FCH-PET/CT in Primary Hyperparathyroidism With Discordant/Negative MIBI Scintigraphy and Ultrasonography.

CONTEXT: The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown. OBJECTIVE: To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX). DESIGN: Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism. SETTING: Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism. PATIENTS: Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX. MAIN OUTCOME MEASURES: To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT. RESULTS: The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients. CONCLUSION: This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.

Netrin-1 Secreted by Human Osteoarthritic Articular Chondrocytes Promotes Angiogenesis in Vitro.

OBJECTIVE: Netrin-1 expression in articular cartilage is correlated with osteoarthritic changes. We aimed to investigate the contribution of Netrin-1 secreted by human osteoarthritic articular chondrocytes to angiogenesis process in vitro. DESIGN: Human articular chondrocytes were extracted from non-osteoarthritic (n = 10) and osteoarthritic (n = 22) joints obtained from surgical specimens and incubated for 24 hours. Medium conditioned by non-osteoarthritic and osteoarthritic articular chondrocytes were collected. Human umbilical vein endothelial cells (HUVEC) were treated with control and conditioned medium and assessed using assays for cell adherence, migration, and tube formation. Netrin-1 expression and secretion was compared between non-osteoarthritic and osteoarthritic chondrocytes by qPCR, Western blot, and ELISA. The role of chondrocyte-secreted Netrin-1 on HUVEC functions was assessed by immunological neutralization using an anti-Netrin-1 monoclonal antibody. RESULTS: As compared with medium conditioned by non-osteoarthritic chondrocytes, medium conditioned by osteoarthritic chondrocytes permitted tube formation by HUVEC. Both non-osteoarthritic and osteoarthritic chondrocytes expressed Netrin-1 at the RNA and protein levels. At the RNA level, Netrin-1 expression did not differ between non-osteoarthritic and osteoarthritic chondrocytes. At the protein level, Netrin-1 appeared as a full protein of 64 kDa in non-osteoarthritic chondrocytes and as two cleaved proteins of 55 kDa and 64 kDa in osteoarthritic chondrocytes. Immunological neutralization of endogenous Netrin-1 reduced the pro-angiogenic and pro-inflammatory transcriptional profile of HUVEC treated with the medium conditioned by osteoarthritic chondrocytes, as well as their capacities to form tubes. CONCLUSIONS: Medium conditioned by osteoarthritic chondrocytes permits tube formation by HUVEC in vitro. This permissive effect is mediated by Netrin-1.

Plasma Endocan as a Biomarker of Thrombotic Events in COVID-19 Patients.

(1) Background: Endocan is a marker of endothelial dysfunction that may be associated with thrombotic events. The aim of the study was to investigate the performance of endocan as a marker of thrombotic events in COVID-19 patients. (2) Methods: We measured endocan in plasma from 79 documented COVID-19 patients classified according to disease severity (from mild to critical). Thrombotic events were recorded. (3) Results: Endocan concentrations at admission were significantly increased according to COVID-19 severity. Levels of endocan were significantly increased in patients experiencing thrombotic events in comparison with those without (16.2 (5.5−26.7) vs. 1.81 (0.71−10.5) ng/mL, p < 0.001). However, endocan concentrations were not different between pulmonary embolism and other thrombotic events. The Receiver Operating Characteristic (ROC) analysis for the identification of thrombotic events showed an area under the ROC curve (AUC) of 0.776 with an optimal threshold at 2.83 ng/mL (93.8% sensitivity and 54.7% specificity). When combining an endocan measurement with D-dimers, the AUC increased to 0.853. When considering both biomarkers, the Kaplan−Meier survival curves showed that the combination of endocan and D-dimers better discriminated patients with thrombotic events than those without. The combination of D-dimers and endocan was independently associated with thrombotic events. (4) Conclusions: Endocan might be a useful and informative biomarker to better identify thrombotic events in COVID-19 patients.

