The Four Pillars for Successful Regenerative Therapy in Endodontics: Stem Cells, Biomaterials, Growth Factors, and Their Synergistic Interactions.

Endodontics has made significant progress in regenerative approaches in recent years, thanks to advances in biologically based procedures or regenerative endodontic therapy (RET). In recent years, our profession has witnessed a clear conceptual shift in this therapy. RET was initially based on a blood clot induced by apical bleeding without harvesting the patient's cells or cell-free RET. Later, the RET encompassed the three principles of tissue engineering, stromal/stem cells, scaffolds, and growth factors, aiming for the regeneration of a functional dentin pulp complex. The regenerated dental pulp will recover the protective mechanisms including innate immunity, tertiary dentin formation, and pain sensitivity. This comprehensive review covers the basic knowledge and practical information for translational applications of stem cell-based RET and tissue engineering procedures for the regeneration of dental pulp. It will also provide overall information on the emerging technologies in biological and synthetic matrices, biomaterials, and signaling molecules, recent advances in stem cell therapy, and updated experimental results. This review brings useful and timely clinical evidence for practitioners to understand the challenges faced for a successful cell-based RET and the importance of preserving or reestablishing tooth vitality. The clinical translation of these current bioengineering approaches will undoubtedly be beneficial to the future practice of endodontics.

Controversies in regenerative medicine: should knee joint osteoarthritis be treated with mesenchymal stromal cells?

Knee joint osteoarthritis is a complex immunological and degenerative disease. Current treatment strategies fail to alter its progression. Mesenchymal stromal cell (MSC) therapy for osteoarthritis has been object of research for more than 30 years. The aim of MSC therapy is intended to be holistic, with regeneration of all affected knee joint structures. The paracrine effect of the MSC secretome has been shown to be central for the regenerative capacity of MSCs. Activation of local knee-joint-specific MSCs leads to an immunomodulatory, anti-catabolic, anti-apoptotic and chondrogenic stimulus. Preclinical models have demonstrated the symptom- and disease-modifying effects of MSC therapy. At the bedside, there is evidence that autologous and allogeneic MSC therapy shows significant improvement in symptom-modifying and functional outcome. Despite this, a variety of contradictory clinical outcomes are available in the literature. The effectiveness of MSC therapy is still unclear, although there have been promising results. Regarding the diversity of cell sources, isolation, culture protocols and other factors, a comparison of different studies is difficult. Clinical translation of disease-modifying effects has not yet been shown. This narrative review presents a controversial overview of the current preclinical and clinical studies on MSC therapy in knee joint osteoarthritis.

[Minimally invasive lumbopelvic stabilization of sacral fracture and sacroiliac injury]. / Minimal-invasive lumbopelvine Stabilisierung bei Sakrumfraktur und Sprengung des Iliosakralgelenks.

OBJECTIVE: Rapid mobilization with full weight bearing by minimally invasive fixation of Os ilium to L5 in fractures of the sacrum and disruption of the sacroiliac joint (SIJ). INDICATIONS: Unstable injuries of the posterior pelvic ring in fractures of the sacrum and disruption of the SIJ. CONTRAINDICATIONS: Fracture of ilium and not injury related implants in the screw trajectory, neurological deficits regarding the fracture, decubitus in the area of surgical approach. SURGICAL TECHNIQUE: Minimally invasive screw placement in the pedicles of L5, access of ilium screw via the posterior superior iliac spine. Radiological display for the iliacal screw bearing trajectory in Os Ilium as a drop-shaped/triangle canal. Insert a Jamshidi needle orthograde in the beam path, change to guide wire and placement of iliacal screw after resection of the bone in the screw head area. Submuscular insertion of the longitudinal rods, in case of double-sided instrumentation similar procedure on the opposite side, reduction of the fracture and fixation of the rods to screws. POSTOPERATIVE MANAGEMENT: Postoperative mobilization with full weight bearing under physiotherapeutic guidance. RESULTS: Patients treated with lumbopelvic stabilization in our facility between 2012 and 2017 were identified via the hospital database and retrospectively evaluated. In 24 patients with median age of 60.1 years and a follow-up-time of 11.8 months, we found no implant displacement, infection and no wound healing problems. Full weight bearing was permitted in 21 of 24 cases, in 3 cases partial load bearing due to other injuries. Three patients reported moderate mechanical irritation of iliacal screws; 1 patient reported severe irritability with removal of the implants after bony healing of fracture 1 year postoperatively.

