Acute loading has minor influence on human articular cartilage gene expression and glycosaminoglycan composition in late-stage knee osteoarthritis: a randomised controlled trial.

OBJECTIVE: Osteoarthritis (OA) remains clinically challenging. Regular physical exercise improves symptoms though it is unclear whether exercise influences cartilage at the molecular level. Thus, we aimed to determine the effect of acute loading on gene expression and glycosaminoglycan (GAG) content in human OA cartilage. DESIGN: Patients with primary knee OA participated in this single-blind randomised controlled trial initiated 3.5 h prior to scheduled joint replacement surgery with or without loading by performing one bout of resistance exercise (one-legged leg press). Cartilage from the medial tibia condyle was sampled centrally, under the meniscus, and from peripheral osteophytes. Samples were analysed for gene expression by real-time reverse transcriptase polymerase chain reaction, and hyaluronidase-extracted matrix was analysed for GAG composition by immuno- and dimethyl-methylene blue assays. RESULTS: Of 32 patients randomised, 31 completed the intervention: mean age 69 ± 7.5 years (SD), 58% female, BMI 29.4 ± 4.4 kg/m2. Exercise increased chondroitin sulphate extractability [95% CI: 1.01 to 2.46; P = 0.0486] but cartilage relevant gene expression was unchanged. Regionally, the submeniscal area showed higher MMP-3, MMP-13, IGF-1Ea, and CTGF, together with lower lubricin and COMP expression compared to the central condylar region. Further, osteophyte expression of MMP-1, MMP-13, IGF-1Ea, and TGF-ß3 was higher than articular cartilage and lower for aggrecan, COMP, and FGF-2. Hyaluronidase-extracted matrix from central condylar cartilage contained more GAGs but less chondroitin sulphate compared to submeniscal cartilage. CONCLUSION: Acute exercise had minor influence on cartilage GAG dynamics, indicating that osteoarthritic cartilage is not significantly affected by acute exercise. However, the regional differences suggest a chronic mechanical influence on human cartilage. GOV REGISTRATION NUMBER: NCT03410745.

The regional turnover of cartilage collagen matrix in late-stage human knee osteoarthritis.

OBJECTIVE: Cartilage collagen has very limited repair potential, though some turnover and incorporation has not been fully excluded. We aim to determine the regional turnover of human osteoarthritis cartilage. DESIGN: Patients scheduled for knee joint replacement surgery due to osteoarthritis were recruited in this prospective study of four weeks duration. Deuterium oxide (D2O) was administered orally by weekly boluses at 70% D2O, initially 150 ml followed by three boluses of 50 ml. Cartilage from the medial tibia plateau was sampled centrally, under the meniscus, and from osteophytes and treated enzymatically with hyaluronidase and trypsin. Samples were analysed for deuterium incorporation in alanine using mass spectrometry and for gene expression by real-time reverse transcriptase polymerase chain reaction. RESULTS: Twenty participants completed the study: mean (SD) age 64 ± 9.1 years, 45% female, BMI 29.5 ± 4.8 kg/m2. Enzymatically treated cartilage from central and submeniscal regions showed similar enrichments at 0.063% APE, while osteophytes showed significantly greater enrichment at 0.072% APE (95% confidence interval of difference) [0.004-0.015]). Fractional synthesis rates were similar for central 0.027%/day and submeniscal cartilage 0.022%/day but 10-fold higher in osteophytes 0.22%/day [0.098-0.363]. When compared to central cartilage, submeniscal cartilage had increased gene expression of MMP-3 and decreased lubricin expression. Untreated cartilage had higher turnover (enrichments at 0.073% APE) than enzymatically treated cartilage (0.063% APE). CONCLUSIONS: In OA, despite regional differences in gene expression, the turnover of the articular cartilage matrix across the entire joint surface is very limited, but higher turnover was observed in osteophyte cartilage.

Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement - a randomized trial.

BACKGROUND: Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. METHODS: In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. RESULTS: IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] µg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] µg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064). FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019). CONCLUSION: A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015.

Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours.

