The alarmins high mobility group box protein 1 and S100A8/A9 display different inflammatory profiles after acute knee injury.

OBJECTIVE: To compare the concentrations of high mobility group box 1 protein (HMGB1) and S100A8/A9 in synovial fluid between patients with knee injuries and osteoarthritis (OA), and knee healthy subjects. To investigate associations of alarmin levels with different joint injuries and with biomarkers of inflammation, Wnt signaling, complement system, bone and cartilage degradation. METHODS: HMGB1 and S100A8/A9 were measured in synovial fluid by immunoassays in patients with knee injuries, with OA and from knee healthy subjects, and were related to time from injury and with biomarkers obtained from previous studies. Hierarchical cluster and enrichment analyses of biomarkers associated to HMGB1 and S100A8/A9 were performed. RESULTS: The synovial fluid HMGB1 and S100A8/A9 concentrations were increased early after knee injury; S100A8/A9 levels were negatively associated to time after injury and was lower in the old compared to recent injury group, while HMGB1 was not associated to time after injury. The S100A8/A9 levels were also increased in OA. The initial inflammatory response was similar between the alarmins, and HMGB1 and S100A8/A9 shared 9 out of 20 enriched pathways. The alarmins displayed distinct response profiles, HMGB1 being associated to cartilage biomarkers while S100A8/A9 was associated to proinflammatory cytokines. CONCLUSIONS: HMGB1 and S100A8/A9 are increased as an immediate response to knee trauma. While they share many features in inflammatory and immunoregulatory mechanisms, S100A8/A9 and HMGB1 are associated to different downstream responses, which may have impact on the OA progression after acute knee injuries.

Cardiovascular risk factors and lifestyle behaviours in relation to longevity: a Mendelian randomization study.

BACKGROUND: The American Heart Association introduced the Life's Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity. OBJECTIVES: This study aimed to investigate causal associations of Life's Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two-sample Mendelian randomization design. METHODS: Instrumental variables for the modifiable risk factors were obtained from large-scale genome-wide association studies. Data on longevity beyond the 90th survival percentile were extracted from a genome-wide association meta-analysis with 11,262 cases and 25,483 controls whose age at death or last contact was ≤ the 60th survival percentile. RESULTS: Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes (OR 0.88; 95% CI: 0.84;0.92), genetically predicted systolic and diastolic blood pressure (per 1-mmHg increase: 0.96; 0.94;0.97 and 0.95; 0.93;0.97), body mass index (per 1-SD increase: 0.80; 0.74;0.86), low-density lipoprotein cholesterol (per 1-SD increase: 0.75; 0.65;0.86) and smoking initiation (0.75; 0.66;0.85). Genetically increased high-density lipoprotein cholesterol (per 1-SD increase: 1.23; 1.08;1.41) and educational level (per 1-SD increase: 1.64; 1.45;1.86) were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity. CONCLUSION: Most of the Life's Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.

Patient-reported Outcome in Surgically Treated Pelvic Ring Injuries at 5 Years Post-surgery.

BACKGROUND AND AIMS: Long-term prospective data on patient-reported outcome after surgical treatment of pelvic ring injuries are scarce. This study aimed at describing results at 5 years post-surgery using validated outcome measures. PATIENTS AND METHODS: Patients admitted for surgical treatment of pelvic ring injuries were prospectively included and asked to report their outcome at 1, 2 and 5 years post-surgery using two patient-reported outcome measures: the generic Short-Form 36 and the condition-specific pelvic discomfort index. Data were evaluated using mixed-effects linear models. RESULTS: There were 108 patients (68 males and 40 females), mean age 38 years. Injury type according to the AO/OTA-classification was B-type in 68 patients and C-type in 40 patients. No domain of the Short-Form 36 reached norm values at 5 years post-surgery. Females reported a worse outcome than males concerning general health (p < 0.01) at 5 years. Recovery of physical function (p < 0.01), mental health (p = 0.04), and pain (p = 0.01) was observed for males at 5 years compared to earlier assessments, while females on the contrary described more pain at this time-point (p = 0.03). Mean pelvic discomfort index at 5 years was 27, indicating moderate residual pelvic discomfort overall. Males reported less pelvic discomfort than females at 5 years (p = 0.02) and improved when compared to results at 2 years (p = 0.02), while females did not. Influence of age, fracture type, and presence of associated injuries on patient-reported outcome was limited. CONCLUSION: Surgically treated pelvic ring injuries are associated with long-standing negative effects on patient-reported outcome. Males report a better outcome than females at 5 years post-surgery.

Interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunit and amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To clarify the causal associations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-2 receptor alpha subunit (IL-2rα) with the risk of amyotrophic lateral sclerosis (ALS). METHODS: A two-sample Mendelian randomization study design was employed. Single-nucleotide polymorphisms associated with IL-1ra (n = 2) and IL-2rα (n = 1) at the genome-wide significance level were used as unbiased instrumental variables. Summary-level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent. RESULTS: Genetic predisposition to higher levels of IL-1ra was significantly associated with lower odds of ALS. For a 1-SD increase of circulating IL-1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46-0.88; P = 0.005). There was a borderline inverse association between IL-2rα levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83-1.00; P = 0.058). CONCLUSIONS: Interleukin-1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin-1 inhibitors may lower the risk of this always fatal disease. The role of IL-2rα levels in ALS needs further verification in causal inference studies with larger sample sizes.

Molecular and imaging biomarkers of local inflammation at 2 years after anterior cruciate ligament injury do not associate with patient reported outcomes at 5 years.

OBJECTIVE: To estimate the association between molecular or imaging inflammatory biomarkers at 2 years after anterior cruciate ligament (ACL) injury and patient-reported outcomes at 5 years. METHODS: For 116 ACL-injured patients, molecular biomarkers of inflammation (synovial fluid and serum cytokines) and Hoffa- and effusion-synovitis as visualized on magnetic resonance imaging (MRI) were assessed 2 years post-injury. Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-36 were assessed at 2 and 5 years. We used multiple imputation to handle biomarker values that were below the level of detection or missing, and linear regression for statistical analyses. RESULTS: None of the synovial fluid cytokines or imaging biomarkers of inflammation at 2 years were associated with any of the patient-reported outcomes at 5 years. With each log10 unit higher of serum tumor necrosis factor concentration the knee-related quality of life of KOOS was increased (i.e., better outcome) by 35 (95% confidence interval 7 to 63) points. No other serum biomarker measured at 2 years was associated with patient-reported outcome at 5 years. CONCLUSION: Local joint inflammation assessed by biomarkers in synovial fluid and Hoffa- and effusion-synovitis on MRI at 2 years after an ACL injury did not associate with patient-reported outcomes at 5 years. Thus, chronic inflammation in the ACL-injured knee, as reflected by the biomarkers studied here, seems not to be a key determinant for the long-term patient-reported outcomes.

Coffee, tea, and caffeine intake and amyotrophic lateral sclerosis mortality in a pooled analysis of eight prospective cohort studies.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to <1 cup per day was 1.04 (95% CI, 0.74-1.47) for coffee and 1.17 (95% CI, 0.77-1.79) for tea. The pooled MVRR comparing the highest with the lowest tertile of caffeine intake (mg/day) was 0.99 (95% CI, 0.80-1.23). No statistically significant results were observed when exposures were modeled as tertiles or continuously. CONCLUSIONS: Our results do not support associations between coffee, tea or total caffeine intake and risk of ALS mortality.

How do macro-level structural determinants affect inequalities in mental health? - a systematic review of the literature.

