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Getah virus (GETV) is an emerging mosquito-borne virus with economic impact on the livestock industry in East Asia. In this study, we successfully produced GETV virus-like particles (VLPs) in insect cells using the baculovirus expression vector system. We show that the GETV envelope glycoproteins were successfully expressed at the surface of the insect cell and were glycosylated. VLPs were isolated from the culture fluid as enveloped particles of 60-80 nm in diameter. Two 1 µg vaccinations with this GETV VLP vaccine, without adjuvant, generated neutralizing antibody responses and protected wild-type C57/BL6 mice against GETV viremia and arthritic disease. The GETV VLP vaccine may find application as a horse and/or pig vaccine in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: The aim of this study was to identify the origin and development of the threshold for surgical intervention, highlight the consequences of residual displacement, and justify the importance of accurate measurement., Methods: A systematic review of three databases was performed to establish the origin and adaptations of the threshold, with papers screened and relevant citations reviewed. This search identified papers investigating functional outcome, including presence of arthritis, following injury. Orthopaedic textbooks were reviewed to ensure no earlier mention of the threshold was present., Results: Knirk and Jupiter (1986) were the first to quantify a threshold, with all their patients developing arthritis with > 2 mm displacement. Some papers have discussed using 1 mm, although 2 mm is most widely reported. Current guidance from the British Society for Surgery of the Hand and a Delphi panel support 2 mm as an appropriate value. Although this paper is still widely cited, the authors published a re-examination of the data showing methodological flaws which is not as widely reported. They claim their conclusions are still relevant today; however, radiological arthritis does not correlate with the clinical presentation. Function following injury has been shown to be equivalent to an uninjured population, with arthritis progressing slowly or not at all. Joint space narrowing has also been shown to often be benign., Conclusion: Knirk and Jupiter originated the threshold value of 2 mm. The lack of correlation between the radiological and clinical presentations warrants further modern investigation. Measurement often varies between observers, calling a threshold concept into question and showing the need for further development in this area. The principle of treatment remains restoration of normal anatomical position. Cite this article: Bone Joint J  2021;103-B(9):1457-1461.

Pararamosis is a medical condition, described in the latex extracting areas of the Amazon (rubber tree regions), resulting from contact with the caterpillar of the Premolis semirufa moth. The disease can present itself in an acute form-similarly to other erucisms (injuries caused by moth larvae in humans)-or in a chronic form, typically characterized by the occurrence of changes in the joints of the hands. Because of its importance, in the context of tropical diseases, the objective of this article was to review the main facets of the disease, emphasizing the different pathogenic aspects of the interaction between the arthropod and man.

Objective: To examine the association between weight change from young adulthood to midlife and the risk of incident arthritis., Methods: Using data from the National Health and Nutrition Examination Survey, we categorized participants into weight-change categories based on their recalled weight during young adulthood and midlife. We estimated the association of weight change and developing an arthritis condition over 10 years using adjusted Cox models. Findings were extrapolated to the US population to determine the proportion of incident arthritis cases that could be averted if the entire population maintained a normal body mass index (BMI) in young adulthood and midlife., Results: Among our sample of adults who were ages 40-69 years at their midlife weight measure (n = 13,669), 3,603 developed an arthritis condition. Compared with adults who maintained a normal-normal BMI, the normal-overweight, normal-obese, overweight-obese, and obese-obese groups had a significantly elevated risk of incident arthritis conditions. The obese-overweight group had a lower risk of incident arthritis conditions compared with the obese-obese group and a comparable risk to the overweight-overweight group. Nearly one-fourth of incident arthritis cases, corresponding to 2.7 million individuals, would have been averted under the hypothetical scenario where all individuals maintained normal weight from young adulthood to midlife., Conclusion: Weight loss from young adulthood to midlife was associated with a substantially reduced risk of developing an arthritis condition. We found no evidence of residual risk from having been heavier earlier in life. Our findings highlight the critical need to expand obesity treatment and prevention to achieve meaningful reductions in the burden of arthritis., (© 2020, American College of Rheumatology.)

Obesity is growing at an alarming rate, which is characterized by increased adipose tissue. It increases the probability of many health complications, such as diabetes, arthritis, cardiac disease, and cancer. In modern society, with a growing population of obese patients, several individuals have increased insulin resistance. Herbal medicines are known as the oldest method of health care treatment for obesity-related secondary health issues. Several traditional medicinal plants and their effective phytoconstituents have shown anti-diabetic and anti-adipogenic activity. Adipose tissue is a major site for lipid accumulation as well as the whole-body insulin sensitivity region. 3T3-L1 cell line model can achieve adipogenesis. Adipocyte characteristics features such as expression of adipocyte markers and aggregation of lipids are chemically induced in the 3T3-L1 fibroblast cell line. Differentiation of 3T3-L1 is an efficient and convenient way to obtain adipocyte like cells in experimental studies. Peroxisome proliferation activated receptor γ (PPARγ) and Cytosine-Cytosine-Adenosine-Adenosine-Thymidine/Enhancer-binding protein α (CCAAT/Enhancer-binding protein α or C/EBPα) are considered to be regulating adipogenesis at the early stage, while adiponectin and fatty acid synthase (FAS) is responsible for the mature adipocyte formation. Excess accumulation of these adipose tissues and lipids leads to obesity. Thus, investigating adipose tissue development and the underlying molecular mechanism is important in the therapeutical approach. This review describes the cellular mechanism of 3T3-L1 fibroblast cells on potential anti-adipogenic herbal bioactive compounds.

