Harmonising knee pain patient-reported outcomes: a systematic literature review and meta-analysis of Patient Acceptable Symptom State (PASS) and individual participant data (IPD).

OBJECTIVE: In order to facilitate data pooling between studies, we explored harmonisation of patient-reported outcome measures (PROMs) in people with knee pain due to osteoarthritis or knee trauma, using the Patient Acceptable Symptom State scores (PASS) as a criterion. METHODS: We undertook a systematic literature review (SLR) of PASS scores, and performed individual participant data (IPD) analysis of score distributions from concurrently completed PROM pairs. Numerical rating scales (NRS), visual analogue scales, KOOS and WOMAC pain questionnaires were standardised to 0 to 100 (worst) scales. Meta-regression explored associations of PASS. Bland Altman plots compared PROM scores within individuals using IPD from WebEx, KICK, MenTOR and NEKO studies. RESULTS: SLR identified 18 studies reporting PASS in people with knee pain. Pooled standardised PASS was 27 (95% CI: 21 to 35; n = 6,339). PASS was statistically similar for each standardised PROM. Lower PASS was associated with lower baseline pain (ß = 0.49, P = 0.01) and longer time from treatment initiation (Q = 6.35, P = 0.04). PASS scores were lowest in ligament rupture (12, 95% CI: 11 to 13), but similar between knee osteoarthritis (31, 95% CI: 26 to 36) and meniscal tear (27, 95% CI: 20 to 35). In IPD, standardised PROMs each revealed similar group mean scores, but scores within individuals diverged between PROMs (LoA between -7 to -38 and +25 to 52). CONCLUSION: Different standardised PROMs give similar PASS thresholds in group data. PASS thresholds may be affected more by patient and treatment characteristics than between PROMs. However, different PROMs give divergent scores within individuals, possibly reflecting different experiences of pain.

Metabolic syndrome and osteoarthritis pain: common molecular mechanisms and potential therapeutic implications.

There is no clear evidence from epidemiological and animal studies of a direct link between metabolic syndrome (MetS) and cartilage degeneration in osteoarthritis (OA) once body mass index (BMI) has been considered. However, recent epidemiological studies indicate a significant role for MetS in predicting increased knee pain after adjustment for BMI. This implies there are mechanisms that underlie both MetS and OA pain. In addition to the common systemic inflammatory and pro-inflammatory components of the two disorders, there are other molecular mechanisms that may link MetS and OA pain. These include regulation of the endocannabinoid system, activation of the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1) channel and gut dysbiosis. These three mechanisms are interlinked and are the target of therapeutic dietary or pharmacological interventions. Exploring and understanding these mechanisms may help improve outcomes for both pain and metabolic comorbidities affecting individuals with OA.

Microarray analyses of the dorsal root ganglia support a role for innate neuro-immune pathways in persistent pain in experimental osteoarthritis.

OBJECTIVE: Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: "post-surgical pain", "early-stage OA pain", and "persistent OA pain". DESIGN: We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n = 3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: "post-surgical pain" (sham and DMM 4-week vs 14-week old naïve), "early OA pain" (DMM 4-week vs sham 4-week), and "persistent OA pain" (DMM 8- and 16-week vs naïve and sham 8- and 16-week). 'Top hit' genes were defined as P < 0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as P < 0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG. RESULTS: For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for "post-surgical pain"; 2/14 for "early OA pain"; 8/37 for "persistent OA pain"). Overlap between groups was limited, with 8 genes differentially regulated (P < 0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (P = 0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (P = 0.002 vs Sham). CONCLUSION: These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA.

Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort.