BACKGROUND: In Europe and elsewhere there is rising concern about inequality in health and increased prevalence of mental ill-health. Structural determinants such as welfare state arrangements may impact on levels of mental health and social inequalities. This systematic review aims to assess the current evidence on whether structural determinants are associated with inequalities in mental health outcomes. METHODS: We conducted a systematic review of quantitative studies published between 1996 and 2017 based on search results from the following databases Medline, Embase, PsychInfo, Web of Science, Sociological Abstracts and Eric. Studies were included if they focused on inequalities (measured by socio-economic position and gender), structural determinants (i.e. public policies affecting the whole population) and showed a change or comparison in mental health status in one (or more) of the Organisation for Economic Cooperation and Development (OECD) countries. All studies were assessed for inclusion and study quality by two independent reviewers. Data were extracted and synthesised using narrative analysis. RESULTS: Twenty-one articles (17 studies) met the inclusion criteria. Studies were heterogeneous with regards to methodology, mental health outcomes and policy settings. More comprehensive and gender inclusive welfare states (e.g. Nordic welfare states) had better mental health outcomes, especially for women, and less gender-related inequality. Nordic welfare regimes may also decrease inequalities between lone and couple mothers. A strong welfare state does not buffer against socio-economic inequalities in mental health outcomes. Austerity measures tended to worsen mental health and increase inequalities. Area-based initiatives and educational policy are understudied. CONCLUSION: Although the literature on structural determinants and inequalities in mental health is limited, our review shows some evidence supporting the causal effects of structural determinants on mental health inequalities. The lack of evidence should not be interpreted as lack of effect. Future studies should apply innovative methods to overcome the inherent methodological challenges in this area, as structural determinants potentially affect both levels of mental health and social inequalities.

Changes in synovial fluid and serum concentrations of cartilage oligomeric matrix protein over 5 years after anterior cruciate ligament rupture: an exploratory analysis in the KANON trial.

OBJECTIVE: To monitor longitudinal changes of cartilage oligomeric matrix protein (COMP) in synovial fluid (sf) and serum (s) over 5 years after acute anterior cruciate ligament (ACL) rupture, and to compare results from two commercial COMP immunoassays. DESIGN: Bio-fluids were collected from 121 patients on six occasions over 5 years after acute ACL injury, and from 25 knee healthy reference subjects. Concentrations of sf- and sCOMP were measured by AnaMar (sCOMP-Ana) and by BioVendor (sf- and sCOMP-Bio) immunoassays; other biomarkers were previously assessed. We used ANCOVA for group comparisons and linear mixed models for associations between biomarkers over 5-years with P < 0.05 considered a statistically significant difference or association. RESULTS: Compared to the reference group, sfCOMP-Bio concentrations were 2-fold elevated within 6 weeks after ACL injury and remained elevated 5 years thereafter, whereas sCOMP-Bio and sCOMP-Ana concentrations were no different from reference levels at any time point. Over the 5-year period, there was an association between sCOMP-Bio and sCOMP-Ana concentrations, although neither sCOMP-Bio nor sCOMP-Ana associated with sfCOMP-Bio. sfCOMP-Bio associated with SF ARGS-aggrecan, urine type I and II collagens (uNTX-I and uCTX-II) and SF cytokines, while sCOMP-Bio associated inversely with uCTX-II, uNTX-I and SF cytokines. CONCLUSION: The local process after an acute ACL injury generates increased SF COMP concentrations in the injured knee up to 5 years after injury. This response is not detected in serum. Discrepancies in associations between sCOMP measured by BioVendor and AnaMar immunoassays with other biomarkers indicate differences in detected COMP fragments.

Coffee consumption and risk of aortic valve stenosis: A prospective study.

BACKGROUND AND AIMS: Coffee contains many biologically active compounds with potential adverse or beneficial effects on the cardiovascular system. Whether coffee consumption is associated with the risk of aortic valve stenosis (AVS) is unknown. The purpose of this study was therefore to examine the association between coffee consumption and AVS incidence. METHODS AND RESULTS: This prospective study included 71 178 men and women who provided information on their coffee consumption through a questionnaire at baseline. Incident cases of AVS were identified through linkage with the Swedish National Patient and Cause of Death Registers. During a mean follow-up of 15.2 years, 1295 participants (777 men and 518 women) were diagnosed with AVS. Coffee consumption was positively associated with risk of AVS in a dose-response manner after adjustment for age, sex, smoking, and other risk factors (P-trend = 0.005). The multivariable hazard ratios were was 1.11 (95% confidence interval 1.04-1.19) per 2 cups/day increase of coffee consumption and 1.65 (95% confidence interval 1.10-2.48) when comparing the highest (≥6 cups/day) with the lowest (<0.5 cup/day) category of coffee consumption. The association was not modified by other risk factors. CONCLUSIONS: This study provides novel evidence that high coffee consumption is associated with an increased risk of AVS.