Interleukin (IL)-38 belongs to the IL-1 family and is part of the IL-36 subfamily due to its binding to the IL-36 Receptor (IL-1R6). In the current study, we assessed the anti-inflammatory properties of IL-38 in murine models of arthritis and systemic inflammation. First, the anti-inflammatory properties of mouse and human IL-38 precursors were compared to forms with a truncated N-terminus. In mouse bone marrow derived dendritic cells (BMDC), human and mouse IL-38 precursors with a truncation of the two N-terminal amino acids (3-152) suppressed LPS-induced IL-6. Recombinant human IL-38 (3-152) was further investigated for its immunomodulatory potential using four murine models of inflammatory disease: streptococcal cell wall (SCW)-induced arthritis, monosodium urate (MSU) crystal-induced arthritis, MSU crystal-induced peritonitis, and systemic endotoxemia. In each of these models IL-38 significantly reduced inflammation. In SCW and MSU crystal-induced arthritis, joint swelling, inflammatory cell influx, and synovial levels of IL-1β, IL-6, and KC were reduced by 50% or greater. These suppressive properties of IL-38 in SCW-induced arthritis were independent of the anti-inflammatory co-receptor IL-1R8, as IL-38 reduced arthritis equally in IL-1R8 deficient and WT mice. In MSU crystal-induced peritonitis, IL-38 reduced hypothermia, while plasma IL-6 and KC and peritoneal KC levels were reduced by 65-70%. In the LPS endotoxemia model, IL-38 pretreatment reduced systemic IL-6, TNFα and KC. Furthermore, in ex vivo cultured bone marrow, LPS-induced IL-6, TNFα and KC were reduced by 75-90%. Overall, IL-38 exhibits broad anti-inflammatory properties in models of systemic and local inflammation and therefore may be an effective cytokine therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Oral tolerance is the physiological process that enables the immune system to differentiate between harmless dietary and microbiota antigens from pathogen derived antigens. It develops at the mucosal surfaces and can result in local and systemic regulatory and anti-inflammatory effects. Translation of these benefits to the clinical practice faces limitations involving specificity and doses of antigen as well as regimens of feeding. To circumvent these problems, we developed a recombinant Hsp65 delivered by the acid lactic bacteria Lactococcus lactis NCDO 2118 directy in the intestinal mucosa. Hsp65 is a ubiquitous protein overexpressed in inflamed tissues and capable of inducing immunoregulatory mechanisms. L. lactis has probiotic properties and is commonly and safely used in dairy products. In this study, we showed that continuous delivery of HSP65 in the gut mucosa by L. lactis is a potent tolerogenic stimulus inducing regulatory CD4 + LAP + T cells that prevented collagen-induced and methylated bovine serum albumin-induced arthritis in mice. Clinical and histological signs of arthritis were inhibited as well as levels of inflammatory cytokines such as IL-17 and IFN-γ, serum titers of anti-collagen antibodies and rheumatoid factor. Oral administration of L. lactis induced alterations in microbiota composition toward an increased abundance of anaerobic bacteria such as Bifidobacterium and Lactobacillus . Tolerance to HSP65 and arthritis prevention induced by the recombinant L. lactis was associated with increase in IL-10 production by B cells and it was dependent on LAP + T cells, IL-10 and TLR2 signaling. Therefore, HSP65-producing treatment induced effective tolerance and prevented arthritis development suggesting it can be used as a therapeutic tool for autoimmune diseases., (Copyright © 2020 Gusmao-Silva, Aguiar, Miranda, Guimarães, Alves, Vieira, Cara, Miyoshi, Azevedo, Oliveira and Faria.)

Background: Stickler syndrome is a collagenopathy caused by mutations in the genes COL2A1 (STL1) or COL11A1 (STL2). Affected patients manifest ocular, auditory, articular, and craniofacial manifestations in varying degrees. Ocular symptoms include myopia, retinal detachment, cataract, and glaucoma. The aim of this systematic review was to evaluate the prevalence of ocular manifestations and the outcome of prophylactic treatment on reducing the risk of retinal detachment., Method: A systematic literature search was performed in the PubMed database. Information on the cross-study prevalence of myopia, retinal detachment, cataract, glaucoma, visual impairment, severity and age of onset of myopia and retinal detachments. Studies that reported on the outcome of prophylactic treatment against a control group were explored., Results: 37 articles with 2324 individual patients were included. Myopia was found in 83% of patients, mostly of a moderate to severe degree. Retinal detachments occurred in 45% of patients. Generally, the first detachment occurred in the second decade of life in STL1 patients and later in STL2. Cataracts were more common in STL2 patients, 59% versus 36% in STL1. Glaucoma (10%) and visual impairment (blind: 6%; vision loss in one eye: 10%) were rare. Three studies reported on the effect of prophylactic treatment being protective., Conclusion: Ocular manifestations are common in Stickler patients, but the comparison between studies was difficult because of inconsistencies in diagnostic and inclusion criteria by different studies. Sight-threatening complications such as retinal detachments are common but although prophylactic therapy is reported to be effective in retrospective studies, evidence from randomized trials is missing.

Chikungunya virus (CHIKV) infection causes acute febrile illness in humans, and some of these individuals develop a debilitating chronic arthritis that can persist for months to years for reasons that remain poorly understood. In this study from India, we characterized antibody response patterns in febrile chikungunya patients and further assessed the association of these initial febrile-phase antibody response patterns with protection versus progression to developing chronic arthritis. We found 5 distinct patterns of the antibody responses in the febrile phase: no CHIKV binding or neutralizing (NT) antibodies but PCR positive, IgM alone with no NT activity, IgM alone with NT activity, IgM and IgG without NT activity, and IgM and IgG with NT activity. A 20-month follow-up showed that appearance of NT activity regardless of antibody isotype or appearance of IgG regardless of NT activity during the initial febrile phase was associated with a robust protection against developing chronic arthritis in the future. These findings, while providing potentially novel insights on correlates of protective immunity against chikungunya-induced chronic arthritis, suggest that qualitative differences in the antibody response patterns that have evolved during the febrile phase can serve as biomarkers that allow prediction of protection or progression to chronic arthritis in the future.

Mesenchymal stromal cell (MSCs) represent a class of biologics with the prospects for employment as immunomodulatory, tissue-protective, and regenerative therapeutics. In parallel with cellular therapy, cell-free therapy based on MSC-secreted bioactive factors is being actively developed. MSCs secrete a variety of protein, peptide, RNA, and lipid mediators which can be concentrated, frozen, or even lyophilized without loss of activity, which gives them a certain advantage over cellular products requiring liquid nitrogen storage and infrastructure to revive frozen cells. This review (i) describes currently conducted clinical trials of cell-free products containing MSC secretome; (ii) summarizes main approaches to the generation and characterization of conditioned media concentrates and extracellular vesicle isolates; (iii) analyzes a variety of preclinical studies where effectiveness of secretome products has been shown; and (iv) summarizes current knowledge about secretome bioactive components obtained by analysis of in vivo models testing the therapeutic potential of the MSC secretome.

