Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4

BACKGROUND: Spontaneous repair is limited after CNS injury or degeneration because neurogenesis and axonal regrowth rarely occur in the adult brain. As a result, cell transplantation has raised much interest as potential treatment for patients with CNS lesions. Several types of cells have been considered as candidates for such cell transplantation and replacement therapies. Foetal brain tissue has already been shown to have significant effects in patients with Parkinson's disease. Clinical use of the foetal brain tissue is, however, limited by ethical and technical problems as it requires high numbers of grafted foetal cells and immunosuppression. Alternatively, several reports suggested that mesenchymal stem cells, isolated from adult bone marrow, are multipotent cells and could be used in autograft approach for replacement therapies. RESULTS: In this study, we addressed the question of the possible influence of mesenchymal stem cells on neural stem cell fate. We have previously reported that adult rat mesenchymal stem cells are able to express nestin in defined culture conditions (in the absence of serum and after 25 cell population doublings) and we report here that nestin-positive (but not nestin-negative) mesenchymal stem cells are able to favour the astroglial lineage in neural progenitors and stem cells cultivated from embryonic striatum. The increase of the number of GFAP-positive cells is associated with a significant decrease of the number of Tuj1- and O4-positive cells. Using quantitative RT-PCR, we demonstrate that mesenchymal stem cells express LIF, CNTF, BMP2 and BMP4 mRNAs, four cytokines known to play a role in astroglial fate decision. In this model, BMP4 is responsible for the astroglial stimulation and oligodendroglial inhibition, as 1) this cytokine is present in a biologically-active form only in nestin-positive mesenchymal stem cells conditioned medium and 2) anti-BMP4 antibodies inhibit the nestin-positive mesenchymal stem cells conditioned medium inducing effect on astrogliogenesis. CONCLUSIONS: When thinking carefully about mesenchymal stem cells as candidates for cellular therapy in neurological diseases, their effects on resident neural cell fate have to be considered

Digging deeper into lymphatic vessel formation in vitro and in vivo

Background Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays distinctive features than blood vasculature, and mechanisms underlying the formation of new lymphatic vessels during physiological and pathological processes are still poorly documented. Most studies on lymphatic vessel formation are focused on organism development rather than lymphangiogenic events occurring in adults. We have here studied lymphatic vessel formation in two in vivo models of pathological lymphangiogenesis (corneal assay and lymphangioma). These data have been confronted to those generated in the recently set up in vitro model of lymphatic ring assay. Ultrastructural analyses through Transmission Electron Microscopy (TEM) were performed to investigate tube morphogenesis, an important differentiating process observed during endothelial cell organization into capillary structures

Experimental Approach of Quadriceps Strength Measurement: Implications for Assessments in Critically Ill Survivors.

(1) Background: The supine testing position is suitable for early quadriceps strength (QS) assessment in intensive care unit, while a seated position is more appropriate for survivors who have regained mobility. Acquiring consistent measurements is essential for longitudinal follow-up. We compared the QS generated in different settings in healthy volunteers. (2) Methods: Isometric QS was assessed using a MicroFet2 and standardised protocols comparing different modalities. Hip and knee flexion angles were, respectively, 45° and 40° (H45-K40) in the supine position, and both at 90° (H90-K90) in the seated position. Dynamometer was either handheld (non-fixed configuration, NFC), or fixed (FC) in a cubicle. (3) Results: QS in H90–K90 and H45-K40 positions were strongly correlated, but QS was higher in the later position regardless of the configuration. Compared to H45-K40, biases of 108.2N (or 28.05%) and 110.3N (27.13%) were observed in H90-K90 position, respectively, in the NFC and FC. These biases were independently and positively associated with QS (p < 0.001). For both position, there were no significant differences between QS measured in NFC or FC. (4) Conclusions: The quadriceps was less efficient in the seated position, compared to the supine position, in healthy volunteers. These findings have practical implications for further assessments and research in critically ill patients

Does Plasminogen Activator Inhibitor-1 Drive Lymphangiogenesis?

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis

The role of diet and exercise and of glucosamine sulfate in the prevention of knee osteoarthritis: Further results from the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study

Background and objectives: The PRevention of knee Osteoarthritis in Overweight Females (PROOF) study (ISRCTN 42823086) described a trend for a decrease in the incidence of knee osteoarthritis (OA) by a tailored diet and exercise program (DEP) or by oral glucosamine sulfate in women at risk for the disease, using a composite clinical and/or radiological outcome. The aim of this updated post-hoc analysis was to re-assess the results according to more precise techniques and take advantage of the 2×2 factorial design. Methods: A total of 407 overweight (BMI ≥ 27 kg/m2) women of 50-60 years of age with no diagnosis of knee OA were randomized to: (1) no DEP + placebo (Control, N = 102), (2) DEP + placebo (DEP, N = 101), (3) glucosamine sulfate + no DEP (GS, N = 102), and (4) DEP + glucosamine sulfate (DEP + GS, N =102) and followed for 2.5 years, with standardized postero-anterior, semiflexed (MTP) view knee radiographs at baseline and end of the study. DEP consisted of a tailored low fat and/or low caloric diet and easy to implement physical activities. Glucosamine was given as oral crystalline glucosamine sulfate 1500 mg once daily, double-blinded vs. placebo. Incident knee OA was defined as radiographic progression of ≥1 mm minimum joint space narrowing (mJSN) in the medial tibiofemoral compartment, as previously assessed by the visual (manual) technique and by a new semi-automated method. Logistic regression analysis was used to calculate the odds ratio for the effect of the interventions. Results: After 2.5 years, 11.8% of control subjects developed knee OA. This incidence was decreased with glucosamine sulfate, either alone or in combination with the DEP, but not by the DEP alone. Since there was no statistical interaction between treatments, the 2×2 factorial design allowed analysis of patients receiving glucosamine sulfate (= 204) vs. those not receiving it (= 203), similarly for those on the DEP (= 203) or not (= 204). Glucosamine sulfate significantly decreased the risk of developing knee OA: odds ratio (OR) = 0.41 (95% CI: 0.20-0.85, P = 0.02) by the manual JSN assessment method and OR = 0.42 (95% CI: 0.20-0.92, P = 0.03) by the semi-automated technique. Conversely, there was no decrease in risk with the DEP. Conclusions: Glucosamine sulfate decreased the risk of developing radiographic knee OA over 2.5 years in overweight, middle-aged women at risk, as determined by medial mJSN progression. Conversely a tailored diet and exercise program exerted no preventive effect, possibly because of the lower than expected effect on weight loss