Dickkopf-related protein 1 and gremlin 1 show different response than frizzled-related protein in human synovial fluid following knee injury and in patients with osteoarthritis.

OBJECTIVE: To explore the involvement of the wingless-type MMTV integration site (WNT) and bone morphogenetic protein (BMP) antagonists dickkopf-related protein 1 (DKK1), frizzled-related protein (FRZB) and gremlin 1 (GREM1) in knee injury and osteoarthritis (OA). DESIGN: The antagonists were immunoassayed in synovial fluid from a cross-sectional cohort of nine knee healthy reference subjects, patients with recent (0-77 days, n = 158) or old (1-37 years, n = 50) knee injuries, and OA (n = 22). Cartilage (ARGS-aggrecan, cartilage oligomeric matrix protein and C2C type II collagen) and other biomarkers were assessed in synovial fluid in a subset of samples. Statistical analysis was by Kendall's tau (τ) correlation, Mann-Whitney U test, and linear regression analysis. RESULTS: Compared to references, median concentration of GREM1 (but not DKK1 and FRZB) was elevated 1.5-fold immediately after injury, and FRZB was reduced 1000-folds in OA. All three antagonists decreased with increasing time after injury as well as with increasing age, but the temporal change after injury was less accentuated for FRZB (peaked 8-22 days after injury) compared to that of DKK1 and GREM1 (peaked immediately after injury). In the recent injury group, there was a correlation between GREM1 and DKK1 (τ = 0.172); FRZB concentrations correlated with concentrations of cartilage biomarkers (τ between 0.257 and 0.369), while DKK1 and GREM1 were inversely correlated (τ between -0.177 and -0.217) with these markers. CONCLUSIONS: Our results indicate separate roles for the antagonists, where DKK1 and GREM1 had similarities in response to injury and in OA, with a different response for FRZB.

Clinical Outcome after Plaster Cast Fixation for 10 Days Versus 1 Month in Reduced Distal Radius Fractures: A Prospective Randomized Study.

INTRODUCTION: This study aimed to evaluate clinical results after plaster cast fixation for 10 days versus 1 month of moderately displaced and reduced distal radius fractures. MATERIAL AND METHODS: In a prospective randomized study, 109 patients with moderately displaced and conservatively treated distal radius fractures (age ≥50 years) were randomized 10 days after reduction to either removal of the plaster cast and immediate mobilization (active group) or to continued plaster cast fixation for another 3 weeks (control group). Grip strength, pincer strength, range of motion, and pain were assessed at 1, 4, and 12 months after reduction. Clinical outcome was evaluated using three functional assessment scores at 12 months. RESULTS: Treatment failed in 3/54 (6%) patients in the active group. One of these patients had the plaster cast reinstituted because of feelings of instability. The fractures in the other two patients displaced severely after mobilization and were therefore treated surgically. For the remaining 51 patients in the active group, the range of wrist motion was slightly better at 1 month compared with the controls, but there were no differences in grip or pincer strength or pain at the 1-month follow-up. There were no differences between the active and control group in any outcome at 4 or 12 months, including functional assessment scores at 12 months. CONCLUSION: Treatment with mobilization 10 days after reduction of moderately displaced distal radius fractures resulted in a few treatment failures compared with none among controls. The only functional benefit for the remaining patients was a small and transient increase in range of motion at the 1-month follow-up. Plaster cast removal 10 days after reduction in moderately displaced distal radius fractures is therefore not recommended.