Fabrication of spectrally sharp Si-based dielectric resonators: combining etaloning with Mie resonances.

We use low-resolution optical lithography joined with solid state dewetting of crystalline, ultra-thin silicon on insulator (c-UT-SOI) to form monocrystalline, atomically smooth, silicon-based Mie resonators in well-controlled large periodic arrays. The dewetted islands have a typical size in the 100 nm range, about one order of magnitude smaller than the etching resolution. Exploiting a 2 µm thick SiO2 layer separating the islands and the underlying bulk silicon wafer, we combine the resonant modes of the antennas with the etalon effect. This approach sets the resonance spectral position and improves the structural colorization and the contrast between scattering maxima and minima of individual resonant antennas. Our results demonstrate that templated dewetting enables the formation of defect-free, faceted islands that are much smaller than the nominal etching resolution and that an appropriate engineering of the substrate improves their scattering properties. These results are relevant to applications in spectral filtering, structural color and beam steering with all-dielectric photonic devices.

Association between socioeconomic indicators and geographic distribution of vestibular schwannomas in West Scotland: a 15-year review.

OBJECTIVE: Socioeconomic risk factors may contribute to geographic variation in diseases, but studies are limited due to lack of large available cohorts. METHOD: A geographic analysis was performed of the association between socioeconomic risk factors and the distribution of vestibular schwannomas in adults diagnosed with sporadic vestibular schwannomas through the National Health Services in the West of Scotland from 2000 to 2015. RESULTS: A total of 511 sporadic vestibular schwannomas were identified in a population of over 3.1 million. Prevalence of vestibular schwannomas were lowest in cases with good health (-0.64, 95 per cent confidence interval: -0.93,-0.38; p = 0.002) and level 1 qualifications (-0.562, 95 per cent confidence interval: -0.882 to -0.26; p = 0.01). However, these risk factors did not demonstrate consistent linearity of correlations. Prevalence was lower in people originating from European Union accession countries from April 2001 to March 2011 (-0.63, 95 per cent confidence interval: -0.84 to -0.43; p = 0.002). No correlation between distribution of vestibular schwannomas and socioeconomic risk factors met our threshold criteria (± 0.7). CONCLUSION: This study demonstrated that there is little variation in distribution of vestibular schwannomas by socioeconomic risk factors.

PPARß/δ-dependent MSC metabolism determines their immunoregulatory properties.

Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARß/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARß/δ on MSC metabolic activity and the relevance of PPARß/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARß/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARß/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARß/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial.

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher's exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

A rare presentation of small diaphragmatic epidermoid cyst with extremely elevated serum CA19-9 level.

Epidermoid cysts are rare lesions that can occur anywhere in the body. They are associated with elevated serum levels of CA 19-9. The spleen represents the most common site of intra-abdominal localisation. Only two cases of diaphragmatic epidermoid cyst are reported in the literature. We present the case of a 61-year-old woman with a small suprasplenic subdiaphragmatic cyst discovered during the investigation of left flank pain. The establishment of an adequate diagnosis was challenging due to the difficulty in specifying the exact localisation of the cyst, the extremely elevated CA 19-9 level of 19,000 and the high uptake on 18-fluoro-2-deoxy-D-glucose positron emission tomography. The definitive diagnosis followed complete surgical excision. Intra-abdominal epidermoid cysts are usually discovered incidentally on imaging for another reason. The cyst is lined by squamous epithelium responsible for the secretion of CA 19-9. The elevation of serum CA 19-9 is due to small rupture or increased intraluminal pressure followed by diffusion to the bloodstream. Surgery with en-bloc resection represents the optimal treatment to avoid any risk of recurrence. The definitive diagnosis is established by demonstrating positive immunohistopathological staining of epithelial cell to CA 19.9.

Assessing and visualising hazard impacts to enhance the resilience of Critical Infrastructures to urban flooding.