BACKGROUND: Testicular germ cell tumours (TGCTs) are characterised by an overall high cisplatin-sensitivity which has been linked to their continued expression of pluripotency factors. Recently, the Nodal signalling pathway has been implicated in the regulation of pluripotency factor expression in fetal germ cells, and the pathway could therefore also be involved in regulating expression of pluripotency factors in malignant germ cells, and hence cisplatin-sensitivity in TGCTs. METHODS: We used in vitro culture of the TGCT-derived cell line NTera2, ex vivo tissue culture of primary TGCT specimens and xenografting of NTera2 cells into nude mice in order to investigate the consequences of manipulating Nodal and Activin signalling on pluripotency factor expression, apoptosis, proliferation and cisplatin-sensitivity. RESULTS: The Nodal signalling factors were markedly expressed concomitantly with the pluripotency factor OCT4 in GCNIS cells, seminomas and embryonal carcinomas. Despite this, inhibition of Nodal and Activin signalling either alone or simultaneously did not affect proliferation or apoptosis in malignant germ cells in vitro or ex vivo. Interestingly, inhibition of Nodal signalling in vitro reduced the expression of pluripotency factors and Nodal pathway genes, while stimulation of the pathway increased their expression. However, cisplatin-sensitivity was not affected following pharmacological inhibition of Nodal/Activin signalling or siRNA-mediated knockdown of the obligate co-receptor CRIPTO in NTera2 cells in vitro or in a xenograft model. CONCLUSION: Our findings suggest that the Nodal signalling pathway may be involved in regulating pluripotency factor expression in malignant germ cells, but manipulation of the pathway does not appear to affect cisplatin-sensitivity or tumour cell proliferation.

Burden, predictors and temporal relationships of comorbidities in patients with hidradenitis suppurativa: a hospital-based cohort study.

AIM: To examine the burden, predictors and temporal relationships of comorbidities in patients with hidradenitis suppurativa (HS). METHODS: Information on HS and ten systemic comorbidities was obtained by interview and clinical examination, including blood pressure, body mass index (BMI) and blood samples, in a cohort of consecutive HS outpatients. RESULTS: A total of 302 patients were included. About 86.6% had at least one comorbidity. The mean number of comorbidities per patient was 2.1. One or more cardiovascular comorbidities were observed in 76.5% with evidence of substantial unawareness and undertreatment; 48.4% had hypertension, 9.3% had diabetes, 57.7% had dyslipidaemia and 36.7% were obese. About 6.6% had inflammatory bowel disease, 6.3% had arthritis, 29.5% had a psychiatric diagnosis, 5.6% had psoriasis, 7.9% had obstructive lung disease, and 6.6% had polycystic ovary syndrome. These comorbidities occurred at different time points in relation to the onset of HS with evidence of shared as well as differential risk factors. Age (per year), HR = 0.87 (0.79-0.96), P < 0.006, age of onset of HS (per year), HR = 1.26 (1.14-1.40), P < 0.001, male sex, HR = 2.51 (0.88-7.16), P = 0.086, Hurley stage III (vs. Hurley I + II), HR = 3.46 (1.25-9.58), P = 0.017, BMI (per unit), HR = 1.12 (1.04-1.20), P = 0.002, and blood glucose (per unit), HR = 1.27 (1.16-1.39), P < 0.001 were significant predictors for onset of diabetes. CONCLUSION: There is a substantial burden, unawareness and undertreatment of several systemic comorbidities in patients with HS. Comorbidities occur at different time points in relation to the onset of HS. This should lead to higher awareness among treating specialists.

Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes.