It starts at home? Climate policies targeting household consumption and behavioral decisions are key to low-carbon futures

Through their consumption behavior, households are responsible for 72% of global greenhouse gas emissions. Thus, they are key actors in reaching the 1.5 °C goal under the Paris Agreement. However, the possible contribution and position of households in climate policies is neither well understood, nor do households receive sufficiently high priority in current climate policy strategies. This paper investigates how behavioral change can achieve a substantial reduction in greenhouse gas emissions in European high-income countries. It uses theoretical thinking and some core results from the HOPE research project, which investigated household preferences for reducing emissions in four European cities in France, Germany, Norway and Sweden. The paper makes five major points: First, car and plane mobility, meat and dairy consumption, as well as heating are the most dominant components of household footprints. Second, household living situations (demographics, size of home) greatly influence the household potential to reduce their footprint, even more than country or city location. Third, household decisions can be sequential and temporally dynamic, shifting through different phases such as childhood, adulthood, and illness. Fourth, short term voluntary efforts will not be sufficient by themselves to reach the drastic reductions needed to achieve the 1.5 °C goal; instead, households need a regulatory framework supporting their behavioral changes. Fifth, there is a mismatch between the roles and responsibilities conveyed by current climate policies and household perceptions of responsibility. We then conclude with further recommendations for research and policy

Decision-based interactive model to determine re-opening conditions of a large university campus in Belgium during the first COVID-19 wave

peer reviewedBackground The role played by large-scale repetitive SARS-CoV-2 screening programs within university populations interacting continuously with an urban environment, is unknown. Our objective was to develop a model capable of predicting the dispersion of viral contamination among university populations dividing their time between social and academic environments. Methods Data was collected through real, large-scale testing developed at the University of Liège, Belgium, during the period Sept. 28th-Oct. 29th 2020. The screening, offered to students and staff (n = 30,000), began 2 weeks after the re-opening of the campus but had to be halted after 5 weeks due to an imposed general lockdown. The data was then used to feed a two-population model (University + surrounding environment) implementing a generalized susceptible-exposed-infected-removed compartmental modeling framework. Results The considered two-population model was sufficiently versatile to capture the known dynamics of the pandemic. The reproduction number was estimated to be significantly larger on campus than in the urban population, with a net difference of 0.5 in the most severe conditions. The low adhesion rate for screening (22.6% on average) and the large reproduction number meant the pandemic could not be contained. However, the weekly screening could have prevented 1393 cases (i.e. 4.6% of the university population; 95% CI: 4.4–4.8%) compared to a modeled situation without testing. Conclusion In a real life setting in a University campus, periodic screening could contribute to limiting the SARS-CoV-2 pandemic cycle but is highly dependent on its environment

A reference case for economic evaluations in osteoarthritis: An expert consensus article from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)

Background: General recommendations for a reference case for economic studies in rheumatic diseases were published in 2002 in an initiative to improve the comparability of cost-effectiveness studies in the field. Since then, economic evaluations in osteoarthritis (OA) continue to show considerable heterogeneity in methodological approach. Objectives: To develop a reference case specific for economic studies in OA, including the standard optimal care, with which to judge new pharmacologic and non-pharmacologic interventions. Methods: Four subgroups of an ESCEO expert working group on economic assessments (13 experts representing diverse aspects of clinical research and/or economic evaluations) were charged with producing lists of recommendations that would potentially improve the comparability of economic analyses in OA: outcome measures, comparators, costs and methodology. These proposals were discussed and refined during a face-to-face meeting in 2013. They are presented here in the format of the recommendations of the recently published Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, so that an initiative on economic analysis methodology might be consolidated with an initiative on reporting standards. Results: Overall, three distinct reference cases are proposed, one for each hand, knee and hip OA; with diagnostic variations in the first two, giving rise to different treatment options: interphalangeal or thumb-based disease for hand OA and the presence or absence of joint malalignment for knee OA. A set of management strategies is proposed, which should be further evaluated to help establish a consensus on the "standard optimal care" in each proposed reference case. The recommendations on outcome measures, cost itemisation and methodological approaches are also provided. Conclusions: The ESCEO group proposes a set of disease-specific recommendations on the conduct and reporting of economic evaluations in OA that could help the standardisation and comparability of studies that evaluate therapeutic strategies of OA in terms of costs and effectiveness