Background. Unstable ankle fractures are treated with open reduction internal fixation (ORIF) to prevent posttraumatic arthritis. Typically, ORIF is performed as an ambulatory surgery several days to a few weeks after injury. It is unclear what effect this delay may have on functional outcome. This study aimed to assess the effect of timing of ankle ORIF on wound complications and functional outcome. Methods. A retrospective review of 121 patients who underwent ankle ORIF was performed. A total of 58 patients had a follow-up of at least 24 months. Time between injury and surgery greater than 14 days was defined as "delayed." Demographic variables, injury characteristics, length of surgery, and postoperative stay were documented. Comparison of demographic variables, wound complications, and functional outcome determined by Foot and Ankle Outcome Score (FAOS) was performed. Results. 118 patients were included. The duration between injury and surgery was 6 days in the "early" group and 19 days in the "delayed" group. There were no significant differences in demographic variables, injury characteristics, and length of surgery between the groups. Wound complications in the early and delayed groups were 5% and 11.8%, although this difference was not statistically significant. Among 58 patients who had a follow-up of at least 24 months, the median follow-up time was 38 (range, 24-76) months. Each subscale of FAOS demonstrated no significant difference. Conclusion. Ankle ORIF more than 14 days after injury did not significantly increase the rate of wound complication, nor did it impair ultimate functional outcome in this group. Levels of Evidence: Level III.

In the present study, the modulatory effects of bifidobacterial spp. (Bifidobacterium breve NCIM 5671, Bifidobacterium longum NCIM 5672 and Bifidobacterium bifidum NCIM 5697) on adjuvant induced arthritis in rats were evaluated. Arthritis was induced in male Wistar rats by injecting 250 μg of Freund's adjuvant directly into the paw. Fifteen days before and 15 days after the induction of arthritis, suspended cultures of bifidobacteria (10 9  cfu/ml) were administered by oral gavage. Paw volume, bone mineral content, oxidative stress markers, antioxidant enzymes, cytokines, eicosanoids and expression of COX2, as well as bone hydrolytic enzymes, were assessed by RT PCR. Although piroxicam-treated groups (drug control) had better effects than bifidobacteria-treated groups, bifidobacteria probiotics administration exhibited significant (P < 0.05) prophylactic effects in terms of downregulating arthritis markers. Parameters including paw volume, bone mineral content, cytokines, and eicosanoids level were significantly (p < 0.05) modulated in bifidobacteria administered groups compared to arthritic control group. Among the three strains tested, B. breve NCIM 5671 exhibited superior prophylactic effects as assessed in the experimental rat model of arthritis. In conclusion, bifidobacteria probiotics administration can downregulate the markers of arthritis and hence can be a potential therapeutic regimen in the treatment of arthritis.

The most common cause for end-stage ankle osteoarthritis is posttraumatic, sometimes resulting from concomitant supramalleolar deformity. Aims of the supramalleolar osteotomy include restoring the lower-leg axis to improve intraarticular load distribution and retarding degeneration of the tibiotalar joint. Preoperative planning is based on conventional weight-bearing radiographs. Often advanced imaging, including computed tomography and/or MRI, is needed for a better understanding of the underlying problem. Postoperative complications are not uncommon, including progression of tibiotalar osteoarthritis in up to 25% within 5 years of all patients who have supramalleolar osteotomies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mycoplasma hyorhinis (Mhr) is a pathogen of pigs causing polyserositis and polyarthritis. The most susceptible population are nursery pigs of approximately 7 weeks of age, although we have shown that clinical signs can persist into finishing aged animals after a late-nursery infection. We have previously demonstrated the efficacy of a novel inactivated Mhr vaccine for the reduction of lameness and polyserositis in caesarian-derived colostrum-deprived (CDCD) pigs vaccinated at 3 weeks and challenged with Mhr at 6 weeks of age. Here we evaluated the duration of immunity (DOI) of the same vaccine. Vaccine or placebo was administered to CDCD pigs at 3 weeks of age. Pigs were challenged with Mhr at either 10 weeks of age (=7 week DOI) or 13 weeks of age (=10 week DOI). In the 7 week DOI, vaccination provided significant reductions in lameness (p = 0.0018), arthritis (p = 0.0002), and pericarditis (p = 0.0312) versus the placebo control. In the 10 week DOI, a significant reduction in arthritis (p = 0.0320) was observed in the vaccine group as compared to the placebo group. Both vaccine groups showed a significant increase (p < 0.0001) in the post-challenge average daily gain (ADG), gaining 0.2 kg/day more than their respective placebo groups., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to evaluate the meniscal regeneration and arthritic changes after partial meniscectomy and application of either polyurethane scaffold or novel multilayer meniscal scaffold in a rabbit model., Methods: Sixteen NewZealand rabbits were randomly divided into three groups. A reproducible 1.5-mm cylindrical defect was created in the avascular zone of the anterior horn of the medial meniscus bilaterally. Defects were filled with the polyurethane scaffold in Group 1 (n:6) and with novel multilayer scaffold in Group 2 (n:6). Rabbits in Group 3 (n:4) did not receive any treatment and defects were left empty. All animals were sacrificed after 8 weeks and bilateral knee joints were taken for macroscopic, biomechanical, and histological analysis. After excision of menisci, inked condylar surfaces and tibial plateaus were evaluated for arthritic changes. Digital photographs of excised menisci were also obtained and surface areas were measured by a computer software. Indentation testing of the tibial condyles and compression tests for the relevant meniscal areas was also performed in all groups. Histological analysis was made and all specimens were scored according to Rodeo scoring system., Results: No signs of inflammation or infection were observed in any animals. A significant difference was observed between meniscus surface areas of the multilayer scaffold group (20.13 ± 1.91 mm 2 ) and the group with empty meniscus defects (15.62 ± 2.04 mm 2 ) (p = 0.047). The results of biomechanical compression tests revealed a significant difference between the Hayes scores of the second group (1.728) and the empty defect group (0,467) (p = 0.029). Intact meniscal tissue showed higher mechanical properties than all the defected samples. Multilayer scaffold group demonstrated the closest results compared to healthy meniscus tissue. Tibia indentation tests and histological evaluation showed no significant differences between groups (p = 0.401 and p = 0.186 respectively)., Conclusions: In this study, the initial evaluation of novel multilayer meniscal scaffold prevented the shrinkage that may occur in the meniscus area and demonstrated superior biomechanical results compared to empty defects. No adverse events related to scaffold material was observed. Besides, promising biomechanical and histological results, comparable to polyurethane scaffold, were obtained., (Copyright © 2019 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Pain catastrophizing has been identified as a prognostic indicator of poor outcome following knee arthroplasty. Interventions to address pain catastrophizing, to our knowledge, have not been tested in patients undergoing knee arthroplasty. The purpose of this study was to determine whether pain coping skills training in persons with moderate to high pain catastrophizing undergoing knee arthroplasty improves outcomes 12 months postoperatively compared with usual care or arthritis education., Methods: A multicenter, 3-arm, single-blinded, randomized comparative effectiveness trial was performed involving 5 university-based medical centers in the United States. There were 402 randomized participants. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Scale, measured at baseline, 2 months, 6 months, and 12 months following the surgical procedure., Results: Participants were recruited from January 2013 to June 2016. In 402 participants, 66% were women and the mean age of the participants (and standard deviation) was 63.2 ± 8.0 years. Three hundred and forty-six participants (90% of those who underwent a surgical procedure) completed a 12-month follow-up. All 3 treatment groups had large improvements in 12-month WOMAC pain scores with no significant differences (p > 0.05) among the 3 treatment arms. No differences were found between WOMAC pain scores at 12 months for the pain coping skills and arthritis education groups (adjusted mean difference, 0.3 [95% confidence interval (CI), -0.9 to 1.5]) or between the pain coping and usual-care groups (adjusted mean difference, 0.4 [95% CI, -0.7 to 1.5]). Secondary outcomes also showed no significant differences (p > 0.05) among the 3 groups., Conclusions: Among adults with pain catastrophizing undergoing knee arthroplasty, cognitive behaviorally based pain coping skills training did not confer pain or functional benefit beyond the large improvements achieved with usual surgical and postoperative care. Future research should develop interventions for the approximately 20% of patients undergoing knee arthroplasty who experience persistent function-limiting pain., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Boswellia dalzielii is a tall tree (more than 13 m high) that produces aromatic white flowers. This plant is commonly used in indigenous medicine across Africa against diarrhea, malaria, vomiting, inflammation and arthritis. The present study focuses on the anti-inflammatory and anti-arthritis potential of methanol extract of Boswellia dalzielii (BDME). Anti-inflammatory activity was evaluated in inflammatory models induced by carrageenan, arachidonic acid, histamine, serotonin, prostaglandin and bradykinin. Anti-arthritis activity was measured using complete Freund's adjuvant model. Intracellular and extracellular ROS production and proliferation of T-cells were evaluated using chemiluminescence and liquid scintillation counter techniques, respectively. TNF-α and IL-1β production were assessed using ELISA and MTT assay performed for cytotoxicity. BDME revealed a significant anti-inflammatory effect by preventing the development of edema caused by carrageenan, arachidonic acid, histamine, serotonin, prostaglandin and bradykinin. For anti-arthritic properties of BDME, the results showed a significant reduction of the joint diameter and a decrease in pain in the treated animals. The extract also showed a noticeable systemic effect, maintaining the values of the evaluated parameters close to normal in treated rats with an inhibition of joint destruction as shown in histopathological analysis. Furthermore, BDME exhibited significant inhibition of extracellular and intracellular ROS production. Still, the extract displayed significant inhibitory activity on T-cell proliferation as well as a reduced production of TNF-α and IL-1β. Boswellia dalzielii could be considered as a promising tract in the prevention and/or management of inflammatory diseases.