OBJECTIVES: We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain in the Community cohort. METHOD: 1471 participants reported knee pain at baseline and responded to a 1-year follow-up questionnaire, of whom 204 underwent pressure pain detection thresholds (PPTs) and radiographic assessment at baseline. Logistic and linear regression models estimated the relative risks (RRs) and associations (ß) between self-report traits, PPTs and pain outcomes. Discriminative performance for each predictor was compared using receiver-operator characteristics (ROC) curves. RESULTS: Baseline Central Mechanisms trait scores predicted pain persistence (Relative Risk, RR = 2.10, P = 0.001) and persistent pain severity (ß = 0.47, P < 0.001), even after adjustment for age, sex, BMI, radiographic scores and symptom duration. Baseline joint-line PPTs also associated with pain persistence (RR range = 0.65 to 0.68, P < 0.02), but only in univariate models. Lower baseline medial joint-line PPT was associated with persistent pain severity (ß = -0.29, P = 0.013) in a fully adjusted model. The Central Mechanisms trait model showed good discrimination of pain persistence cases from resolved pain cases (Area Under the Curve, AUC = 0.70). The discrimination power of other predictors (PPTs (AUC range = 0.51 to 0.59), radiographic OA (AUC = 0.62), age, sex and BMI (AUC range = 0.51 to 0.64), improved significantly (P < 0.05) when the central mechanisms trait was included in each logistic regression model (AUC range = 0.69 to 0.74). CONCLUSION: A simple summary self-report Central Mechanisms trait score may indicate a contribution of central mechanisms to poor knee pain prognosis.

Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population.

OBJECTIVE: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. METHODS: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. RESULTS: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. CONCLUSIONS: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.

Contribution of central and peripheral risk factors to prevalence, incidence and progression of knee pain: a community-based cohort study.

AIM: To explore risk factors that may influence knee pain (KP) through central or peripheral mechanisms. METHODS: A questionnaire-based prospective community cohort study with KP defined as pain in or around a knee on most days for at least a month. Baseline prevalence, and one year incidence and progression (KP worsening) were examined. Central (e.g., Pain Catastrophizing Scale (PCS)) and peripheral (e.g., significant injury) risk factors were examined. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Proportional risk contribution (PRC) was estimated using receiver-operator-characteristic (ROC) analysis. RESULTS: Of 9506 baseline participants, 4288 (45%) had KP (men 1826; women, 2462). KP incidence was 12% (men 11%, women 13%), and KP progression 19% (men 16%, women 21%) at one year. While both central and peripheral factors contributed to prevalence, central factors contributed more to progression, and peripheral factors more to incidence of KP. For example, although PCS (OR 2.06, 95% CI 1.88-2.25) and injury (5.62, 4.92-6.42) associated with KP prevalence, PCS associated with progression (2.27, 1.83-2.83) but not incidence (1.14, 0.86-1.52), whereas injury more strongly associated with incidence (69.27, 24.15-198.7) than progression (2.52, 1.48-4.30). The PRC of central and peripheral factors were 19% and 23% for prevalence, 14% and 29% for incidence, and 29% and 5% for progression, respectively. CONCLUSIONS: Both central and peripheral risk factors influence KP but relative contributions may differ in terms of development (mainly peripheral) and progression (mainly central). Further study of such relative contributions may inform primary and secondary prevention strategies.

Validation of an inhibition enzyme-linked immunosorbent assay system for the diagnosis of Toxoplasma gondii infection in buffaloes (Bubalus bubalis). / Validación de un sistema inmunoenzimático de inhibición de un anticuerpo para el diagnóstico de infección por Toxoplasma gondii en búfalos (Bubalus bubalis).

Toxoplasmosis is one of the most widespread zoonoses in the world, due to the existence of a wide variety of Toxoplasma gondii hosts, which include several domestic animal species. In Cuba, there is sustained production of the Bubalus species, which is highly adaptable and disease resistant, although it has been identified as a reservoir for a range of aetiological agents. Several countries have reported buffaloes as the intermediate host of T. gondii, noting the need to carry out epidemiological studies and confirm the possible presence of this parasitic infection in the Bubalus species. The current study was conducted to validate an inhibition enzyme-linked immunosorbent assay (i/ELISA) system for the diagnosis of T. gondii infection in buffaloes (Bubalus bubalis). This involved evaluating its performance in relation to that of a latex agglutination test. With buffalo sera, the i/ELISA assay showed a sensitivity of 100%, a specificity of 99.5%,and a concordance of 0.99 (considered very good) with respect to the reference diagnostic method. The conclusion is that i/ELISA performs extremely well as a serological test for the diagnosis of T. gondii in buffaloes.