STUDY QUESTION: Does experimental manipulation of fibroblast growth factor 9 (FGF9)-signalling in human fetal gonads alter sex-specific gonadal differentiation? SUMMARY ANSWER: Inhibition of FGFR signalling following SU5402 treatment impaired germ cell survival in both sexes and severely altered the developing somatic niche in testes, while stimulation of FGF9 signalling promoted Sertoli cell proliferation in testes and inhibited meiotic entry of germ cells in ovaries. WHAT IS KNOWN ALREADY: Sex-specific differentiation of bipotential gonads involves a complex signalling cascade that includes a combination of factors promoting either testicular or ovarian differentiation and inhibition of the opposing pathway. In mice, FGF9/FGFR2 signalling has been shown to promote testicular differentiation and antagonize the female developmental pathway through inhibition of WNT4. STUDY DESIGN, SIZE, DURATION: FGF signalling was manipulated in human fetal gonads in an established ex vivo culture model by treatments with recombinant FGF9 (25 ng/ml) and the tyrosine kinase inhibitor SU5402 (10 µM) that was used to inhibit FGFR signalling. Human fetal testis and ovary tissues were cultured for 14 days and effects on gonadal development and expression of cell lineage markers were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Gonadal tissues from 44 male and 33 female embryos/fetuses from first trimester were used for ex vivo culture experiments. Tissues were analyzed by evaluation of histology and immunohistochemical analysis of markers for germ cells, somatic cells, proliferation and apoptosis. Culture media were collected throughout the experimental period and production of steroid hormone metabolites was analyzed in media from fetal testis cultures by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE: Treatment with SU5402 resulted in near complete loss of gonocytes (224 vs. 14 OCT4+ cells per mm2, P < 0.05) and oogonia (1456 vs. 28 OCT4+ cells per mm2, P < 0.001) in human fetal testes and ovaries, respectively. This was a result of both increased apoptosis and reduced proliferation in the germ cells. Addition of exogenous FGF9 to the culture media resulted in a reduced number of germ cells entering meiosis in fetal ovaries (102 vs. 60 γH2AX+ germ cells per mm2, P < 0.05), while in fetal testes FGF9 stimulation resulted in an increased number of Sertoli cells (2503 vs. 3872 SOX9+ cells per mm2, P < 0.05). In fetal testes, inhibition of FGFR signalling by SU5402 treatment altered seminiferous cord morphology and reduced the AMH expression as well as the number of SOX9-positive Sertoli cells (2503 vs. 1561 SOX9+ cells per mm2, P < 0.05). In interstitial cells, reduced expression of COUP-TFII and increased expression of CYP11A1 and CYP17A1 in fetal Leydig cells was observed, although there were no subsequent changes in steroidogenesis. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Ex vivo culture may not replicate all aspects of fetal gonadal development and function in vivo. Although the effects of FGF9 were studied in ex vivo culture experiments, there is no direct evidence that FGF9 acts in vivo during human fetal gonadogenesis. The FGFR inhibitor (SU5402) used in this study is not specific to FGFR2 but inhibits all FGF receptors and off-target effects on unrelated tyrosine kinases should be considered. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study suggest that dysregulation of FGFR-mediated signalling may affect both testicular and ovarian development, in particular impacting the fetal germ cell populations in both sexes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.JØ. Additional funding was obtained from the Erichsen Family Fund (A.JØ.), the Aase and Ejnar Danielsens Fund (A.JØ.), the Danish Government's support for the EDMaRC programme (A.JU.) and a Wellcome Trust Intermediate Clinical Fellowship (R.T.M., Grant no. 098522). The Medical Research Council (MRC) Centre for Reproductive Health (R.T.M.) is supported by an MRC Centre Grant (MR/N022556/1). The authors have no conflict of interest to disclose.