Arthritis occurs in 27% of adults in Montana, among whom 50% have activity limitations, 16% have social participation restrictions, and 23% have severe joint pain attributable to arthritis (1). Physical activity is beneficial in managing arthritis symptoms and in preventing other chronic diseases (2). Walk With Ease is a 6-week evidence-based physical activity program recommended by CDC to increase physical activity and help improve arthritis symptoms (3). In 2015, Walk With Ease was added to an ongoing workplace wellness program for Montana state employees; the results for five outcomes (minutes spent walking, engaging in other physical activity [including swimming, bicycling, other aerobic equipment use, and other aerobic exercise], stretching, pain, and fatigue) were analyzed by the Montana Department of Public Health and Human Services and CDC. Outcomes at baseline (pretest), 6 weeks after the program (posttest), and 6 months later (follow-up) were analyzed by self-reported arthritis status at the time the participant enrolled in the program. Significant increases (p<0.05) in the mean number of minutes spent per week walking and engaging in other physical activity were observed among participants with and without arthritis at the 6-week posttest. Time spent stretching did not change significantly at posttest for either group. Mean pain levels among participants without arthritis increased significantly both at the 6-week posttest and 6-month follow-up; however, pain and fatigue decreased significantly at posttest and follow-up for participants with or without arthritis who began the program with moderate or severe pain and fatigue levels. The data from these analyses suggest that, as a component of a workplace wellness program, self-directed Walk With Ease might be effective in increasing physical activity not only among adults with arthritis, but also among persons without arthritis., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Objective: We undertook a systematic review and meta-analysis of direct and indirect trial evidence to evaluate the efficacy of treatments for patients with undifferentiated arthritis (UA)., Methods: We searched 4 electronic databases from inception to January 2016, clinicaltrials.gov, and bibliographies of relevant articles. Two reviewers independently screened and evaluated the studies. The primary outcome was development of rheumatoid arthritis (RA)., Results: Nine studies were included. Interventions included methotrexate, abatacept, infliximab, intraarticular or intramuscular glucocorticoids, and radiation synovectomy. Treating patients resulted in lower rates of RA at 12 months compared to placebo or no treatment (odds ratio [OR] 0.49 [95% confidence interval (95% CI) 0.26, 0.90]). From direct meta-analysis, patients treated with methotrexate were less likely to develop RA at 12 months compared to patients treated without methotrexate (OR 0.13 [95% CI 0.03, 0.48]). This difference was no longer significant at 30 or 60 months. From indirect comparisons, most interventions showed decreased risk of developing RA compared to placebo at 12 months, reaching statistical significance for methotrexate (OR 0.16 [95% CI 0.08, 0.33]) and intramuscular methylprednisolone (OR 0.72 [95% CI 0.53, 0.99]). Most individual interventions included a limited number of studies., Conclusion: Treating patients with UA resulted in a statistically significant delay in the development of RA, with the largest effect observed for methotrexate. These findings suggest that there is a window of opportunity to treat patients with UA early, to delay subsequent progression to RA., (© 2017, American College of Rheumatology.)

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-γ-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-γ expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-γ production, but also the protective function of iNKT cells in arthritis.