Exposure of human cerebral microvascular endothelial cells hCMEC/D3 to laminar shear stress induces vascular protective responses.

Endothelial cells (ECs) are constantly submitted in vivo to hemodynamical forces derived from the blood circulation, including shear stress (SS). ECs are able to detect SS and consequently adapt their phenotype, thus affecting many endothelial functions. If a plethora of shear stress-regulated molecular networks have been described in peripheral ECs, less is known about the molecular responses of microvascular brain ECs which constitute the blood-brain barrier (BBB). In this work, we investigated the response of human cerebral microvascular ECs to laminar physiological shear stress using the well characterized hCMEC/D3 cell line. Interestingly, we showed that hCMEC/D3 cells responded to shear stress by aligning perpendicularly to the flow direction, contrary to peripheral endothelial cells which aligned in the flow direction. Whole proteomic profiles were compared between hCMEC/D3 cells cultured either in static condition or under 5 or 10 dyn.cm-2 SS for 3 days. 3592 proteins were identified and expression levels were significantly affected for 3% of them upon both SS conditions. Pathway analyses were performed which revealed that most proteins overexpressed by SS refer to the antioxidant defense, probably mediated by activation of the NRF2 transcriptional factor. Regarding down-regulated proteins, most of them participate to the pro-inflammatory response, cell motility and proliferation. These findings confirm the induction of EC quiescence by laminar physiological SS and reveal a strong protective effect of SS on hCMEC/D3 cells, suggesting a similar effect on the BBB. Our results also showed that SS did not significantly increase expression levels nor did it affect the localization of junctional proteins and did not afect either the functional activity of several ABC transporters (P-glycoprotein and MRPs). This work provides new insights on the response of microvascular brain ECs to SS and on the importance of SS for optimizing in vitro BBB models.

Low serum progesterone affects live birth rate in cryopreserved blastocyst transfer cycles using hormone replacement therapy.

RESEARCH QUESTION: Does serum progesterone concentration on the day of vitrified-warmed embryo transfer affect live birth rate (LBR) with hormonal replacement therapy (HRT) cycles? DESIGN: Observational cohort study of patients (n = 915) undergoing single autologous vitrified-warmed blastocyst transfer under HRT using vaginal micronized progesterone. Women were included once, between January 2019 and March 2020. Serum progesterone concentration was measured by a single laboratory on the morning of embryo transfer. The primary end point was LBR. Univariate and multivariate logistic regression models were used for statistical analyses. RESULTS: Median (25th-75th percentile) serum progesterone concentration on the day of embryo transfer was 12.5 ng/ml (9.8-15.3). The LBR was 31.5% (288/915) in the overall population. No significant differences were found in implantation rates (40.7% versus 44.9%); LBR was significantly lower in women with a progesterone concentration ≤25th percentile (≤9.8 ng/ml) (26.1% versus 33.2%, P = 0.045) versus women with a progesterone concentration >25th percentile. This correlated with a significantly higher early miscarriage rate (35.9% versus 21.6%, P = 0.005). After adjusting for potential confounding factors in multivariate analysis, low serum progesterone levels (≤9.8 ng/ml) remained significantly associated with lower LBR (OR 0.68 95% CI 0.48 to 0.97). CONCLUSION: A minimum serum progesterone concentration is needed to optimize reproductive outcomes in HRT cycles with single autologous vitrified-warmed blastocyst transfer. Whether modifications of progesterone administration routes, dosage, or both, can improve pregnancy rates needs further study so that treatment of patients undergoing HRT cycles can be further individualized.

Oxidative Stress and Inflammatory Biomarkers for the Prediction of Severity and ICU Admission in Unselected Patients Hospitalized with COVID-19.