Investigating the Nature of Late-Time High-Energy GRB Emission Through Joint Fermi /Swift Observations.

We use joint observations by the Neil Gehrels Swift X-ray Telescope (XRT) and the Fermi Large Area Telescope (LAT) of gamma-ray burst (GRB) afterglows to investigate the nature of the long-lived high-energy emission observed by Fermi LAT. Joint broadband spectral modeling of XRT and LAT data reveal that LAT non-detections of bright X-ray afterglows are consistent with a cooling break in the inferred electron synchrotron spectrum below the LAT and/or XRT energy ranges. Such a break is sufficient to suppress the high-energy emission so as to be below the LAT detection threshold. By contrast, LAT-detected bursts are best fit by a synchrotron spectrum with a cooling break that lies either between or above the XRT and LAT energy ranges. We speculate that the primary difference between GRBs with LAT afterglow detections and the non-detected population may be in the type of circumstellar environment in which these bursts occur, with late-time LAT detections preferentially selecting GRBs that occur in low wind-like circumburst density profiles. Furthermore, we find no evidence of high-energy emission in the LAT-detected population significantly in excess of the flux expected from the electron synchrotron spectrum fit to the observed X-ray emission. The lack of excess emission at high energies could be due to a shocked external medium in which the energy density in the magnetic field is stronger than or comparable to that of the relativistic electrons behind the shock, precluding the production of a dominant synchrotron self-Compton (SSC) component in the LAT energy range. Alternatively, the peak of the SSC emission could be beyond the 0.1-100 GeV energy range considered for this analysis.

Enhanced ventricular-arterial coupling during a 2-year physical activity programme in patients with rheumatoid arthritis: a prospective substudy of the physical activity in rheumatoid arthritis 2010 trial.

OBJECTIVE: To establish how guided physical activity in patients with rheumatoid arthritis (RA) without known cardiovascular disease affected vascular and cardiac function, and how these two entities were prospectively interconnected in this patient group. METHODS: Prospective substudy of 29 participants in the Physical Activity in RA (PARA) 2010 trial. All subjects were examined at baseline, at year 1 and 2 with measures of pulse wave velocity and arterial augmentation index, as well as echocardiographic evaluation of diastolic parameters and ventricular-arterial coupling. Muscle strength and aerobic exercise capacity were assessed at baseline and yearly. All participants performed physiotherapist-guided aerobic and muscle strength exercise during 2 years and were reminded through SMS to report physical activity progress. RESULTS: This cohort of patients with RA exhibited increased vascular stiffness despite normal blood pressure. At baseline, lower muscle strength was associated with increased vascular stiffness (ß = 0.68; P = 0.004), whereas lower aerobic working capacity was associated with left ventricular diastolic dysfunction (ß = 0.85; P = 0.03). There was a significant positive correlation between vascular stiffness and diastolic dysfunction at baseline (R2  = 0.64) and for the changes in those parameters observed during 2 years of guided physical activity. Finally, a significant improvement in ventricular-arterial coupling was observed after exercise (P < 0.001). CONCLUSION: These results indicate that although differentially associated with physical capacity parameters, improved vascular stiffness and improved diastolic dysfunction are interrelated, and that an optimization of the ventricular-arterial coupling may contribute to the beneficial effects of physical activity in patients with RA.

Combined impact of healthy lifestyle factors on lifespan: two prospective cohorts.