Background: Periprosthetic joint infection is a major complication of total joint replacement surgery and is associated with significant morbidity, mortality and financial burden. Surgical body suits (space suits), originally designed to reduce the incidence of infection, have paradoxically been implicated in increased periprosthetic joint infection rates recently. Air exhausted from space suits may contribute to this increased rate of periprosthetic joint infection., Aim: To investigate the flow of air exhausted from space suits commonly used in modern operating theatres., Methods: The exhaust airflow patterns of four commercially available space suit systems were compared using a fog machine and serial still photographs., Findings: The space suit systems tested all air exhausted into the operating room. The single fan systems with a standard surgical gown exhausted air laterally from the posterior gown fold at approximately the level of the surgical field. The single fan system with a dedicated zippered suit exhausted air at a level below the surgical field. The dual fan system exhausted air out of the top of the helmet at a level above the surgical field., Conclusions: Space suit systems currently in use in joint replacement surgery differ significantly from traditional body exhaust systems; rather than removing contaminated air from the operating environment, modern systems exhaust this air into the operating room, in some cases potentially towards the sterile instrument tray and the surgical field., (Copyright © 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Streptococcus suis is a major Gram-positive swine pathogen associated with a wide variety of diseases in pigs. The efforts made to develop vaccines against this pathogen have failed because of lack of common cross-reactive antigens against different serotypes. Nowadays the interest has moved to surface and secreted proteins, as they have the highest chances to raise an effective immune response because they are in direct contact with host cells and are really exposed and accessible to antibodies. In this work, we have performed a comparative immunosecretomic approach to identify a set of immunoreactive secreted proteins common to the most prevalent serotypes of S. suis. Among the 67 proteins identified, three (SSU0020, SSU0934, and SSU0215) were those predicted extracellular proteins most widely found within the studied serotypes. These immunoreactive proteins may be interesting targets for future vaccine development as they could provide possible cross-reactivity among different serotypes of this pathogen., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Problem/condition: Doctor-diagnosed arthritis is a common chronic condition affecting an estimated 23% (54 million) of adults in the United States, greatly influencing quality of life and costing approximately $300 billion annually. The geographic variations in arthritis prevalence, health-related characteristics, and management among states and territories are unknown. Therefore, public health professionals need to understand arthritis in their areas to target dissemination of evidence-based interventions that reduce arthritis morbidity., Reporting Period: 2015., Description of System: The Behavioral Risk Factor Surveillance System is an annual, random-digit-dialed landline and cellular telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. Self-reported data are collected from the 50 states, the District of Columbia, Guam, and Puerto Rico. Unadjusted and age-standardized prevalences of arthritis, arthritis health-related characteristics, and arthritis management were calculated. County-level estimates were calculated using a validated statistical modeling method., Results: In 2015, in the 50 states and the District of Columbia, median age-standardized prevalence of arthritis was 23.0% (range: 17.2%-33.6%). Modeled prevalence of arthritis varied considerably by county (range: 11.2%-42.7%). In 13 states that administered the arthritis management module, among adults with arthritis, the age-standardized median percentage of participation in a self-management education course was 14.5% (range: 9.1%-19.0%), being told by a health care provider to engage in physical activity or exercise was 58.5% (range: 52.3%-61.9%), and being told to lose weight to manage arthritis symptoms (if overweight or obese) was 44.5% (range: 35.1%-53.2%). Respondents with arthritis who lived in the quartile of states with the highest prevalences of arthritis had the highest percentages of negative health-related characteristics (i.e., arthritis-attributable activity limitations, arthritis-attributable severe joint pain, and arthritis-attributable social participation restriction; ≥14 physically unhealthy days during the past 30 days; ≥14 mentally unhealthy days during the past 30 days; obesity; and leisure-time physical inactivity) and the lowest percentage of leisure-time walking., Interpretation: The prevalence, health-related characteristics, and management of arthritis varied substantially across states. The modeled prevalence of arthritis varied considerably by county., Public Health Action: The findings highlight notable geographic variability in prevalence, health-related characteristics, and management of arthritis. Targeted use of evidence-based interventions that focus on physical activity and self-management education can reduce pain and improve function and quality of life for adults with arthritis and thus might reduce these geographic disparities.

Early treatment is associated with improved outcomes in patients with rheumatoid arthritis (RA), suggesting that a 'window of opportunity', in which the disease is most susceptible to disease-modifying treatment, exists. Autoantibodies and markers of systemic inflammation can be present long before clinical arthritis, and maturation of the immune response seems to coincide with the development of RA. The pre-arthritis phase associated with symptoms such as as joint pain without clinical arthritis (athralgia) is now hypothesized to fall within the aforementioned window of opportunity. Consequently, disease modulation in this phase might prevent the occurrence of clinically apparent arthritis, which would result in a persistent disease course if untreated. Several ongoing proof-of-concept trials are now testing this hypothesis. This Review highlights the importance of adequate risk prediction for the correct design, execution and interpretation of results of these prevention trials, as well as considerations when translating these findings into clinical practice. The patients' perspectives are discussed, and the accuracy with which RA development can be predicted in patients presenting with arthralgia is evaluated. Currently, the best starting position for preventive studies is proposed to be the inclusion of patients with an increased risk of RA, such as those identified as fulfilling the EULAR definition of 'arthralgia suspicious for progression to RA'.

Focal chondral lesions are a common cause of chronic wrist pain, with no ideal treatment. The authors developed arthroscopic transplantation of osteochondral autograft from lateral femoral condyle to distal radius with satisfactory outcome in 4 consecutive patients between December 2006 and December 2010. In all cases, graft incorporation was completed by 3 months to 4 months postoperation. All patients showed improvement in wrist function with no pain at follow-up at an average of 70.5 months (range 24-116 months). Second-look arthroscopy in 3 patients confirmed the preservation of normal articular cartilage. Patient satisfaction was high with no complications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: In 2016, leisure time physical activity among U.S. adults aged ≥18 years with and without arthritis was studied to provide estimates using contemporary guidelines (2008 Physical Activity Guidelines for Americans) and population-based data (U.S. National Health Interview Survey)., Methods: Estimated prevalence of: (1) meeting aerobic, muscle strengthening, and both aerobic and muscle strengthening guidelines, by arthritis status, from 2008 to 2015; and (2) meeting guidelines across selected sociodemographic characteristics and health status and behaviors, among adults with arthritis, in 2015., Results: In 2015, 36.2%, 17.9%, and 13.7% of adults with arthritis met aerobic, muscle strengthening, and both guidelines, respectively; age-standardized prevalence of meeting each guideline was significantly lower among those with arthritis versus those without (e.g., 41.9% [95% CI=39.5%, 44.3%] and 52.2% [95% CI=51.2%, 53.2%] met the aerobic guideline, respectively; p<0.001). From 2008 to 2015, meeting aerobic guideline rose modestly (3 percentage points) among those with arthritis compared with larger gains (7 percentage points) among those without arthritis; the percentage of adults with arthritis meeting muscle strengthening and both guidelines remained the same in contrast to modest (statistically significant) increases among those without arthritis. Among adults with arthritis, age-standardized percentage meeting each guideline was highest among those with at least a university degree., Conclusions: Percentage meeting each guideline was persistently low among adults with arthritis. The lower prevalence among adults with arthritis versus those without suggests that adults with arthritis need additional strategies to address potential barriers (e.g., pain, psychological distress, inadequate medical support) to physical activity., (Published by Elsevier Inc.)