OBJECTIVE: We aimed to investigate the prognostic performances of oxidative stress (OS), inflammatory and cell activation biomarkers measured at admission in COVID-19 patients. DESIGN: retrospective monocentric study. SETTING: patients with suspected SARS-CoV-2 infection (COVID-19) admitted to the hospital. PATIENTS: One hundred and sixty documented and unselected COVID-19-patients. Disease severity (from mild to critical) was scored according to NIH's classification. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: We measured OS biomarkers (thiol, advanced oxidation protein products (AOPP), ischemia-modified albumin (IMA)), inflammation biomarkers (interleukin-6 (IL-6), presepsin) and cellular activation biomarkers (calprotectin) in plasma at admission. Thiol concentrations decreased while IMA, IL-6, calprotectin and PSEP increased with disease severity in COVID-19 patients and were associated with increased O2 needs and ICU admission. The best area under the receiver-operating-characteristics curve (AUC) for the prediction of ICU admission was for thiol (AUC = 0.762). A thiol concentration <154 µmol/L was predictive for ICU admission (79.7% sensitivity, 64.6% specificity, 58.8% positive predictive value, 78.9% negative predictive value). In a stepwise logistic regression, we found that being overweight, having dyspnoea, and thiol and IL-6 plasmatic concentrations were independently associated with ICU admission. In contrast, calprotectin was the best biomarker to predict mortality (AUC = 0.792), with an optimal threshold at 24.1 mg/L (94.1% sensitivity, 64.9% specificity, 97.1% positive predictive value and 98.9% negative predictive value), and survival curves indicated that high IL-6 and calprotectin concentrations were associated with a significantly increased risk of mortality. CONCLUSIONS: Thiol measurement at admission is a promising tool to predict ICU admission in COVID-19-patients, whereas IL-6 and calprotectin measurements effectively predict mortality.

Prognostic value of soluble urokinase plasminogen activator receptor in patients presenting to the emergency department with chest pain suggestive of acute coronary syndrome.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a prognostic biomarker of cardiovascular disease. OBJECTIVES: We aimed to evaluate the early prognostic value of suPAR in patients presenting to the emergency department (ED) with chest pain suggestive of acute coronary syndrome (ACS). PATIENTS AND METHODS: In a post-hoc analysis from a multicenter study including patients with a chest pain < 6 h, suPAR concentrations at ED admission were studied according to the outcome at 30-days. RESULTS: 198 patients (median age 56 years) in whom 16% had an ACS, were included. Fifteen (7.3%) patients presented a 30-day event. At ED admission, median (IQR) suPAR concentrations were higher in patients with a 30-day event in comparison to patients without event (4.54 (3.09-8.61) vs. 2.72 (2.10-3.43) ng/mL, p < 0.001). The ROC curve AUC of suPAR for the prediction of a 30-days event was 0.775 [95%CI: 0.710-0.831]. The optimal threshold was 3.3 ng/mL, with a sensitivity of 73 [45-92] % and a specificity of 72 [65-79] %. The association of a suPAR < 3.3 ng/mL AND a NT-proBNP < 160 ng/L AND a HEART score < 4 had a negative predictive value of 99 [91-100] %. A suPAR value at admission above 3.3 ng/mL was independently and significantly associated with a 30-day event in chest pain emergency patients (OR 4.87 [1.35-17.51], p = 0.015). CONCLUSION: suPAR is a promising biomarker for early prediction of events in chest pain emergency patients.

Changes in bone formation regulator biomarkers in early axial spondyloarthritis.