The design, construction and maintenance of Critical Infrastructures (CI) is commonly based on standards that are rigorous, so as to withstand any climate or weather-linked pressures. However, due to climate change, climate characteristics may shift, resulting in increased frequency/magnitude of potential failures, or exposure to new unknown risks. As vital components for the normal functioning of modern societies, the resilience of CIs under climate stressors encompasses their structural integrity, their operational elements, and their capacity to maximize business output. In this work, we propose an integrated and participatory methodological approach to enhance the resilience of interconnected CIs to urban flooding under climate change, by assessing the risk and introducing adaptation measures. The main objectives of the proposed methodology and approach are: (i) to provide scientific evidence for better understanding of how future climate regimes might affect normal operation of interconnected CI in urban areas during their lifespan; (ii) to assess the cost-effectiveness of different adaptation measures; (iii) to involve local stakeholders and operators in the co-design of the approach, as well as the assessment and the evaluation of adaptation measures; (iv) to combine computational modelling with advanced 3D visualisation techniques for effectively engaging stakeholders in decision making; (v) to include risk assessment and damage functions co-designed by end-users and local stakeholders; (vi) to integrate all of the aforementioned components in a specifically designed cloud platform as a Decision Support System for end-users, (vii) to validate the DSS by the end users and local stakeholders. The paper presents the computational background and tools. Additionally, it describes a Case Study in Torbay, UK, where the full methodology and the proposed participatory approach have been applied, with all the specifics, i.e., the scenarios of extreme flooding, the numerical and visualisation results, the response of the stakeholders and the evaluation of selected adaptation measures.

Breast sonoelastography: Now and in the future.

PURPOSE: The purpose of this study was to identify practice trends and opinions concerning breast sonoelastography in two different health care systems, one in Europe (France) and the other in North America (Province of Québec/Canada). MATERIALS AND METHODS: We distributed an 11-item online survey among French and Canadian breast radiologists. The survey comprised of four sections: (i) personal practice characteristics, (ii) breast sonoelastography usage in daily practice and evaluation of its usefulness, (iii) limitations and roles of sonoelastogrpahy in their clinical practice, and (iv) types of elastographic technique and interpretation. RESULTS: We found that sonoelastography of the breast appears unpopular among Canadian radiologists, and poorly credible among French radiologists, who perceive it as an unreliable technique. To date, its real impact in clinical practice remains uncertain. CONCLUSION: Continued learning and awareness of the indications, advantages and limitations of breast sonoelastography may motivate breast radiologists to adopt its use.

Training the Twenty-First Century Cancer Epidemiologist.

To assess and advance training of twenty-first century cancer epidemiologists, the National Cancer Institute (NCI) sought to obtain a snapshot of the cancer epidemiology training landscape by conducting a survey across academic institutions and cancer centers, focusing on four key training areas driving current cancer epidemiology research ("drivers"): (1) collaboration, (2) novel methods/technologies, (3) multilevel analysis, and (4) knowledge integration. Complementary to the survey, we conducted a portfolio analysis of active NCI-funded training grants. In the present report, we provide our findings from this effort and contribute to the on-going conversation regarding the training of next-generation cancer epidemiologists. Analyses and insights gained from conversations with leaders/educators across 24 academic institutions/cancer centers and the portfolio analysis of training grants echoed contemporaneous conversation that cancer epidemiology training must adapt to meet the needs of the changing research environment. Currently, with the exception of novel methods/technologies, cancer epidemiology trainees receive the majority of their training in collaboration, multilevel approaches, and knowledge integration/translation either informally, ad hoc, or not at all; exposure to these identified drivers varied considerably by institution, mentor, and other external as well as internal factors.

Breast magnetic resonance imaging: are those who need it getting it?

BACKGROUND: Indications for breast magnetic resonance imaging (mri), a very sensitive but less-specific tool for breast investigation, remain controversial, and accessibility is limited. The purposes of our study were to determine the proportion of breast mri exams performed for various clinical indications, to assess the wait times for breast mri, and to create a list of evidence-based indications for breast mri. METHODS: The indications for breast mri exams performed in September 2013 at our academic centre were audited. A multidisciplinary meeting held in May 2014 established a list of evidence-based indications for breast mri, after which, in September 2014 and 2015, breast mri exams were re-audited for clinical indications, and pending requests were calculated. RESULTS: In September 2013, surveillance of women with a prior diagnosis of breast cancer represented 21% of breast mri exams (24 of 113), with preoperative staging representing 18% of exams (20 of 113) and high-risk screening representing 12% (13 of 113). Of pending mri requests, 230 were within the recommended delay period, and 457 exceeded the recommended delay. After elaboration of evidence-based guidelines, repeat audits in September 2014 and September 2015 showed that mri performed for women with a prior breast cancer diagnosis represented 23% (33 of 141) and 7% (10 of 143) of exams respectively, with preoperative staging having declined to 9% (13 of 141) and 11% (16 of 143) of exams, and high-risk screening having increased to 36% (51 of 141) and 46% (66 of 143) of exams. Overall, wait times were improved for all breast mri indications. CONCLUSIONS: Through multidisciplinary discussion, we actualized a list of breast mri indications, prioritized requests more adequately, and improved wait times.

