Allogeneic Adipose-Derived Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Regulating Self-Reactive T Cell Responses and Dendritic Cell Function

Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising therapy for autoimmune diseases, including multiple sclerosis (MS). Administration of MSCs to MS patients has proven safe with signs of immunomodulation but their therapeutic efficacy remains low. The aim of the current study has been to further characterize the immunomodulatory mechanisms of adipose tissue-derived MSCs (ASCs) in vitro and in vivo using the EAE model of chronic brain inflammation in mice. We found that murine ASCs (mASCs) suppress T cell proliferation in vitro via inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 1/2 activities. mASCs also prevented the lipopolysaccharide- (LPS-) induced maturation of dendritic cells (DCs) in vitro. The addition of the COX-1/2 inhibitor indomethacin, but not the iNOS inhibitor L-NAME, reversed the block in DC maturation implicating prostaglandin (PG) E2 in this process. In vivo, early administration of murine and human ASCs (hASCs) ameliorated myelin oligodendrocyte protein- (MOG35-55-) induced EAE in C57Bl/6 mice. Mechanistic studies showed that mASCs suppressed the function of autoantigen-specific T cells and also decreased the frequency of activated (CD11c+ and CD11c+TNF-α+) DCs in draining lymph nodes (DLNs). In summary, these data suggest that mASCs reduce EAE severity, in part, through the impairment of DC and T cell function.This work has been financed by the Instituto de Salud Carlos III, Spain (http://www.isciii.es) and Fondo Europeo de Desarrollo Regional (FEDER, http://ec.europa.eu/regional_policy/es/funding/erdf/) from the European Union, through the Research Grants PI15/00794, CP09/00228, and CPII15/00032 (Per Anderson); PI12/01097, PI15/02015, and ISCIII Red de Terapia Celular (RD12/0019/0006, http://www.red-tercel.com/) (Francisco Martin); and PS09-00928 (Mario Delgado). Mario Delgado was supported by a grant (PSE-010000-2009-3) from the Ministerio de Ciencia e Innovación, Spain (http://www.idi.mineco.gob.es/), and P09-CTS-4723 from the Junta de Andalucia (Proyecto de Excelencia). Francisco Martin is funded by the Fundación Progreso y Salud (Consejería de Salud, Junta de Andalucía, http://www.juntadeandalucia.es/fundacionprogresoysalud/)

Sauvé-Kapandji and reverse Sauvé-Kapandji procedures for treating chronic longitudinal radioulnar dissociation with capitellum fracture

Almost all reported cases of longitudinal radioulnar dissociation have involved fracture of the radial head, rupture of the interosseous membrane, and disruption of the distal radioulnar joint, although unusual patterns of Essex-Lopresti injury have also been described. To our knowledge, this is the first report of a chronic Essex-Lopresti variant including fracture of the capitellum. A displaced capitellum fracture must alert to the possibility of longitudinal radioulnar dissociation, even without concomitant radial head fracture or symptoms at the forearm and ulnar wrist. Successful mid-term results can be achieved by treating malunion of humeral condyle and proximal migration of the radius with simultaneous Sauvé-Kapandji procedure at the wrist and reverse Sauvé-Kapandji at the elbow.Essex-Lopresti lezyonlarının nadir görülen bazı atipik formları tanımlanmış olsa da, literatürde bildirilen longitudinal radioulnar instabilite olgularında genellikle radius başı kırığı ve proksimal ve distal radioulnar eklemlerde yaralanma söz konusudur. Bu çalışmada kapitellum kırığı ile birlikte Essex- Lopresti lezyonu olan bir hastayı bildiriyoruz. Olgumuzda el bileğinde Sauvé-Kapandji ve dirsekte ters Sauvé-Kapandji tekniklerinin kombine olarak uygulanması ile orta vadede başarılı sonuçlar alınmıştır. El bileği ve önkol yakınması olmasa bile deplase kapitellum kırıklı hastalarda longitudinal radioulnar instabilite akla getirilmelidir

PARP inhibition promotes endothelial-like traits in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry

Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM+ tumors. PARP inhibition and hypoxia modulated melanoma tube formation in vitro, inducing a more sparse and regular tubular architecture. Wholetranscriptome profiling revealed that olaparib treatment under hypoxic conditions modulated the expression of genes implicated in vasculogenesis during tube formation, enhancing the endothelial-like phenotype of VM+ uveal melanoma cells. PARP inhibition, especially during hypoxia, upregulated PDGFβ, which is essential for pericyte recruitment. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM+ cells, modulate pericyte coverage, and reduce metastatic spread in VM+ melanoma.Spanish Government Ministry of Science and Innovation, Spain (MICINN) Spanish Government SAF2015-70520-R RTI2018-098968-B-I00 RTICC RD12/0036/0026CIBER Cancer ISCIII CB16/12/00421Junta de Andalucia PY20_01179Fundacion Domingo Martine

Composite Alloplastic Biomaterial vs. Autologous Platelet-Rich Fibrin in Ridge Preservation

Aim: The aim of this study was to examine the clinical and histological differences of using a combination of alloplastic beta triphasic calcium phosphate (_ β-TCP) and a cross-linked collagen membrane versus autologous platelet-rich fibrin (PRF-L) in ridge preservation after dental extraction. Material and methods: Fifty-one patients were included in this observational case-series study. Dental extractions were performed, after which 25 patients were grafted with _-TCP and 26 with PRF-L. After four months of healing, clinical, radiological, histomorphometric and histological evaluations were performed. Results: A significantly higher percentage of mineralized tissue was observed in samples from the PRF-L grafted areas. Cellularity was higher in PRF-L grafted areas (osteocytes in newly formed bone per mm2 = 123.25 (5.12) vs. 84.02 (26.53) for PRF-L and β-TCP, respectively, p = 0.01). However, sockets grafted with PRF-L showed a higher reduction in the bucco-lingual dimension after four months of healing (2.19 (0.80) vs. 1.16 (0.55) mm, p < 0.001), as well as a higher alteration in the final position of the mid muco-gingival junction (1.73 (1.34) vs. 0.88 (0.88) mm, p < 0.01). Conclusion: PRF-L concentrate accelerates wound healing in post-extraction sockets in terms of new mineralized tissue component. However, the use of β-TCP biomaterial appears to be superior to maintain bucco-lingual volume and the final position of the muco-gingival junction.The authors of this manuscript were partially supported by Research Groups #CTS-138 (FO) and #CTS-1028 (PGM, MPM) (Junta de Andalucía, Spain). Grafting materials were generously provided by Dentium Co., Ltd., Seoul, Korea

The Influence of History of Severe Periodontitis on Estimated Long-Term Marginal Bone Loss around Implants Restored with Fixed Segmented Full-Arch Rehabilitation

The authors of this manuscript are partially supported by Research Groups #CTS-138, #CTS-176 and #CTS-1028 (Junta de Andalucía, Spain).The aim of this study was to analyze the long-term marginal bone level (MBL) of implants supporting fixed full-arch restoration in patients who had previously lost their dentition due to severe periodontitis. This retrospective study included 35 patients in whom 342 implants with internal tapered conical connections were placed. MBL was analyzed radiographically over time and a long-term estimation of MBL was calculated. A mixed linear model with abutment height, graft, diameter and location (maxilla/mandible) as factors and gender, age, implant length and prosthetic variables as covariates was used to evaluate the influence on MBL. MBL in these patients showed an estimator of predictions at 4108 days after loading of −0.307 mm, SE = 0.042. Only 0.15% of implants were radiographically affected with MBL of 3 mm or more. The mixed linear model results showed a main effect of the type of opposing dentition, gender, implant diameter, and abutment height. Particularly, an abutment height of 1 mm had associated larger MBL than the remaining heights. Thus, it can be concluded that dental implants restored with fixed segmented full-arch rehabilitation in patients with a history of severe periodontal disease do not suffer important marginal bone loss if some specific factors are considered, mainly the use of long transmucosal abutments (≥2 mm).Junta de Andalucía CTS-138, CTS-176, CTS-102