OBJECTIVE: The hallmark of advanced axial SpA (axSpA) is spine ankylosis due to excessive ectopic bone formation. This prospective study aimed to describe the changes in serum levels of different regulators [sclerostin, dickkopf-1 (DKK-1)] and markers of bone formation [bone morphogenetic protein 7 (BMP-7)] over 5 years in early axSpA patients and to assess determinants of such changes. METHODS: The DEvenir des Spondyloarthropathies Indifférenciées Récentes cohort is a prospective, multicentre French study of 708 patients with early (>3 months-<3 years) inflammatory back pain suggestive of axSpA. Serum levels of BMP-7, sclerostin and DKK-1 were assessed at baseline and after 2 and 5 years. Changes in bone formation regulators over time were analysed using mixed linear models. RESULTS: Serum BMP-7 significantly increased over time, with a median relative change of 223.7% [interquartile range (IQR) 0-10 700 (0.17 pg/ml/month), P < 0.001]. Serum sclerostin significantly increased over time, with a median relative change of 14.8% [IQR -7.9-41.4% (0.001 ng/ml/month), P < 0.001]. Serum DKK-1 did not significantly change over time. Serum BMP-7 increased over time in active disease (Ankylosing Spondylitis Disease Activity Score with CRP ≥1.3, P = 0.01), but the increase was less pronounced with TNF inhibitor (TNFi) use (P < 0.001). No determinant was associated with serum sclerostin change. CONCLUSION: Serum BMP-7 change over 5 years was related with inflammation; it was increased in active disease, but the increase was low with TNFi use. Serum sclerostin levels significantly increased over time, but to a lesser degree than for serum BMP-7. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, NCT01648907.

Aging Cartilage in Wild-Type Mice: An Observational Study.

OBJECTIVE: To describe the spontaneous evolution of age-related changes affecting knee joint articular cartilage, walking speed and a serum biomarker of cartilage remodeling in C57BL/6-JRj wild-type male mice. DESIGN: Histological changes were assessed by the Osteoarthritis Research Society International (OARSI) score (0=normal, 6=vertical clefts/erosion to the calcified cartilage extending >75% of the articular surface) in newborn, 1-week- and 1-, 3-, 6-, 9- and 12-month-old C57BL/6-JRj wild-type male mice, walking speed by the Locotronic system, and serum C-terminal telopeptide of type II collagen (CTX-II) content by ELISA in 1-, 3-, 6-, and 9-month-old C57BL/6-JRj wild-type male mice. RESULTS: Mean (SD) OARSI score significantly increased from 0.2 (0.3) to 1.3 (0.6) (p=0.03) between 1 and 3 months of age and from 1.3 (0.6) to 3.3 (0.6) (p=0.04) between 3 and 6 months of age. Mean walking speed was stable between 1 and 6 months of age but significantly decreased from 11.4 (1.8) to 3.2 (0.8) cm.s-1 (p=0.03) between 6 and 9 months of age. Serum CTX-II content was maximal at 1 month of age, then decreased from 12.2 (8.5) to 2.4 (8.4) pg/ml (p=0.02) between 1 and 3 months of age, remaining low and stable thereafter. CONCLUSIONS: C57BL/6-JRj wild-type male mice showed continuously increasing osteoarthritic changes but delayed decreasing walking speed with age. These variations were maximal between 3 and 9 months of age. Maximal serum CTX-II content preceded these changes.

Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed.

Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity. Hepcidin is the key iron regulator in organisms; however, no studies have investigated its role in maintaining neutrophil iron homeostasis or characterized neutrophil function in patients with hereditary hemochromatosis (HH), a common iron overload genetic disorder that results from a defect in hepcidin production. To explore these issues, we studied 2 mouse models of iron overload: an experimentally induced iron overload model (EIO), in which hepcidin is increased, and a genetic HH model of iron overload with a deletion of hepatic hepcidin. We found that iron-dependent increase of hepatic hepcidin results in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. In contrast, in both HH mouse models and HH patients, the lack of hepcidin expression protects neutrophils from toxic iron accumulation. Moreover, systemic iron overload correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. Indeed, important factors in neutrophil priming and activation, such as tumor necrosis factor α (TNF-α), VCAM-1, and ICAM-1 are increased in the plasma of HH patients and are associated with an increase in HH neutrophil phagocytosis capacity and a decrease in L-selectin surface expression. This is the first study to characterize neutrophil iron homeostasis and associated functions in patients with HH.

Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.

Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.

PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

Non-linearity and gaps in results distribution over successive Roche Lipase method applications: improvement but persistence.