Serum and blister-fluid elevation and decreased epidermal content of high-mobility group box 1 protein in drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: High-mobility group box 1 (HMGB1) is a damage-associated molecular-pattern protein. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune-mediated skin-blistering conditions. OBJECTIVES: To determine serum and/or blister-fluid total HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed, paraffin-embedded (FFPE) SJS/TEN skin vs. healthy and maculopapular exanthema (MPE) skin. Methods Serum HMGB1 was quantified in Malawian nevirapine-induced hypersensitivity, Taiwanese SJS/TEN and Spanish SJS/TEN cohorts. FFPE skin (healthy skin, MPE, SJS/TEN) was stained and assessed for HMGB1 expression. RESULTS: Serum total HMGB1 was not significantly elevated in patients with nevirapine-induced SJS/TEN (3·98 ± 2·17 ng mL-1 ), MPE (3·92 ± 2·75 ng mL-1 ) or drug reaction with eosinophilia and systemic symptoms (4·73 ± 3·00 ng mL-1 ) vs. tolerant controls (2·97 ± 3·00 ng mL-1 ). HMGB1 was significantly elevated in Taiwanese patients with SJS/TEN, highest during the acute phase (32·6 ± 26·6 ng mL-1 ) vs. the maximal (19·7 ± 23·2 ng mL-1 ; P = 0·007) and recovery (24·6 ± 25·3 ng mL-1 ; P = 0·027) phases. In blister fluid from Spanish patients with SJS/TEN, HMGB1 (486·8 ± 687·9 ng mL-1 ) was significantly higher than in serum (8·8 ± 7·6 ng mL-1 ; P <0·001). Preblistered SJS/TEN skin showed decreased epidermal nuclear HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression. CONCLUSIONS: Epidermal HMGB1 expression was decreased in SJS/TEN skin. Retained basal/suprabasal epidermal HMGB1 expression may exacerbate localized injury in SJS/TEN.

Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial.

OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial. METHOD: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year. RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003). CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

Comparison of the analgesic effect of an adductor canal block using a new suture-method catheter vs. standard perineural catheter vs. single-injection: a randomised, blinded, controlled study.

We performed a randomised, blinded, controlled study with adult patients scheduled for primary total knee arthroplasty under spinal anaesthesia. The aim was to investigate the analgesic effects of adductor canal block using catheter-based repeated boluses, either through a new suture-method catheter or a standard perineural catheter, compared with a single-injection technique. All patients received an adductor canal block after surgery with an initial bolus of 20 ml ropivacaine 0.75%, followed by 20 ml of ropivacaine 0.2% every 8 h in the standard and suture-method catheter groups, and sham boluses for the single-injection group. The primary outcome measure was total opioid consumption (intravenous morphine equivalents) from the end of surgery until 12:00 on postoperative day 2. Secondary outcomes were pain, muscle strength and ambulation. We randomly assigned (1:1:1) and analysed 153 patients. Total opioid consumption was median (IQR [range]) 24 (11-37 [0-148]) mg in the suture-method group, 38 (17-51 [0-123]) mg in the standard catheter group and 37 (14-57 [0-158]) mg in the single-injection group (p = 0.049). Differences were not statistically significant after Bonferroni correction (α = 0.05/3). There were no differences between groups on postoperative day 1. On postoperative day 2, there were no differences between catheter groups, but muscle strength and ambulation were improved compared with the single-injection group. We conclude that providing repeated boluses via a catheter did not decrease opioid consumption or pain compared with a single injection, but improved muscle strength and ambulation on postoperative day 2. The two types of catheters were similar.

Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects - a randomized controlled trial.

BACKGROUND: Chloride is speculated to have nephrotoxic properties. In healthy subjects we tested the hypothesis that acute chloride loading with 3% saline would induce kidney injury, which could be prevented with the loop-diuretic furosemide. METHODS: The study was designed as a randomized, placebo-controlled, crossover study. Subjects were given 3% saline accompanied by either placebo or furosemide. Before, during and after infusion of 3% saline we measured glomerular filtration rate (GFR), fractional excretion of sodium (FENa), urinary chloride excretion (u-Cl), urinary excretions of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ), neutrophil gelatinase-associated lipocalin (u-NGAL) and kidney injury molecule-1 (u-KIM-1) as marker of kidney injury and vasoactive hormones: renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and arginine vasopressin (p-AVP). Four days prior to each of the two examinations subjects were given a standardized fluid and diet intake. RESULTS: After 3% saline infusion u-NGAL and KIM-1 excretion increased slightly (u-NGAL: 17 ± 24 during placebo vs. -7 ± 23 ng/min during furosemide, p = 0.039, u-KIM-1: 0.21 ± 0.23 vs - 0.06 ± 0.14 ng/ml, p <  0.001). The increase in u-NGAL was absent when furosemide was given simultaneously, and the responses in u-NGAL were not significantly different from placebo control. Furosemide changed responses in u-KIM-1 where a delayed increase was observed. GFR was increased by 3% saline but decreased when furosemide accompanied the infusion. U-Na, FENa, u-Cl, and u-osmolality increased in response to saline, and the increase was markedly pronounced when furosemide was added. FEK decreased slightly during 3% saline infusion, but simultaneously furosemide increased FEK. U-AQP2 increased after 3% saline and placebo, and the response was further increased by furosemide. U-ENaCγ decreased to the same extent after 3% saline infusion in the two groups. 3% saline significantly reduced PRC, p-AngII and p-Aldo, and responses were attenuated by furosemide. p-AVP was increased by 3% saline, with a larger increase during furosemide. CONCLUSION: This study shows minor increases in markers of kidney injury after 3% saline infusion Furosemide abolished the increase in NGAL and postponed the increase in u-KIM-1. The clinical importance of these findings needs further investigation. TRIAL REGISTRATION: (EU Clinical trials register number: 2015-002585-23 , registered on 5th November 2015).