La toxoplasmose est l'une des zoonoses les plus répandues dans le monde, ce qui s'explique par le très large spectre d'hôtes de Toxoplasma gondii, dont plusieurs espèces d'animaux domestiques. À Cuba, les buffles font l'objet d'un élevage durable et présentent de bonnes aptitudes d'adaptation et de résistance aux maladies, bien que cette espèce joue un rôle avéré de réservoir pour un certain nombre d'agents pathogènes. Des rapports émanant de plusieurs pays ont fait état du rôle joué par les buffles en tant qu'hôtes intermédiaires de T. gondii, d'où la nécessité d'effectuer des études épidémiologiques afin de confirmer la présence éventuelle de cette parasitose chez cette espèce. Les auteurs présentent des résultats d'une étude de validation d'une méthode immuno-enzymatique d'inhibition des anticorps pour le diagnostic de T. gondii chez le buffle (Bubalusbubalis). Pour ce faire, les performances de cette méthode ont été évaluées par rapport à celles du test d'agglutination au latex. La comparaison à partir de sérums de buffles a montré que la sensibilité de l'épreuve immuno-enzymatique était de 100 % et sa spécificité de 99,5%, avec une concordance par rapport à la méthode de référence de 0,99, ce qui est considéré un très bon résultat. Cette étude démontre l'aptitude de l'ELISA d'inhibition pour le diagnostic sérologique de T. gondii chez le buffle et conclut à son excellente performance diagnostique.

La toxoplasmosis es una de las zoonosis más difundidas en el mundo debido a que existe una amplia variedad de hospedadores de Toxoplasma gondii, entre los que se encuentran varias de las especies de animales domésticos. En Cuba, la especie bufalina se produce de manera sostenida con buena adaptabilidad y resistencia a las enfermedades, aunque se ha identificado como reservorio de diversos agentes etiológicos. En varios países se ha informado que los búfalos son hospedadores intermediarios de T. gondii y se ha indicado la necesidad derealizar estudios epidemiológicos y de comprobar la posible presencia de dicha parasitosis en esta especie. Este trabajo se realizó para validar un sistema inmunoenzimático de inhibición de un anticuerpo (ELISA/i) para el diagnósticode infección por T. gondii en búfalos (Bubalus bubalis). Para ello, se evaluó su rendimiento respecto a una prueba de aglutinación por látex. Frente a sueros de búfalo, el sistema inmunoenzimático demostró tener una sensibilidad del 100%, una especificidad del 99,5% y una concordancia de 0,99, considerada muy buena, respecto al método de diagnóstico de referencia. Se concluye que el ELISA/i permite el diagnóstico serológico de T. gondii en búfalos con un excelente rendimiento diagnóstico.

Gut microbiome diversity and high-fibre intake are related to lower long-term weight gain.

BACKGROUND: Cross-sectional studies suggest that the microbes in the human gut have a role in obesity by influencing the human body's ability to extract and store calories. The aim of this study was to assess if there is a correlation between change in body weight over time and gut microbiome composition. METHODS: We analysed 16S ribosomal RNA gene sequence data derived from the faecal samples of 1632 healthy females from TwinsUK to investigate the association between gut microbiome measured cross-sectionally and longitudinal weight gain (adjusted for caloric intake and baseline body mass index). Dietary fibre intake was investigated as a possible modifier. RESULTS: Less than half of the variation in long-term weight change was found to be heritable (h2=0.41 (0.31, 0.47)). Gut microbiota diversity was negatively associated with long-term weight gain, whereas it was positively correlated with fibre intake. Nine bacterial operational taxonomic units (OTUs) were significantly associated with weight gain after adjusting for covariates, family relatedness and multiple testing (false discovery rate <0.05). OTUs associated with lower long-term weight gain included those assigned to Ruminococcaceae (associated in mice with improved energy metabolism) and Lachnospiraceae. A Bacterioides species OTU was associated with increased risk of weight gain but this appears to be driven by its correlation with lower levels of diversity. CONCLUSIONS: High gut microbiome diversity, high-fibre intake and OTUs implicated in animal models of improved energy metabolism are all correlated with lower term weight gain in humans independently of calorie intake and other confounders.

Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling.

BACKGROUND/OBJECTIVES: Higher visceral fat mass (VFM) is associated with an increased risk for developing cardio-metabolic diseases. The mechanisms by which an unhealthy diet pattern may influence visceral fat (VF) development has yet to be examined through cutting-edge multi-omic methods. Therefore, our objective was to examine the dietary influences on VFM and identify gut microbiome and metabolite profiles that link food intakes to VFM. SUBJECTS/METHODS: In 2218 twins with VFM, food intake and metabolomics data available we identified food intakes most strongly associated with VFM in 50% of the sample, then constructed and tested the 'VFM diet score' in the remainder of the sample. Using linear regression (adjusted for covariates, including body mass index and total fat mass), we investigated associations between the VFM diet score, the blood metabolomics profile and the fecal microbiome (n=889), and confirmed these associations with VFM. We replicated top findings in monozygotic (MZ) twins discordant (⩾1 s.d. apart) for VFM, matched for age, sex and the baseline genetic sequence. RESULTS: Four metabolites were associated with the VFM diet score and VFM: hippurate, alpha-hydroxyisovalerate, bilirubin (Z,Z) and butyrylcarnitine. We replicated associations between VFM and the diet score (beta (s.e.): 0.281 (0.091); P=0.002), butyrylcarnitine (0.199 (0.087); P=0.023) and hippurate (-0.297 (0.095); P=0.002) in VFM-discordant MZ twins. We identified a single species, Eubacterium dolichum to be associated with the VFM diet score (0.042 (0.011), P=8.47 × 10-5), VFM (0.057 (0.019), P=2.73 × 10-3) and hippurate (-0.075 (0.032), P=0.021). Moreover, higher blood hippurate was associated with elevated adipose tissue expression neuroglobin, with roles in cellular oxygen homeostasis (0.016 (0.004), P=9.82x10-6). CONCLUSIONS: We linked a dietary VFM score and VFM to E. dolichum and four metabolites in the blood. In particular, the relationship between hippurate, a metabolite derived from microbial metabolism of dietary polyphenols, and reduced VFM, the microbiome and increased adipose tissue expression of neuroglobin provides potential mechanistic insight into the influence of diet on VFM.

Knee pain and related health in the community study (KPIC): a cohort study protocol.

BACKGROUND: The incidence, progression and related risk factors for recent-onset knee pain (KP) remain uncertain. This study aims to examine the natural history of KP including incidence and progression and to identify possible phenotypes and their associated risk factors. METHODS: A prospective community-based cohort of men and women aged 40 years or over within the East Midlands region (UK) will be recruited via a postal questionnaire from their general practices. The questionnaire will enquire about: presence and onset of KP; pain severity (0­10 numerical rating scale (NRS)); pain catastrophizing and neuropathic-like pain (NP) using the painDETECT questionnaires (definite NP scores ≥19­38); risk factors for KP and/ or osteoarthritis (OA) (age, body mass index, constitutional knee alignment, nodal OA, index: ring finger length (2D4D) ratio); quality of life (SF12); and mental health (Hospital Anxiety and Depression Scale). Clinical assessments will be undertaken in a sample of 400 participants comprising three groups: early KP (≤3 year's duration), established KP (>3 years) and no KP. Assessments will include knee radiographs (standing semi-flexed and 30(0) skyline views); knee ultrasound (synovial effusion, hypertrophy, and Doppler activity); quantitative sensory testing; muscle strength (quadriceps, hip abductor, and hand-grip); balance; gait analysis (GAITrite); and biomarker sampling. A repeat questionnaire will be sent to responders at years 1 and 3. The baseline early KP group will undergo repeat assessments at year 1 (apart from radiographs) and year 3 (with radiographs). Any incident KP individuals identified at year 1 or 3 questionnaires will have clinical and radiographic assessments at the respective time points. DISCUSSION: Baseline data will be used to examine risk factors for early onset KP and to identify KP phenotypes. Subsequent prospective data, at least to Year 3, will allow examination of the natural history of KP and risk factors for incidence and progression. TRIAL REGISTRATION: The study was registered on the clinicaltrials.gov portal: NCT02098070) on the 14th of March 2014.