Non-linearity within the primary measurement range of a lipase assay (<300 U/L) has been shown on Cobas® Roche analyzers, causing gaps in results distribution between 300 and 400 U/L. Since, new lipase method applications (LMAs) have been used. The purpose is to retrospectively evaluate their impact on relative frequencies of lipase results (RFLs).Plasma lipase results from two hospital laboratories, assayed over 7.2 years, were collected. Over this period, three successive LMAs, characterized by automated repeat-on-dilution (1/11, 1/2, or 1/10), were applied for lipase results >300 U/L: LMA1 and LMA2 on the Modular®P800, Cobas®c501 and Cobas®C701 analyzers, and LMA3 on the Cobas®C701. RFLs were determined, linearity tests were performed, and inter-agreements between lipase results corrected and uncorrected for nonlinear biases were assessed, using 180 U/L as a decisional cut-off for acute pancreatitis.Overall, RFL gaps narrowed from LMA1 (300 to ∼380 U/L) to LMA3 (300 to ∼330 U/L). For a lipase activity fixed at 300 U/L, non-linearity biases were determined at -11.2% on the Modular®P800 (LMA1), -20.8% on the Cobas®c501 (LMA1), and -3.5% (LMA2) and -2.2% (LM3) on the Cobas®C701. Diagnostically, a maximum of 0.48% lipase results were misclassified as negative (LMA1 on the Cobas®c501), and a minimum of 0.01% misclassified as negative (LMA3 on the Cobas®C701). In conclusion, successive Roche lipase method applications improved linearity within the primary measurement range. While persisting, gaps in lipase results distribution narrowed with the evolution of the methods, with a minor impact in terms of diagnostic of acute pancreatitis.

Pre-, post- or no acidification of urine samples for calcium analysis: does it matter?

Background Measuring 24 h-urine calcium concentration is essential to evaluate calcium metabolism and excretion. Manufacturers recommend acidifying the urine before a measurement to ensure calcium solubility, but the literature offers controversial information on this pre-analytical treatment. The objectives of the study were (1) to compare pre-acidification (during urine collection) versus post-acidification (in the laboratory), and (2) to evaluate the impact of acidification on urinary calcium measurements in a large cohort. Methods We evaluated the effects of pre- and post-acidification on 24-h urine samples collected from 10 healthy volunteers. We further studied the impact of acidification on the calcium results for 567 urine samples from routine laboratory practice, including 46 hypercalciuria (≥7.5 mmol/24 h) samples. Results Calciuria values in healthy volunteers ranged from 0.6 to 12.5 mmol/24 h, and no statistical significance was found between non-acidified, pre-acidified and post-acidified conditions. A comparison of the values (ranging from 0.21 to 29.32 mmol/L) for 567 urine samples before and after acidification indicated 25 samples (4.4%) with analytical differences outside limits of acceptance. The bias observed for these deviant values ranged from -3.07 to 1.32 mmol/L; no patient was re-classified as hypercalciuric after acidification, and three patients with hypercalciuria were classified as normocalciuric after acidification. These three deviant patients represent 6.5% of hypercalciuric patients. Conclusions Our results indicate that pre- and post-acidification of urine is not necessary prior to routine calcium analysis.

Serum biomarkers in people with chronic low back pain and Modic 1 changes: a case-control study.