Clues for early detection of autoimmune Addison's disease - myths and realities.

BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001). CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

Clinical predictors of active LN development in children - evidence from the UK JSLE Cohort Study.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) patients may develop lupus nephritis (LN) during their initial presentation, or later in their disease. This study aimed to assess whether clinical/demographic factors characterize patients with LN within the United Kingdom JSLE Cohort Study, and whether such factors predict subsequent LN development. METHODS: Univariate logistic regression modelling compared clinical/demographic factors in patients with and without LN at baseline. For those who subsequently developed LN, Cox proportional-hazard modelling was used to test the association between such factors and time to LN development. Covariates with p < 0.2 univariately were included within a multiple-regression model. RESULTS: A total of 121/331 (37%) patients presented with active LN at baseline, with first American College of Rheumatology (ACR) score ( p < 2.0 × 10-16), severe hypertension ( p = 0.0006), proteinuria ( p < 2.0 × 10-16), creatinine ( p = 1.0 × 10-16), erythrocyte sedimentation rate ( p = 1.0 × 10-16), neutrophils ( p < 2.0 × 10-16), complement 3 (C3) ( p = 4.0 × 10-16) and ethnicity ( p = 3.0 × 10-13) differing between those with and without LN. Of the 210 individuals without active LN at baseline, 13 patients had a single visit and were excluded from further analysis. Thirty-four of 197 (17%) developed LN after a median of 2.04 years (interquartile range, 0.8-3.7), with higher ACR scores ( p = 0.014 , hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.08-1.95) and lower C3 levels ( p = 0.0082 , HR = 0.27, 95% CI = 0.10-0.68) demonstrated as predictors of subsequent LN. CONCLUSIONS: Clinical and demographic factors can help to characterize patients at increased risk of LN.

Growing international evidence for urinary biomarker panels identifying lupus nephritis in children - verification within the South African Paediatric Lupus Cohort.

BACKGROUND: A urinary biomarker panel including alpha-1-acid-glycoprotein (AGP), lipocalin-like-prostaglandin-D-synthase (LPGDS), transferrin and ceruloplasmin demonstrates an 'excellent' ability for identifying active lupus nephritis in UK/US children. This study aimed to assess whether this panel identifies active lupus nephritis within the South African Paediatric Lupus Cohort. METHODS: Juvenile-onset-systemic lupus erythematosus (JSLE) patients aged < 19 years at diagnosis and healthy controls were recruited. Patients were categorized as having active lupus nephritis (renal BILAG score; A/B and previous histological confirmation) or inactive lupus nephritis (renal BILAG score: D/E). Urinary biomarkers were quantified by ELISA. Mann-Whitney U-test compared biomarker levels between groups. Binary logistic regression and receiver operating curve analysis assessed biomarker combinations. RESULTS: Twenty-three juvenile-onset-systemic lupus erythematosus patients were recruited with a median age of 13.5 years (interquartile range (IQR) 12.7-14.9) and disease duration of 2.6 years (IQR 1.8-4.0). Eighteen healthy controls had a median age of 11.0 years (IQR 10.0-12.0). AGP, LPGDS, transferrin, ceruloplasmin and VCAM-1 were significantly higher in active than in inactive lupus nephritis patients (corrected p-values, all pc < 0.05), with no difference between inactive lupus nephritis patients and healthy controls (all pc = 1.0). The optimal biomarker combination included AGP, ceruloplasmin, LPGDS and transferrin (area under the curve = 1.0). CONCLUSIONS: A urinary biomarker panel comprising AGP, ceruloplasmin, LPGDS and transferrin previously validated within UK/US cohorts also performed excellently within a racially distinct South African cohort which displayed more severe lupus nephritis.

