper acquisition system. Consistent with this role in copper acquisition, mbs have a high affinity for copper ions. Following binding, mbs rapidly reduce Cu2+ to Cu1+. In addition to binding copper, mbs will bind most transition metals and near-transition metals and protect the host methanotroph as well as other bacteria from toxic metals. Several other physiological functions have been assigned to mbs, based primarily on their redox and metal-binding properties. In this review, we examine the current state of knowledge of this novel type of metal-binding peptide. We also explore its potential applications, how mbs may alter the bioavailability of multiple metals, and the many roles mbs may play in the physiology of methanotrophs

Modelling the impact and cost-effectiveness of the HIV intervention programme amongst commercial sex workers in Ahmedabad, Gujarat, India.

BACKGROUND: Ahmedabad is an industrial city in Gujarat, India. In 2003, the HIV prevalence among commercial sex workers (CSWs) in Ahmedabad reached 13.0%. In response, the Jyoti Sangh HIV prevention programme for CSWs was initiated, which involves outreach, peer education, condom distribution, and free STD clinics. Two surveys were performed among CSWs in 1999 and 2003. This study estimates the cost-effectiveness of the Jyoti Sangh HIV prevention programme. METHODS: A dynamic mathematical model was used with survey and intervention-specific data from Ahmedabad to estimate the HIV impact of the Jyoti Sangh project for the 51 months between the two CSW surveys. Uncertainty analysis was used to obtain different model fits to the HIV/STI epidemiological data, producing a range for the HIV impact of the project. Financial and economic costs of the intervention were estimated from the providers perspective for the same time period. The cost per HIV-infection averted was estimated. RESULTS: Over 51 months, projections suggest that the intervention averted 624 and 5,131 HIV cases among the CSWs and their clients, respectively. This equates to a 54% and 51% decrease in the HIV infections that would have occurred among the CSWs and clients without the intervention. In the absence of intervention, the model predicts that the HIV prevalence amongst the CSWs in 2003 would have been 26%, almost twice that with the intervention. Cost per HIV infection averted, excluding and including peer educator economic costs, was USD 59 and USD 98 respectively. CONCLUSION: This study demonstrated that targeted CSW interventions in India can be cost-effective, and highlights the importance of replicating this effort in other similar settings.Published versio

Uncemented and cemented primary total hip arthroplasty in the Swedish Hip Arthroplasty Register: Evaluation of 170,413 operations

BACKGROUND AND PURPOSE: Since the introduction of total hip arthroplasty (THA) in Sweden, both components have most commonly been cemented. A decade ago the frequency of uncemented fixation started to increase, and this change in practice has continued. We therefore analyzed implant survival of cemented and uncemented THA, and whether the modes of failure differ between the two methods of fixation. PATIENTS AND METHODS: All patients registered in the Swedish Hip Arthroplasty Register between 1992 and 2007 who received either totally cemented or totally uncemented THA were identified (n = 170,413). Kaplan-Meier survival analysis with revision of any component, and for any reason, as the endpoints was performed. Cox regression models were used to calculate risk ratios (RRs) for revision for various reasons, adjusted for sex, age, and primary diagnosis. RESULTS: Revision-free 10-year survival of uncemented THA was lower than that of cemented THA (85% vs. 94%, p &lt; 0.001). No age or diagnosis groups benefited from the use of uncemented fixation. Cox regression analysis confirmed that uncemented THA had a higher risk of revision for any reason (RR = 1.5, 95% CI: 1.4-1.6) and for aseptic loosening (RR = 1.5, CI: 1.3-1.6). Uncemented cup components had a higher risk of cup revision due to aseptic loosening (RR = 1.8, CI: 1.6-2.0), whereas uncemented stem components had a lower risk of stem revision due to aseptic loosening (RR = 0.4, CI: 0.3-0.5) when compared to cemented components. Uncemented stems were more frequently revised due to periprosthetic fracture during the first 2 postoperative years than cemented stems (RR = 8, CI: 5-14). The 5 most common uncemented cups had no increased risk of revision for any reason when compared with the 5 most commonly used cemented cups (RR = 0.9, CI: 0.6-1.1). There was no significant difference in the risk of revision due to infection between cemented and uncemented THA. INTERPRETATION: Survival of uncemented THA is inferior to that of cemented THA, and this appears to be mainly related to poorer performance of uncemented cups. Uncemented stems perform better than cemented stems; however, unrecognized intraoperative femoral fractures may be an important reason for early failure of uncemented stems. The risk of revision of the most common uncemented cup designs is similar to that of cemented cups, indicating that some of the problems with uncemented cup fixation may have been solved.Open Access - This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited

Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials

<p>Abstract</p> <p>Background</p> <p>Multiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful.</p> <p>Methods</p> <p>The Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression.</p> <p>Results</p> <p>A total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified.</p> <p>Conclusions</p> <p>Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease.</p