We aimed to compare serum biomarkers of inflammation, redox status and cartilage degradation between chronic low back pain (cLBP) patients with and without Modic 1 changes. We used a convenience sample of patients recruited from a single center, case-control study, conducted in a tertiary care center. From December, 2014 to May, 2016, 2,292 patients were consecutively screened, 34 met inclusion criteria and were prospectively enrolled in the present study. Cases (n = 13) were defined as patients with Modic 1 changes detected on MRI and controls (n = 21) as cLBP patients without (Modic 0). To assess serum biomarkers of inflammation, redox status and cartilage degradation, fasting serum samples were collected in a standardized manner and analyzed by immunoassays and spectrophotometry. Mean (95% CI) age was 44.1 (40.0-48.1) years and mean LBP duration was 72.5 (53.0-91.9) months. Serum biomarkers of inflammation (IL-1ß, IL-6, IL-8 and TNF-α), redox status (total thiols, advanced oxidation protein products and carbonyl groups) and cartilage degradation (Coll2-1 and Coll2-1NO2) did not differ between cLBP patients with and without Modic 1 changes. In summary, we did not find any differences in serum biomarkers between cLBP patients with and without Modic 1 changes. Interpretation is limited by convenience sampling and small sample size.

Mechanical Stretch of High Magnitude Provokes Axonal Injury, Elongation of Paranodal Junctions, and Signaling Alterations in Oligodendrocytes.

Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination.

Impact of MPO-ANCA-mediated oxidative imbalance on renal vasculitis.

Glomerulonephritis is a severe complication of microscopic polyangiitis (MPA), a small-vessel vasculitis associated with anti-myeloperoxidase antibodies (MPO-ANCA). We previously showed the pathogenic effects of MPO-ANCA that activate MPO to trigger an oxidative burst mainly through HOCl production, contributing to endothelial injury and lung fibrosis. The aim of this study was to investigate the relationship between MPO-induced oxidative stress, anti-oxidant defenses and renal histological lesions in MPA patients. We therefore analyzed histological data from a prospective cohort of ANCA-associated glomerulonephritis. Serum-mediated HOCl production, advanced oxidation protein products (AOPP), and thiol concentration in sera were determined. From 38 patients included, histological classification noted 50% focal glomerulonephritis, 15.8% crescentic-glomerulonephritis, and 34.2% mixed-glomerulonephritis. MPA patients' sera displayed higher HOCl production by MPO ( P < 0.001), higher AOPP ( P < 0.001) and thiol ( P < 0.01) levels, compared with healthy subjects. The presence of cellular crescents was associated with higher serum-mediated HOCl production ( P = 0.049) and lower thiol levels ( P = 0.022) at disease onset. Higher thiol concentrations were associated with focal glomerulonephritis ( P = 0.042), less interstitial fibrosis ( P = 0.039) and hyalinosis ( P = 0.066). In remission, HOCl production was decreased ( P < 0.01), and thiol concentration remained high ( P = 0.39). Our findings suggest that HOCl production by activated MPO could contribute to the very early stage of glomerulonephritis, whereas thiol may exert a protective effect against the development of renal vasculitis and glomerulosclerosis. This study highlights the importance of oxidative defenses to counteract the process of MPO-ANCA associated glomerulonephritis.

Bone mineral density and bone remodeling markers in chronic low back pain patients with active discopathy: A case-control exploratory study.

OBJECTIVE: We aimed to compare bone mineral density (BMD) and bone remodeling markers in chronic low back pain (cLBP) patients with and without active discopathy (Modic 1 changes). DESIGN: We conducted a single center case-control exploratory study. For 18 months, all patients referred to a tertiary care physical medicine and rehabilitation department in France were consecutively screened. Patients fulfilling the inclusion criteria were prospectively enrolled. Cases were defined as cLBP patients with lumbar active discopathy detected on MRI and controls as cLBP patients without active discopathy. Bone mineral density (BMD) at the spine, femoral neck and total femur was assessed by dual-energy X-ray absorptiometry, and bone remodeling markers were assessed in fasting serum samples. Overall, 37 cLBP patients (13 cases and 24 controls) fulfilled inclusion criteria and were included. RESULTS: The median age was 42.0 years (Q1-Q3: 36.0-51.0) and mean (SD) LBP duration 72.3 (57.4) months. We found that BMD and levels of bone remodeling markers in cLBP patients did not differ with and without active discopathy. CONCLUSION: Our results do not support the association between active discopathy and systemic bone fragility.