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There are no nationally representative population-based studies investigating the relationship between physical activity, chronic conditions and multimorbidity (i.e., two or more chronic conditions) in low- and middle-income countries (LMICs), and studies on a multi-national level are lacking. This is an important research gap, given the rapid increase in the prevalence of chronic diseases associated with lifestyle changes in these countries. This cross-sectional study aimed to assess the association between chronic conditions, multimorbidity and low physical activity (PA) among community-dwelling adults in 46 LMICs, and explore the mediators of these relationships., Methods: World Health Survey data included 228,024 adults aged ≥18 years from 46 LMICs. PA was assessed by the International Physical Activity Questionnaire (IPAQ). Nine chronic physical conditions (chronic back pain, angina, arthritis, asthma, diabetes, hearing problems, tuberculosis, visual impairment and edentulism) were assessed. Multivariable logistic regression and mediation analyses were used to assess the association between chronic conditions or multimorbidity and low PA., Results: Overall, in the multivariable analysis, arthritis (OR = 1.12), asthma (1.19), diabetes (OR = 1.33), edentulism (OR = 1.46), hearing problems (OR = 1.90), tuberculosis (OR = 1.24), visual impairment (OR = 2.29), multimorbidity (OR = 1.31; 95% CI = 1.21-1.42) were significantly associated with low PA. More significant associations were observed in individuals aged ≥50 years. In older adults, depression mediated between 5.1% (visual impairment) to 23.5% (angina) of the association between a chronic condition and low PA. Mobility difficulties explained more than 25% of the association for seven of the eight chronic conditions. Pain was a strong mediator for angina (65.9%) and arthritis (64.9%), while sleep problems mediated up to 43.7% (angina) of the association., Conclusions: In LMICs, those with chronic conditions and multimorbidity are significantly less physically active (especially older adults). Research on the efficacy and effectiveness of PA in the management of chronic diseases in LMICs is urgently needed. Targeted promotion of physical activity to populations in LMICs experiencing chronic conditions may ameliorate associated depression, mobility difficulties and pain that are themselves important barriers for initiating or adopting an active lifestyle.

Chikungunya virus (CHIKV) is a re-emerging alphavirus that causes debilitating acute and chronic arthritis. Infection by CHIKV induces a robust immune response that is characterized by production of type I IFNs, recruitment of innate and adaptive immune cells, and development of neutralizing Abs. Despite this response, chronic arthritis can develop in some individuals, which may be due to a failure to eliminate viral RNA and Ag and/or persistent immune responses that cause chronic joint inflammation. In this review, based primarily on advances from recent studies in mice, we discuss the innate and adaptive immune factors that control CHIKV dissemination and clearance or contribute to pathogenesis., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Purpose: Post-traumatic arthritis is common in long-term follow-up of patients undergoing hemi-hamate arthroplasty (HHA). We hypothesize that anatomic mismatch could play a role in the development of arthritis. The purpose of this study is to establish a novel, computed tomography (CT)-based imaging technique for pre-operative assessment in HHA. With this technique, our group aims to identify digits with a high likelihood for anatomical mismatch between the donor graft and recipient interphalangeal joint. Using this technique to eliminate cases with high-likelihood of incongruent anatomy, we hypothesize the rates of arthritis could be reduced., Methods: We conducted a retrospective review of upper extremity CT scans from 2007 to 2014 at our institution. Those studies meeting our inclusion criteria were exported to a clinical radiology software suite. Subsequently, angular and linear measurements of the hamate and potential recipient proximal interphalangeal joints were collected. Angular and linear comparisons were then made between the donor hamate graft and the individual recipient sites. Using pre-established cutoff values, matches were deemed to be inconsistent or consistent., Results: The study included 31 CT scans. The rate of anatomical consistency was low; the small finger was most often consistent (38.7 %) and the index finger was least often consistent (12.9 %). Linear inconsistency was common in all joints besides the small finger; angular inconsistency was most prevalent in the index and long fingers., Conclusions: This novel use of CT scans as a tool for pre-operative HHA planning is a crucial first step in trying to reduce the observed rates of arthritis after HHA.

Aberrant production of proinflammatory cytokines is linked to many autoimmune diseases, and their inhibition by small molecule compounds is considered beneficial. Here, we performed phenotypic screening in IFNγ/LPS-activated RAW264.7, mouse macrophage cells, and discovered AS2677131 and AS2795440 as novel and potent inhibitors of IL-12p40, a subunit of IL-23. Interestingly, these compounds exhibited unique pharmacological activities in their inhibition of the production of IL-12p40, IL-6 and IL-1β but not TNFα in activated macrophages or dendritic cells, and expression of IgM-induced MHC class II on B cells. To reveal these mechanisms, we synthesized two different activity probes which were structurally related to the AS compounds, and identified probe-specific binding proteins, including PIKfyve, a Class III PI kinase. The AS compounds inhibited PIKfyve activity and mimicked the properties of PIKfyve-deficient cells, eventually validating PIKfyve as target molecule. Regarding mechanism, AS2677131 regulated DNA binding activity of c-Rel on IL-12p40 and IL-1β promoter. As expected, a PIKfyve inhibitor prevented the development of arthritis in rats. Taken together, our findings of the novel and potent PIKfyve inhibitors AS2677131 and AS2795440 reveal the critical role of PIKfyve in proinflammatory cytokine production and B cell activation, and may indicate a potential new therapeutic option for treatment of inflammatory diseases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Most vaccines for protection against Mycoplasma bovis disease are made of bacterins, and they offer varying degrees of protection. Our focus is on the development of a subunit-based protective vaccine, and to that end, we have identified 10 novel vaccine candidates. After formulation of these candidates with TriAdj, an experimental tri-component novel vaccine adjuvant developed at VIDO-InterVac, we measured humoral and cell-mediated immune responses in vaccinated animals. In addition, we compared the immune responses after formulation with TriAdj with the responses measured in animals vaccinated with a mix of a commercial adjuvant (Emulsigen™) and 2 of the components of the TriAdj, namely polyinosinic:polycytidylic acid (poly I:C) and the cationic innate defense regulator (IDR) peptide 1002 (VQRWLIVWRIRK). In this latter trial, we detected significant IgG1 humoral immune responses to 8 out of 10 M. bovis proteins, and IgG2 responses to 7 out of 10 proteins. Thus, we concluded that the commercial adjuvant formulated with poly I:C and the IDR peptide 1002 is the best formulation for the experimental vaccine.