BACKGROUND: The impact of multiple healthy lifestyle factors on survival time is unclear. OBJECTIVE: The aim of this study was to examine differences in survival time associated with a healthy lifestyle versus a less healthy lifestyle. METHODS: This study consisted of 33 454 men (Cohort of Swedish Men) and 30 639 women (Swedish Mammography Cohort) aged 45-83 years and free of cancer and cardiovascular disease at baseline. The healthy lifestyle factors included the following: (i) nonsmoking; (ii) physical activity at least 150 min per week; (iii) alcohol consumption of 0-14 drinks per week; (iv) and healthy diet defined as a modified Dietary Approaches to Stop Hypertension Diet score above the median. Cox proportional hazards regression models and Laplace regression were used to estimate, respectively, hazard ratios of all-cause mortality and differences in survival time. RESULTS: During follow-up from 1998 through 2014, 8630 deaths amongst men and 6730 deaths amongst women were ascertained through linkage to the Swedish Cause of Death Register. Each of the four healthy lifestyle factors was inversely associated with all-cause mortality and increased survival time. Compared with individuals with no or one healthy lifestyle factor, the multivariable hazard ratios of all-cause mortality for individuals with all four health behaviours were 0.47 (95% 95% confidence interval [CI]: 0.44-0.51) in men and 0.39 (95% CI: 0.35-0.44) in women. This corresponded to a difference in survival time of 4.1 (95% CI: 3.6-4.6) years in men and 4.9 (95% CI: 4.3-5.6) years in women. CONCLUSION: Adopting healthy lifestyle behaviours may markedly increase lifespan.

Alcohol consumption, cigarette smoking and incidence of aortic valve stenosis.

BACKGROUND: Alcohol consumption and cigarette smoking are modifiable lifestyle factors with important impact on public health. It is unclear whether these factors influence the risk of aortic valve stenosis (AVS). OBJECTIVE: To investigate the associations of alcohol consumption and smoking, including smoking intensity and time since cessation, with AVS incidence in two prospective cohorts. METHODS: This analysis was based on data from the Swedish Mammography Cohort and the Cohort of Swedish Men, comprising 69 365 adults without cardiovascular disease at baseline. Participants were followed for AVS incidence and death by linkage to the Swedish National Patient and Causes of Death Registers. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression. RESULTS: Over a mean follow-up of 15.3 years, 1249 cases of AVS (494 in women and 755 in men) were recorded. Compared with never drinkers of alcohol (lifelong abstainers), the risk of AVS was significantly lower in current light drinkers (1-6 drinks per week [1 drink = 12 g alcohol]; multivariable HR 0.82; 95% CI: 0.68-0.99). The risk of AVS increased with increasing smoking intensity. Compared with never smokers, the HR was 1.46 (95% CI: 1.16-1.85) in current smokers of ≥30 pack-years. Former smokers who had quit smoking 10 or more years previously had similar risk for AVS as never smokers. CONCLUSIONS: This study suggests that current light alcohol consumption is associated with a lower risk of AVS, and indicates that the association between smoking and AVS risk is reversible.

Surgical reconstruction of ruptured anterior cruciate ligament prolongs trauma-induced increase of inflammatory cytokines in synovial fluid: an exploratory analysis in the KANON trial.

OBJECTIVE: Prospectively monitor how treatment of acutely ruptured anterior cruciate ligament (ACL) affects biomarkers of inflammation and proteolytic degradation over 5 years. DESIGN: We studied 119 subjects with acute ACL injury from the randomized controlled knee anterior cruciate ligament, non-surgical versus surgical treatment (KANON)-trial (Clinical trial ISRCTN 84752559) who had synovial fluid, serum and urine samples available from at least two out of six visits over 5 years after acute ACL rupture. All subjects followed a similar rehabilitation protocol where, according to randomization, 60 also had early ACL reconstruction and 59 had the option to undergo a delayed ACL reconstruction if needed. Interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFNγ), tumor necrosis factor (TNF), amino acids alanine, arginine, glycine, serine (ARGS)-aggrecan, C-terminal crosslinking telopeptide type II collagen (CTX-II) and N-terminal crosslinking telopeptide type I collagen (NTX-I) were quantified by enzyme-linked immunosorbent assays (ELISA). RESULTS: Subjects randomized to early ACL reconstruction had higher cytokine concentrations in index knee synovial fluid at 4 months (IL-6, IL-8, IL-10, TNF), 8 months (IL-6 and TNF) and at 5 years (IFNγ) compared to those randomized to optional delayed reconstruction. Those that underwent delayed ACL reconstruction within 5 years (30 subjects), had higher synovial fluid concentrations of IL-6 at 5 years compared to those treated with rehabilitation alone. No differences between groups were noted for ARGS-aggrecan in synovial fluid and serum or CTX-II and NTX-I in urine over 5 years, neither as randomized nor as treated. CONCLUSIONS: Surgical ACL reconstruction constitutes a second trauma to the acutely injured joint resulting in a prolonged elevation of already high synovial fluid levels of inflammatory cytokines.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data.