Use of topical glucocorticoids: a population-based cohort study.

BACKGROUND: Little is known about the prescriptions of topical glucocorticoids in the general population. OBJECTIVES: To report an overall picture of topical glucocorticoid prescriptions in France. METHODS: This study used the Echantillon Généraliste de Bénéficiaires (EGB) database, a 1/97th random sampling of the French population covered by the main national healthcare insurance system (approximately 90% of the whole population). All patients prescribed topical glucocorticoids over a 5-year period (1 January 2011 to 31 December 2015) were identified using a specific code list for topical glucocorticoids. RESULTS: Over the 5-year study period, 662 531 individuals were recorded for at least 1 day in the EGB. Among them, 220 345 (33.3%) were prescribed at least once topical glucocorticoid. The prevalence of topical glucocorticoid prescription increased regularly from 2011 (11.7%) to 2015 (12.5%). A total of 922 026 tubes of topical glucocorticoids were dispensed, mainly high-potency glucocorticoids, and were mainly prescribed by general practitioners (73.1%). A total of 1713 (0.8%) patients were prescribed at least 24 tubes over a calendar year. These patients were more frequently men (P < 0.001) and older (P < 0.001) than the overall population of patients prescribed topical glucocorticoids. The 124 844 tubes prescribed to these patients had stronger potency than those prescribed to the overall population (P < 0.001) and were mostly prescribed by general practitioners (68.1%). The reasons for prescription were available for only 371 patients (21.7%) and were mainly psoriasis, auto-immune bullous dermatoses and eczema. CONCLUSION: About 12% of the French general population is prescribed topical glucocorticoids at least once each year. Most prescriptions are issued by general practitioners, dermatologists being the prescribers in less than one-quarter of cases.

The multi-spectral line-polarization MSE system on Alcator C-Mod.

A multi-spectral line-polarization motional Stark effect (MSE-MSLP) diagnostic has been developed for the Alcator C-Mod tokamak wherein the Stokes vector is measured in multiple wavelength bands simultaneously on the same sightline to enable better polarized background subtraction. A ten-sightline, four wavelength MSE-MSLP detector system was designed, constructed, and qualified. This system consists of a high-throughput polychromator for each sightline designed to provide large étendue and precise spectral filtering in a cost-effective manner. Each polychromator utilizes four narrow bandpass interference filters and four custom large diameter avalanche photodiode detectors. Two filters collect light to the red and blue of the MSE emission spectrum while the remaining two filters collect the beam pi and sigma emission generated at the same viewing volume. The filter wavelengths are temperature tuned using custom ovens in an automated manner. All system functions are remote controllable and the system can be easily retrofitted to existing single-wavelength line-polarization MSE systems.

Acute intraoperative heparin-induced thrombocytopenia (HIT) and thrombosis during coronary artery bypass grafting: Two case reports providing evidence for the role of preoperative LMWH in triggering sensitization.

INTRODUCTION: Systemic anticoagulation is necessary during cardiac surgery. To date, the only well established anticoagulation protocol involves the use of heparin. However, heparin can cause heparin-induced thrombocytopenia (HIT) a potentially life threatening immune-mediated thromboembolic syndrome. Until now, devastating consequences of HIT syndrome in patients undergoing heart surgery have been described, but only postoperatively. Here we report the development of HIT syndrome during cardiac revascularization by intra-operative heparin administration in two patients previously exposed to LMWH. PATIENTS/METHODS: We report on two patients who developed rapid and profound intravascular coagulation with severe thrombocytopenia (platelet count decreased from ≥250×109/L to 50×109/L) due to HIT development caused by heparin administration during coronary artery bypass graft surgery. In addition we report that fondaparinux, given intra-operatively in association with antithrombin, may be a suitable alternative anticoagulant for successfully preventing the devastating consequences of intra-operative HIT development. CONCLUSION: To our knowledge, this is the first report describing the development of acute intra-operative HIT, secondary to high-dose UFH administered for coronary revascularization, in which the unexpected presence of platelet-activating anti-PF4/heparin antibodies at surgery was explained by preoperative administration of a one-week course of LMWH but without any preoperative evidence for HIT.