Objective: We investigated the associations between DSM-IV mental disorders and subsequent arthritis onset, with and without mental disorder comorbidity adjustment. We aimed to determine whether specific types of mental disorders and increasing numbers of mental disorders were associated with the onset of arthritis later in life., Method: Data were collected using face-to-face household surveys, conducted in 19 countries from different regions of the world (n=52,095). Lifetime prevalence and age at onset of 16 DSM-IV mental disorders were assessed retrospectively with the World Health Organization (WHO) Composite International Diagnostic Interview (WHO-CIDI). Arthritis was assessed by self-report of lifetime history of arthritis and age at onset. Survival analyses estimated the association of initial onset of mental disorders with subsequent onset of arthritis., Results: After adjusting for comorbidity, the number of mood, anxiety, impulse-control, and substance disorders remained significantly associated with arthritis onset showing odds ratios (ORs) ranging from 1.2 to 1.4. Additionally, the risk of developing arthritis increased as the number of mental disorders increased from one to five or more disorders., Conclusion: This study suggests links between mental disorders and subsequent arthritis onset using a large, multi-country dataset. These associations lend support to the idea that it may be possible to reduce the severity of mental disorder-arthritis comorbidity through early identification and effective treatment of mental disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Malunions and nonunions after central or peripheral fractures of the talar body frequently lead to pain and disability. In properly selected, compliant patients without symptomatic arthritis or total avascular necrosis leading to collapse of the talar dome, and sufficient bone stock, secondary anatomic reconstruction with osteotomy along the former fracture plane and preservation of the essential peritalar joints may lead to considerable functional improvement. Bone grafting is needed after resection of a fibrous pseudarthrosis, sclerotic, or necrotic bone. Malunions and nonunions of the lateral or posterior process are treated with excision of the malunited or loose fragments., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Little is known about the degree of articular cartilage degeneration after subtotal/total lateral meniscectomy in patients who later undergo isolated lateral meniscal allograft transplantation (LMAT). It has not yet been studied whether arthritic changes as shown on radiographs were lower during the posttransplantation period than during the meniscus-deficient period., Hypothesis: Articular cartilage will significantly degenerate during the meniscus-deficient period, but the progression in radiographic arthrosis is reduced after LMAT., Study Design: Case series; Level of evidence, 4., Methods: This study retrospectively reviewed 49 patients who underwent subtotal/total lateral meniscectomy before isolated LMAT performed over 1 year later by the same surgeon. International Cartilage Repair Society (ICRS) grades of the femorotibial joint at the time of subtotal/total meniscectomy and at LMAT were compared. Radiographic evaluation was performed at the time of initial meniscectomy, LMAT, and the latest follow-up in 38 patients (after 11 patients whose radiographs showed incomplete ossification at the time of meniscectomy were excluded). Arthrosis, based on Kellgren-Lawrence (K-L) grades, was determined on standing anteroposterior views. Joint space width (JSW) was measured on weightbearing flexion posteroanterior views., Results: Over a mean meniscus-deficient period of 4.5 years (range, 1-13 years), articular cartilage significantly degenerated on the femoral and tibial sides (P < .001). Grade ≥3 degeneration on the lateral tibial plateau was observed in 13 patients (27%) at the time of initial meniscectomy; this incidence doubled to 28 patients (57%) by the time of LMAT. The K-L grades worsened (P < .001) and JSWs narrowed significantly (-0.65 ± 1.09 mm; P = .001) during the mean meniscus-deficient period of 3.1 years. At radiographic assessment, however, the K-L grades (P = .097) and JSWs (4.06 ± 1.19 vs 3.92 ± 1.21 mm; mean difference, -0.14 ± 0.68 mm; P = .213) did not significantly change during the mean posttransplantation period of 3.8 years. The changes in ICRS grade and JSW during the meniscus-deficient period were not associated with age, body mass index, mechanical axis deviation, or Tegner activity level (P > .05 for all relationships)., Conclusion: Patients who underwent isolated LMAT showed substantial articular cartilage degeneration at the time of initial subtotal/total lateral meniscectomy, and this degeneration progressed thereafter. Further progression of radiographic arthrosis was delayed after LMAT., (© 2015 The Author(s).)

Background: The aim of this study was to compare the prosthetic joint infection (PJI) rate after knee revision arthroplasty in two consecutive periods with different antibiotic prophylaxis: short (one day) versus long (five days)., Methods: From January 2007 to September 2010 antibiotic prophylaxis consisted of 800 mg of teicoplanin and 2 g of ceftazidime intravenously and 1 g of ceftazidime two hours after the first dose. From October 2010, it was prolonged post-operatively using vancomycin and ceftazidime intravenously until the fifth day., Results: During the study period, 341 revision surgeries met the inclusion criteria. The PJI rate was lower in the long-prophylaxis group (2.2% versus 6.9%, p=0.049). Prolonged post-operative antibiotic treatment was the only variable associated independently with a lower rate of PJI (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.07-0.99).