Platelet-Rich Plasma for the Treatment of Photodamage of the Skin of the Hands. / Plasma rico en plaquetas en el tratamiento del fotodaño cutáneo en las manos.

BACKGROUND: Platelet-rich plasma (PRP) provides growth factors that stimulate fibroblast activation and induce the synthesis of collagen and other components of the extracellular matrix. The objective of this study was to evaluate the effect of PRP in the treatment of photodamage of the skin of the hands. MATERIAL AND METHODS: Experimental study enrolling persons with photoaged skin on the dorsum of the hands (Glogau photoaging scale, type III, or Fitzpatrick wrinkle classification, type II) were included between August 2012 and January 2013. A histological comparison was made of skin biopsies taken before and after the application of PRP to the skin of the dorsum of the hands. RESULTS: The mean (SD) age of the 18 women enrolled was 47.9 (4.3) years. Histological analysis showed an increase in the number of fibroblasts (P<.001), number of vessels (P<.001), and collagen density (P=.27). These changes produced significant improvements in the Fitzpatrick wrinkle and elastosis scale (P<.001) and in the Glogau photoaging scale (P=.01). CONCLUSIONS: PRP induced a reduction in the manifestations of skin aging, including an improvement in wrinkles and elastosis.

KIR haplotypes are associated with late-onset type 1 diabetes in European-American families.

Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups.

Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors.

OBJECTIVE: To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction. METHODS: The prognostic model was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study. RESULTS: In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study. CONCLUSIONS: Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.

Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis.

OBJECTIVE: To evaluate the role of three cartilage-derived biomarkers on osteoarthritis (OA): urinary C-terminal telopeptide (uCTX-II), serum cartilage oligomeric protein (sCOMP), and serum MMP degraded type II collagen (sC2M). SUBJECTS AND METHODS: Samples from 3582 individuals from the Rotterdam Study, the Genetics osteoArthritis and Progression (GARP), the Chingford Study and the TwinsUK cohort were assayed using enzyme-linked immune sorbent assays. Log10 of concentration levels were correlated with risk of hip, hand and knee OA, hip and knee OA severity and incidence, and progression of knee OA, adjusting for age, gender and body mass index (BMI). Results were meta-analysed to assess overall significance. RESULTS: After adjusting for covariates, sCOMP was associated with knee OA and hip and knee OA incidence. Furthermore, sC2M was associated with knee OA incidence and progression. After adjustment for multiple tests (Bonferroni P < 0.002) only the association between sCOMP and knee OA remained significant (odds ratio (OR) = 3.26 (95%CI 1.63-10.1) P = 0.0008 for each standard deviation (SD) increase in biomarker levels). Levels of uCTX-II were significantly associated with risk of hand, hip and knee OA, progression and incidence of knee OA. A receiver operating characteristics (ROC) analysis showed a consistent improvement in prediction of knee OA progression from an average area under the curve (AUC) is 0.646 for age, sex and BMI alone to an AUC = 0.668 including uCTX-II for prediction. CONCLUSIONS: uCTX-II is the most informative biochemical marker for prediction of OA. Both sCOMP and C2M showed some association with OA, thus indicating that they are descriptive of disease activity.

Modelling the role of enzymatic pathways in the metabolism of docosahexaenoic acid by monocytes and its association with osteoarthritic pain.