Blood-flow restricted resistance training in patients with sporadic inclusion body myositis: a randomized controlled trial.

OBJECTIVES: To investigate the effect of 12 weeks of low-load blood-flow restricted resistance (BFR) training on self-reported and objective physical function, and maximal muscle strength in patients with sporadic inclusion body myositis (sIBM). METHOD: Twenty-two patients with sIBM were randomized into a training group (BFR group) or a non-exercising control group, according to CONsolidated Standards Of Reporting Trials (CONSORT) guidelines. The BFR group performed 12 weeks of BFR training twice per week. The primary outcome was the physical function domain of the 36-item Short Form Health Survey (pf-SF-36), which was used to measure self-reported physical function. All patients performed physical function tests (2-Minute Walk Test, Timed Up and Go, and 30-Second Chair Stand), completed the Inclusion Body Myositis Functional Rating Scale (IBMFRS), and were tested for isolated knee extensor muscle strength. RESULTS: No effects of the training intervention were observed for pf-SF-36 or the objective physical function tests. Leg muscle strength decreased in controls (-9.2%, p = 0.02), but was unaltered in the BFR group (+0.9%, p = 0.87), resulting in a between-group difference in the per-protocol analysis (p = 0.026). Between-group differences in baseline to follow-up changes emerged for IBMFRS, in favour of the BFR group (p = 0.018). CONCLUSION: Twelve weeks of BFR training did not improve self-reported or objective physical function in these sIBM patients. However, the training protocol had a preventive (retaining) effect on the disease-related decline in leg muscle strength, which may aid the long-term preservation of physical function and postpone the need for healthcare assistance.

Do classic blood biomarkers of JSLE identify active lupus nephritis? Evidence from the UK JSLE Cohort Study.

Background Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus (JSLE) patients. The value of commonly available biomarkers, such as anti-dsDNA antibodies, complement (C3/C4), ESR and full blood count parameters in the identification of active LN remains uncertain. Methods Participants from the UK JSLE Cohort Study, aged <16 years at diagnosis, were categorized as having active or inactive LN according to the renal domain of the British Isles Lupus Assessment Group score. Classic biomarkers: anti-dsDNA, C3, C4, ESR, CRP, haemoglobin, total white cells, neutrophils, lymphocytes, platelets and immunoglobulins were assessed for their ability to identify active LN using binary logistic regression modeling, with stepAIC function applied to select a final model. Receiver-operating curve analysis was used to assess diagnostic accuracy. Results A total of 370 patients were recruited; 191 (52%) had active LN and 179 (48%) had inactive LN. Binary logistic regression modeling demonstrated a combination of ESR, C3, white cell count, neutrophils, lymphocytes and IgG to be best for the identification of active LN (area under the curve 0.724). Conclusions At best, combining common classic blood biomarkers of lupus activity using multivariate analysis provides a 'fair' ability to identify active LN. Urine biomarkers were not included in these analyses. These results add to the concern that classic blood biomarkers are limited in monitoring discrete JSLE manifestations such as LN.

Rosacea is associated with Helicobacter pylori: a systematic review and meta-analysis.