Harnessing the Angiogenic Potential of Stem Cell-Derived Exosomes for Vascular Regeneration.

Mesenchymal stem cells (MSCs) are known to display important regenerative properties through the secretion of proangiogenic factors. Recent evidence pointed at the key role played by exosomes released from MSCs in this paracrine mechanism. Exosomes are key mediators of intercellular communication and contain a cargo that includes a modifiable content of microRNA (miRNA), mRNA, and proteins. Since the biogenesis of the MSCs-derived exosomes is regulated by the cross talk between MSCs and their niche, the content of the exosomes and consequently their biological function are dependent on the cell of origin and the physiologic or pathologic status of their microenvironment. Recent preclinical studies revealed that MSCs-derived exosomes have a critical implication in the angiogenic process since the use of exosomes-depleted conditioned medium impaired the MSCs angiogenesis response. In this review, we discuss the current knowledge related to the angiogenic potential of MSCs-exosomes and methods to enhance their biological activities for improved vascular regeneration. The current gain of insight in exosomes studies highlights the power of combining cell based therapies and their secreted products in therapeutic angiogenesis.

PPARß/δ directs the therapeutic potential of mesenchymal stem cells in arthritis.

OBJECTIVES: To define how peroxisome proliferator-activated receptor (PPAR) ß/δ expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPARß/δ interacts with factors such as nuclear factor-kappa B (NF-κB) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPARß/δ on MSC immunosuppressive properties. METHODS: We either treated human MSCs (hMSCs) with the irreversible PPARß/δ antagonist (GSK3787) or derived MSCs from mice deficient for PPARß/δ (PPARß/δ-/- MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays. RESULTS: Modulation of PPARß/δ expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPARß/δ-/- MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPARß/δ+/+ MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPARß/δ-/- MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPARß/δ+/+ MSCs. The enhanced NO2 production by PPARß/δ-/- MSCs was due to the increased retention of NF-κB p65 subunit on the κB elements of the inducible nitric oxide synthase promoter resulting from PPARß/δ silencing. CONCLUSIONS: Our study is the first to show that the inhibition or knockdown of PPARß/δ in MSCs primes their immunoregulatory functions. Thus, the regulation of PPARß/δ expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.

Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth.

Mesenchymal stem cells (MSCs) obtained from bone marrow (BM) have been shown to promote neuronal growth and survival. However, the comparative effects of MSCs of different sources, including menstrual MSCs (MenSCs), BM, umbilical cord and chorion stem cells on neurite outgrowth have not yet been explored. Moreover, the modulatory effects of MSCs may be mediated by paracrine mechanisms, i.e. by molecules contained in the MSC secretome that includes soluble factors and extracellular vesicles such as microvesicles and/or exosomes. The biogenesis of microvesicles, characterized by a vesicle diameter of 50 to 1000 nm, involves membrane shedding while exosomes, of 30 to 100 nm in diameter, originate in the multivesicular bodies within cells. Both vesicle types, which can be harvested from the conditioned media of cell cultures by differential centrifugation steps, regulate the function of target cells due to their molecular content of microRNA, mRNA, proteins and lipids. Here, we compared the effect of human menstrual MSCs (MenSCs) mediated by cell-cell contact, by their total secretome or by secretome-derived extracellular vesicles on neuritic outgrowth in primary neuronal cultures. The contact of MenSCs with cortical neurons inhibited neurite outgrowth while their total secretome enhanced it. The extracellular vesicle fractions showed a distinctive effect: while the exosome-enriched fraction enhanced neurite outgrowth, the microvesicle-enriched fraction displayed an inhibitory effect. When we compared exosome fractions of different human MSC sources, MenSC exosomes showed superior effects on the growth of the longest neurite in cortical neurons and had a comparable effect to BM-SC exosomes on neurite outgrowth in dorsal root ganglia neurons. Thus, the growth-stimulating effects of exosomes derived from MenSCs as well as the opposing effects of both extracellular vesicle fractions provide important information regarding the potential use of MenSCs as therapeutic conveyors in neurodegenerative pathologies.