Chronic pain is a major cause of disability and suffering in osteoarthritis (OA) patients. Endogenous specialised pro-resolving molecules (SPMs) curtail pro-inflammatory responses. One of the SPM intermediate oxylipins, 17-hydroxydocasahexaenoic acid (17-HDHA, a metabolite of docosahexaenoic acid (DHA)), is significantly associated with OA pain. The aim of this multidisciplinary work is to develop a mathematical model to describe the contributions of enzymatic pathways (and the genes that encode them) to the metabolism of DHA by monocytes and to the levels of the down-stream metabolites, 17-HDHA and 14-hydroxydocasahexaenoic acid (14-HDHA), motivated by novel clinical data from a study involving 30 participants with OA. The data include measurements of oxylipin levels, mRNA levels, measures of OA severity and self-reported pain scores. We propose a system of ordinary differential equations to characterise associations between the different datasets, in order to determine the homeostatic concentrations of DHA, 17-HDHA and 14-HDHA, dependent upon the gene expression of the associated metabolic enzymes. Using parameter-fitting methods, local sensitivity and uncertainty analysis, the model is shown to fit well qualitatively to experimental data. The model suggests that up-regulation of some ALOX genes may lead to the down-regulation of 17-HDHA and that dosing with 17-HDHA increases the production of resolvins, which helps to down-regulate the inflammatory response. More generally, we explore the challenges and limitations of modelling real data, in particular individual variability, and also discuss the value of gathering additional experimental data motivated by the modelling insights.

Osteoarthritis in the UK Armed Forces: a review of its impact, treatment and future research.

Within the UK Armed Forces, musculoskeletal injuries account for over half of all medical downgrades and discharges. Data from other Armed Forces show that osteoarthritis (OA), more common in military personnel, is likely to contribute to this, both in its primary form and following injury (post-traumatic OA, PTOA), which typically presents in the third or fourth decade. OA is not a progressive 'wear and tear' disease, as previously thought, but a heterogenous condition with multiple aetiologies and modulators, including joint damage, abnormal morphology, altered biomechanics, genetics, low-grade inflammation and dysregulated metabolism. Currently, clinical diagnosis, based on symptomatic or radiological criteria, is followed by supportive measures, including education, exercise, analgesia, potentially surgical intervention, with a particular focus on exercise rehabilitation within the UK military. Developments in OA have led to a new paradigm of organ failure, with an emphasis on early diagnosis and risk stratification, prevention strategies (primary, secondary and tertiary) and improved aetiological classification using genotypes and phenotypes to guide management, with the introduction of biological markers (biomarkers) potentially having a role in all these areas. In the UK Armed Forces, there are multiple research studies focused on OA risk factors, epidemiology, biomarkers and effectiveness of different interventions. This review aims to highlight OA, especially PTOA, as an important diagnosis to consider in serving personnel, outline current and future management options, and detail current research trends within the Defence Medical Services.

Sustainable use of giant reed to produce industrialized enzymes.

The giant reed (Arundo donax) is a fast-growing plant adapted to different climatic and soil conditions; although its origin is Asian, the species has spread throughout the world. During its development, it consumes three times more water than typical native vegetation and is responsible for changing the landscape of riparian areas; the high biomass productivity and the annual harvest period make this crop an alternative to produce and/or extract industrial bioproducts. The main objective of this research was to evaluate the feasibility of using giant reed in a bioprocess that produces enzymes by a solid-state fermentation experiment, four fungal species were tested (Aspergillus niger GH1, Aspergillus niger PSH, Trichoderma harzianum, and Rhizopus oryzae); enzyme activities were performed using reported methodologies varying only reaction volumes. The A. niger GH1 and PSH strains were the best adapted to the plant material, A. niger GH1 was capable to produce 4 of the 5 evaluated enzymes (cellulase-endoglucanase (174.39 ± 19.62 U/L), xylanase (1313.31 ± 39.25 U/L), invertase (642.22 ± 23.55 U/L), and polyphenol oxidase (6094.01 ± 306.54) while A. niger PSH was able to produce 3 of the 5 evaluated enzymes (cellulase-endoglucanase (147.09 ± 13.88 U/L), xylanase (1307.76 ± 31.40 U/L), and invertase (603.92 ± 3.14 U/L).

Use of class I and class II HLA loci for predicting age at onset of type 1 diabetes in multiple populations.