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10^{-3}. We take into account systematic effects that could mimic true anisotropies at this level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. The present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.

Fish consumption and all-cause mortality in a cohort of Swedish men and women.

BACKGROUND: Epidemiological studies of fish consumption and all-cause mortality have provided inconsistent results. OBJECTIVE: We examined the dose-response association between fish consumption and mortality from all causes in a large population-based cohort of Swedish men and women. METHODS: The study included 72 522 participants (33 973 women and 38 549 men), aged 45-83 years, from the Swedish Mammography Cohort and the Cohort of Swedish Men. Information on fish consumption was obtained through a self-administered questionnaire in 1997. Participants were followed for 17 years (1 January 1998 to 31 December 2014), and data on death and causes of death were ascertained through linkage to the Swedish Cause of Death Register. We used Cox proportional hazard regression to estimate hazard ratios (HRs) of death. Fish consumption was evaluated as a continuous predictor, flexibly modelled with restricted cubic splines to assess potential nonlinear associations. RESULTS: During follow-up, 16 730 deaths (7168 women and 9562 men) were recorded. The dose-response association between fish consumption and all-cause mortality was U-shaped. Compared with the median fish consumption (women: 25.0; men: 30.5 g day-1 ), lower levels of consumption were progressively associated with higher mortality risk up to 25% for women [HR 1.25; 95% confidence interval (CI): 1.11, 1.40] and 19% for men (HR 1.19; 95% CI: 1.07, 1.32) with no reported consumption. Increasingly higher levels of fish consumption were associated with higher mortality risk only amongst women, with a 39% higher mortality risk amongst women reporting the highest level of fish consumption (80 g day-1 ; HR 1.39; 95% CI: 1.15, 1.68). CONCLUSION: These results indicate a U-shaped association between fish consumption and all-cause mortality, particularly amongst women.

Low-dose developmental exposure to bisphenol A alters the femoral bone geometry in wistar rats.

BACKGROUND: Bisphenol A (BPA) is a chemical produced in large volumes for use in manufacturing of consumer products and industrial applications, and an endocrine disruptor known to affect several hormonal systems. Bone produces hormones and is additionally a sensitive hormone target tissue, and is thus potentially sensitive to low doses of endocrine disruptors such as BPA, especially during development. METHODS: 110 pregnant Wistar rats were gavaged with 0; 25 µg; 250 µg; 5000 µg or 50,000 µg BPA/kg bodyweight (bw)/day from gestational day 7 until weaning at postnatal day 22. The three-month-old offspring were sacrificed and right femurs collected for length measurements, geometrical measurements by peripheral quantitative computed tomography (pQCT), as well as for analyses of biomechanical properties using the three-point-bending method. RESULTS: The femur was elongated in female offspring of dams exposed to 25 or 5000 µg BPA/kg bw/day (1.8% and 2.1%, respectively), and increased cortical thickness (4.7%) was observed in male offspring of dams exposed to 25 µg BPA/kg bw/day, compared to controls (p < 0.005). The biomechanical properties of the bone were not significantly altered. CONCLUSIONS: In utero and lactational exposure to the lowest BPA dose used in this study altered femoral geometry in both male and female offspring. This was observed at 25 µg BPA/kg bw/day, a dose lower than the Human Equivalent Dose (HED) applied by EFSA to set a temporary TDI (609 µg BPA/kg bw/day), and far lower than the No-Observed-Adverse-Effect-Level (NOAEL) (5000 µg BPA/kg bw/day) on which the US FDA TDI is based.