BACKGROUND: Rosacea is a common skin disease characterized by facial erythema, telangiectasia, papules and pustules. Helicobacter pylori infection has been suggested to play a role in the etiopathogenesis of rosacea. OBJECTIVE: To systematically review and meta-analyse the relationship between rosacea and infection with Helicobacter pylori. METHODS: A literature search was performed using PubMed, EMBASE and Web of Science. Data extraction and analyses were performed on descriptive data. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects models with DerSimonian-Laird methods were utilized to estimate pooled odds ratios (ORs), with 95% confidence intervals (95% CIs). Heterogeneity of results was assessed using I² statistics. RESULTS: A total of 454 articles were identified and 42 full-text articles were chosen for further review. Fourteen studies were included in the quantitative meta-analysis, comprising a total of 928 rosacea patients and 1527 controls. The overall association between Helicobacter pylori infection and rosacea was non-significant (OR 1.68, 95% CI 1.00-2.84, P = 0.052), but analysis restricted to C-urea breath test showed a significant association (OR 3.12, 95% CI 1.92-5.07, P < 0.0001). Effect of eradication treatment on rosacea symptoms was assessed in seven studies, but without significant effect (RR 1.28, 95% CI 0.98-1.67, P = 0.069). CONCLUSION: This meta-analysis found weak associations between rosacea and Helicobacter pylori infection as well as an effect of Helicobacter pylori therapy on rosacea symptoms, albeit that these did not reach statistical significance. Whether a pathogenic link between the two conditions exists, or whether Helicobacter pylori infection represents a proxy for other factors remains unknown.

A survey of the distribution of the PKD-parasite Tetracapsuloides bryosalmonae (Cnidaria: Myxozoa: Malacosporea) in salmonids in Norwegian rivers - additional information gleaned from formerly collected fish.

The malacosporean Tetracapsuloides bryosalmonae was detected in kidneys from Atlantic salmon parr in 64 of 91 sampled Norwegian rivers. Using real-time PCR, this parasite was found to be present in Atlantic salmon parr in rivers along the whole coast, from the northernmost and southernmost areas of the country. In addition, T. bryosalmonae was found in kidneys from brown trout parr in 17 of 19 sampled rivers in south-east Norway, and in Arctic charr sampled in the River Risfjordelva, located at the northernmost edge of the European mainland. In conclusion, T. bryosalmonae has a widespread distribution in salmonids in Norwegian watercourses. Proliferative kidney disease (PKD) caused by T. bryosalmonae and PKD-induced mortality has been observed in salmonids in several Norwegian rivers and it can be speculated that more PKD outbreaks will occur as a result of climate change.

Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis.

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo-adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA).

OBJECTIVES: To study clinical and radiographic outcomes after withdrawing 1 year's adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647). METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate (20 mg/week) and intra-articular triamcinolone (20 mg/ml) for 2 years. In addition, they were randomised to receive placebo adalimumab (DMARD group, n=91) or adalimumab (40 mg/every other week) (DMARD+adalimumab group, n=89) during the first year. Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months. During year 2, synthetic DMARDs continued. Adalimumab was (re)initiated if active disease reoccurred. Clinical response, remission, disability, quality of life and radiographic changes were assessed. RESULTS: One year after adalimumab withdrawal, treatment profiles and clinical responses did not differ between groups. In the DMARD/DMARD+adalimumab groups, the median 2-year methotrexate dose was 20/20 mg/week (p=0.45), triple DMARD therapy had been initiated in 33/27 patients (p=0.49), adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg (p=0.15). The treatment target (disease activity score, 4 variables, C-reactive protein (DAS28CRP) ≤3.2 or DAS28>3.2 without swollen joints) was achieved at all visits in ≥85% of patients in year 2; remission rates were DAS28CRP<2.6:69%/66%; Clinical Disease Activity Index ≤2.8:55%/57%; Simplified Disease Activity Index <3.3:54%/49%; American College of Rheumatology/European League against Rheumatism (28 joints):44%/45% (p=0.66-1.00). Radiographic progression (Δtotal Sharp score/year) was similar 1.31/0.53 (p=0.12). Erosive progression (Δerosion score (ES)/year) was year 1:0.57/0.06 (p=0.02); year 2:0.38/0.05 (p=0.005). Proportion of patients without erosive progression (ΔES≤0) was year 1: 59%/76% (p=0.03); year 2:64%/79% (p=0.04). CONCLUSIONS: An aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy. ES progression was slightly less during and following adalimumab induction therapy. TRIAL REGISTRATION NUMBER: NCT00660647.