AIMS/HYPOTHESIS: The study aimed to assess, in multiple populations, the role of HLA alleles on early and late age at onset of type 1 diabetes. METHODS: Stepwise linear regression models were used to determine which HLA class I and class II risk alleles to include. High-resolution genotyping data for patients from the Type 1 Diabetes Genetics Consortium (T1DGC) collection (n = 2,278) and four independent cohorts from Denmark, Sardinia and the USA (Human Biological Data Interchange [HBDI] and Joslin Diabetes Center) (n = 1,324) (total n = 3,602) were used to assess the role of HLA variation on age of onset and predict early onset (age ≤ 5 years) and late onset (age ≥ 15 years) of type 1 diabetes. RESULTS: In addition to carriage of HLA class I alleles A*24:02, B*39:06, B*44:03 and B*18:01, HLA class II DRB1-DQB1 loci significantly contributed to age at onset, explaining 3.4% of its variance in the combined data. HLA genotypes, together with sex, were able to predict late onset in all cohorts studied, with AUC values ranging from 0.58 to 0.63. Similar AUC values (0.59-0.70) were obtained for early onset for most cohorts, except in the Sardinian study, in which none of the models tested had significant predictive power. CONCLUSIONS/INTERPRETATION: HLA associations with age of onset are consistent across most white populations and HLA information can predict some of the risk of early and late onset of type 1 diabetes. Considerable heterogeneity was observed between Sardinian and other populations, particularly with regard to early age of onset.

Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice.

AIMS/HYPOTHESIS: Liver X receptor (LXR)α regulates the genes involved in cholesterol, fatty acid and glucose metabolism. Soy protein (SP) consumption reduces the hepatic accumulation of cholesterol and triacylglycerol, and improves insulin sensitivity. However, it is not known whether these effects are mediated via LXRα. We therefore investigated whether the consumption of SP regulates metabolic changes in cholesterol metabolism and insulin sensitivity via LXRα. METHODS: Wild-type (WT) and Lxrα(-/-) (Lxrα, also known as Nr1h3) mice were fed an SP diet with or without cholesterol for 28 days. The expression of LXRα target genes was measured in liver and intestine, as were hepatic lipid content and faecal bile acid concentration. Oral glucose and insulin tolerance tests were also performed. Hepatocytes were used to study the effect of isoflavones on LXR activity. RESULTS: The livers of WT and Lxrα(-/-) mice fed an SP high-cholesterol diet showed less steatosis than those fed casein. The SP diet increased the expression of the ATP-binding cassette (ABC) sub-family genes Abca1, Abcg5 and Abcg8 in the liver and intestine, as well as increasing total faecal bile acid excretion and insulin sensitivity in WT mice compared with mice fed a casein diet. However, these effects of SP were not observed in Lxrα(-/-) mice. The SP isoflavone, genistein, repressed the activation of LXRα target genes by T0901317, whereas it stimulated the activation of LXRß target genes. The AMP-activated protein kinase inhibitor, compound C, had the opposite effects to those of genistein. CONCLUSIONS/INTERPRETATION: Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRß, resulting in different biological effects for each LXR isoform.

GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc degeneration in Northern European women.

OBJECTIVE: Lumbar disc degeneration (LDD) is a serious social and medical problem which has been shown to be highly heritable. It has similarities with peripheral joint osteoarthritis (OA) in terms of both epidemiology and pathologic processes. A few known genetic variants have been identified using a candidate gene approach, but many more are thought to exist. GDF5 is a gene whose variants have been shown to play a role in skeletal height as well as predisposing to peripheral joint OA. In vitro, the gene product growth differentiation factor 5 has been shown to promote growth and repair of animal disc. This study was undertaken to investigate whether the GDF5 gene plays a role in LDD. METHODS: We investigated whether the 5' upstream single-nucleotide polymorphism (SNP) variant rs143383 was associated with LDD, using plain radiography and magnetic resonance imaging to identify disc space narrowing and osteophytes, in 5 population cohorts from Northern Europe. RESULTS: An association between LDD and the SNP rs143383 was identified in women, with the same risk allele as in knee and hip OA (odds ratio 1.72 [95% confidence interval 1.15-2.57], P = 0.008). CONCLUSION: Our findings in 5 population cohorts from Northern Europe indicate that a variant in the GDF5 gene is a risk factor for LDD in women. Many more such variants are predicted to exist, but this result highlights the growth and differentiation cellular pathway as a possible route to a better understanding of the process behind lumbar disc degeneration.