Objectives: To study, in normal cartilage explants (CEs) challenged with lipopolysaccharide (LPS), the temporal effects (at 48 and 96h) of leukocyte- and platelet-rich gel (L-PRG) and pure platelet-rich gel (P-PRG) supernatants on the production and degradation of platelet-associated growth factors (GFs) (platelet-derived GF isoform BB [PDGF-BB] and transforming growth factor beta-1 [TGF-β1]), pro-inflammatory (tumour necrosis factor alpha [TNF-α]) and anti-inflammatory cytokines (interleukin 4 [IL-4] and IL-1 receptor antagonist [IL-1ra])., Methods: CEs from six horses were challenged with LPS and cultured for 96h with L-PRG and P-PRG supernatants at concentrations of 25% and 50%, respectively. The CE culture medium was changed every 48h and used for determination, by ELISA, of PDGF-BB, TGF-β1, TNF-α, IL-4 and IL-1ra., Results: Both the 25% and 50% PRG supernatants produced a different molecular profile in the culture media, unlike that of the CE challenged with LPS only. 50% L-PRG produced the most sustained release of growth factors and anti-inflammatory cytokines, although it produced the highest TNF-α release. PDGF-BB was significantly correlated with IL-1ra and TNF-α concentrations, whereas TNF-α was correlated with IL-4., Conclusions: 50% L-PRG supernatant produced a more sustained concentration of growth factors and anti-inflammatory cytokines than the other hemoderivatives evaluated. This substance could be evaluated in animal models of arthritis or in patients with arthropathies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Left untreated, scapholunate dissociation can lead to posttraumatic wrist arthritis. Multiple surgical procedures have been designed to reduce the scapholunate interval, restore normal wrist kinematics, and prevent the development of arthritis. Unfortunately, current surgical procedures have not been shown to consistently maintain radiographic alignment at long-term follow-up and result in decreased wrist range of motion and strength compared with the contralateral side. The purpose of this article is to review the current reconstructive options for scapholunate ligament tears without evidence of radiographic arthritis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Non-communicable diseases (NCDs) are of increasing concern in low- and middle-income countries (LMICs) affected humanitarian crises. Humanitarian agencies and governments are increasingly challenged with how to effectively tackle NCDs. Reviewing the evidence of interventions for NCDs in humanitarian crises can help guide future policies and research by identifying effective interventions and evidence gaps. The aim of this paper is to systematically review evidence on the effectiveness of interventions targeting NCDs during humanitarian crises in LMICs., Methods: A systematic review methodology was followed using PRISMA standards. Studies were selected on NCD interventions with civilian populations affected by humanitarian crises in low- and middle-income countries. Five bibliographic databases and a range of grey literature sources were searched. Descriptive analysis was applied and a quality assessment conducted using the Newcastle-Ottawa Quality Assessment Scale for observational studies and the Cochrane Risk of Bias Tool for experimental studies., Results: The search yielded 4919 references of which 8 studies met inclusion criteria. Seven of the 8 studies were observational, and one study was a non-blinded randomised-controlled trial. Diseases examined included hypertension, heart failure, diabetes mellitus, chronic kidney disease, thalassaemia, and arthritis. Study settings included locations in the Middle East, Eastern Europe, and South Asia. Interventions featuring disease-management protocols and/or cohort monitoring demonstrated the strongest evidence of effectiveness. No studies examined intervention costs. The quality of studies was limited, with a reliance on observational study designs, limited use of control groups, biases associated with missing data and inadequate patient-follow-up, and confounding was poorly addressed., Conclusions: The review highlights the extremely limited quantity and quality of evidence on this topic. Interventions that incorporate standardisation and facilitate patient follow-up appear beneficial. However, substantially more research is needed, including data on costs.

The concept of using phytochemicals has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biological effects of this molecule. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compound also exerts its beneficial effects by modulating different signalling molecules including transcription factors, chemokines, cytokines, tumour suppressor genes, adhesion molecules, microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metabolism and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clinical biology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

An estimated 12% of patients seeking surgical intervention for symptomatic arthritis have an etiology of post-traumatic arthritis (PTA). The onset of PTA is rapid in the setting of articular fracture (AF). The investigation began with development of a murine model of a closed AF that develops PTA. In the process of characterizing this model a technique was developed for assessing quantitative synovial fluid biomarker concentrations. The work began with observations of the natural history of PTA development in the C57BL/6 strain of mice. A species of mice (MRL/MpJ) was found that is protected from PTA after AF. Further work identified key differences between mouse strains that did and did not develop PTA. This knowledge led to an intervention based on anti-cytokine (interleukin 1 receptor antagonist, (IL-1Ra) delivery in the C57BL/6 strain of mice that successfully prevented PTA following AF. This success in preventing PTA in the murine model has elucidated several important clinical implications: 1) Pro-inflammatory cytokines play an important role in the development of PTA after joint injury, 2) Pharmacologic intervention can lessen the severity of PTA after an AF, and 3) The murine AF model of joint injury provides a novel means of studying mechanisms of PTA development., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Haemophilia prophylaxis is superior to on-demand treatment to prevent joint damage. 'High-dose prophylaxis' as used in Sweden is more effective in preventing arthropathy than an 'intermediate-dose regimen' (the Netherlands) and the Canadian tailored primary prophylaxis. Prophylaxis may reduce the risk of developing inhibitors. There is no difference in inhibitor risk between plasma derived and recombinant factor VIII (rFVIII) products but the Rodin study showed increased risk with second-generation rFVIII products. MRI is a new and very sensitive tool to detect the symptoms of early arthropathy but some results (soft tissue changes in 'bleed-free joints') still need to be investigated. Ultrasound is a very helpful method to aid diagnosis especially during the acute phase of a bleed. The risk of infection with central venous access remains a matter of debate. A fully implanted central venous access device (CVAD) has a significant lower risk of infection compared to external CVADs. Patient's age under 6 yr and inhibitor presence are additional risk factors for infections. The role of arteriovenous fistulae needs to be investigated because significant complications have been reported. Disease-specific quality of life instruments are complementary to generic instruments evaluating QoL in patients with haemophilia and have become important health outcome measures., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Increased IL-17-producing helper T (Th17) cells have been observed in patients with rheumatoid arthritis (RA). The retinoic-acid-related orphan nuclear receptor (RORγt) is the master regulator of Th17 cells. Our previous research showed that FC99 possesses anti-inflammation activity. However, to date the effects of FC99 on RORγt expression in Th17 cell differentiation have not been investigated yet. In the present study, we found that FC99 significantly attenuated arthritis-like symptoms, i.e., suppressing the development of paw edema in zymosan-induced arthritis (ZIA) mice. H&E staining showed that the infiltration of inflammatory cells in ankle synovial tissues was significantly suppressed. FC99 also reduced the mRNA levels of pro-inflammatory cytokines in ankle synovial tissues as shown by Q-PCR analysis. The protein levels of the pro-inflammatory cytokines in sera were also suppressed after FC99 treatment. Moreover, FC99 decreased the RORγt mRNA level in spleen tissues. Th17 cell percentage was significantly decreased in spleens and draining lymph nodes (dLNs). The mRNA and protein levels of IL-17A and IL-23 were reduced after FC99 treatment in ZIA mice. Furthermore, in vitro experiments showed that FC99 inhibited the expression of IL-6 in LPS-induced RAW264.7 cells and BMDCs. Moreover, FC99 significantly inhibited the RORγt expression in PMA-induced CD4(+) T cells and LPS-induced RAW264.7 cells. These data indicate that FC99 improves arthritis-like pathological symptoms in vivo and in vitro, which might be related to the inhibition of RORγt expression in Th17 cells. Our findings suggest that FC99 may be a potential therapeutic candidate for the treatment of RA and other inflammatory disorders., (© The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)

Introduction: Interleukin (IL)-36α is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), its ligand IL-36α and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36α induces MAP-kinase and NFκB signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines., Methods: To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36α signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36α was tested in murine and human osteoclast assays., Results: Diseased mice showed an increased expression of IL-36R and IL-36α in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays., Conclusion: Thus we conclude that IL-36α does not affect the development of inflammatory arthritis.