Neutrophil Extracellular Traps in Periodontitis

Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis

Bacteria associated with periodontal disease are also increased in health

The objective of this cross-sectional clinical study was to analyze the differences in the microbiome in gingival sulci of adult patients in the presence or absence of chronic periodontitis. Patients with or without periodontal disease were included in this cross-sectional study. Subgingival biofilm samples were collected and analyzed by 16S massive pyrosequencing. Functional analyses were also performed. A total of 15 phyla, 154 genera and 351 species were detected globally. Differences between disease and non-disease samples were observed in all taxonomical levels which suggest functional profile changes in the community. It was found that the main species associated with non-disease samples were reduced in disease but not completely suppressed. Analysis of the functional potential of the biofilms revealed a significantly higher activity related to endocytosis and phosphatidylinositol signaling in the disease group but lower cell adhesion molecules. Specific differences between health and disease suggest functional profile changes in the community, although bacteria associated with periodontal disease are also increased in health. Transcriptome studies should be conducted to confirm and deepen metabolic dysfunctions

Bone Regeneration from PLGA Micro-Nanoparticles

Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed.The authors wish to express their appreciation for the financial support granted by the “Ministerio de Educación y Ciencia” (MEC, Spain), Projects MAT2013-43922-R, and Research Groups no. FQM-115, no. CTS-138, and no. CTS-583 (Junta de Andalucía, Spain). Partial support was also provided by the Andalucía Talent Hub Program from the Andalusian Knowledge Agency, cofunded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND, Grant Agreement no. 291780) and the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucía (Miguel Padial-Molina)

Clinical Application of Mesenchymal Stem Cells and Novel Supportive Therapies for Oral Bone Regeneration

This work has been also recommended by the PACT (Platelet and Advanced Cell Therapies) Forum Civitatis of the POSEIDO Academic Consortium (Periodontology, Oral Surgery, Esthetic and Implant Dentistry Organization).Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes.The authors of this paper were partially supported by the Talentia Scholarship Program (Junta de Andalucía, Spain) (MPM), the International Team for Implantology through the ITI Scholarship Program (AL), and the Research Groups #CTS-138 and #CTS-583 (Junta de Andalucía, Spain) (All)

Inflammasomes NLRP3 and AIM2 in peri-implantitis: A cross-sectional study

Background: Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase-1 and IL-1β. They have not been yet evaluated in samples from patients with active peri-implantitis. Thus, the aim of the present study is to analyze the expression of inflammasomes NLRP3 and AIM2 and subsequent caspase 1 and IL-1β assessing the microenvironment of leukocyte subsets in samples from patients with active peri-implantitis. Methods: Biopsies were collected from 33 implants in 21 patients being treated for peri-implantitis. Biopsies from gingival tissues from 15 patients with healthy periodontium were also collected for control. These tissues were evaluated through conventional histological stainings. Then, immunohistochemical detection was performed to analyze NLRP3, AIM2, caspase-1, and IL-1β and markers of different leukocyte subsets. PCR for inflammasomes and related genes was also done. Results: This manuscript reveals a high immunohistochemical and mRNA expression of NLRP3 and AIM2 inflammasomes, caspase-1, and IL-1β in biopsies collected from human peri-implantitis. The expression of the tested markers was significantly correlated with the increase in inflammatory infiltrate, probing depth, presence of biofilm, and bleeding on probing. In these peri-implantitis lesions, the area of biopsy tissue occupied by inflammatory infiltrate was intense while the area occupied by collagen was significantly lower. In comparison with periodontal healthy tissues, the inflammatory infiltrate was statistically significantly higher in the peri-implantitis biopsies and was mainly composed of plasma cells, followed by T and B lymphocytes. Conclusion: In human peri-implantitis, chronic inflammation can be explained in part by the action of IL-1β/ caspase 1 induced through NLRP3 and AIM2 inflammasome activation.Junta de Andalucía, Grant/Award Number: CTS-138CTS-1028; Universidad de Granada, Grant/Award Number: B-CTS- 504- UGR18Universidad de Granada/CBU