Modeling new trends in bone regeneration, using the BERTopic approach.

Aim: Bibliometric surveys are time-consuming endeavors, which cannot be scaled up to meet the challenges of ever-expanding fields, such as bone regeneration. Artificial intelligence, however, can provide smart tools to screen massive amounts of literature, and we relied on this technology to automatically identify research topics. Materials & methods: We used the BERTopic algorithm to detect the topics in a corpus of MEDLINE manuscripts, mapping their similarities and highlighting research hotspots. Results: Using BERTopic, we identified 372 topics and were able to assess the growing importance of innovative and recent fields of investigation such as 3D printing and extracellular vescicles. Conclusion: BERTopic appears as a suitable tool to set up automatic screening routines to track the progress in bone regeneration.

Granular cell tumor of the neurohypophysis presenting as a third ventricle mass.

Granular cell tumors of the neurohypophysis (GCT) are rare benign neoplasms belonging, along with pituicytoma and spindle cell oncocytoma, to the family of TTF1-positive low-grade neoplasms of the posterior pituitary gland. GCT usually present as a solid sellar mass, slowly growing and causing compressive symptoms over time, occasionally with suprasellar extension. They comprise polygonal monomorphous cells with abundant granular cytoplasm, which is ultrastructurally filled with lysosomes. Here we report the case of a GCT presenting as a third ventricle mass, radiologically mimicking chordoid glioma, with aberrant expression of GFAP and Annexin-A, which lends itself as an example of an integrated diagnostic approach to sellar/suprasellar and third ventricle masses.

Primary Large B-Cell Lymphoma of Immune-Privileged Sites of the Cerebellum: A Case Series and Review of the Literature.

Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is a rare malignant hematological neoplasm. Involvement of the cerebellum is even rarer and its diagnosis is often difficult to make due to its non-specific clinical and radiological presentation. METHODS: We reported 3 cases of cerebellar IP-LBCL followed at our hospital and reviewed the medical literature to unravel the peculiarities of this poorly studied entity. OUTCOMES: Analyzing our cases and reviewing the literature, we could collect and study 26 cases of cerebellar IP-LBCL. To the best of our knowledge, this is the largest cohort of such patients currently published. CONCLUSION: Cerebellar IP-LBCL presents more often in adult females with cerebellum-related focal neurological signs such as ataxia, headache, and nausea. Histological confirmation is mandatory for a correct diagnosis and treatment and all cases feature diffuse large B-cell lymphoma histopathology. Compared to other encephalic IP-LBCL, cerebellar cases seem to include a higher number of cases with germinal center B-cell phenotype and better survival. These differences may be related to a different immune microenvironment and especially immunoregulation that distinguishes the cerebellum from other areas of the CNS.

Tolerable upper intake level for dietary sugars.

Following a request from five European Nordic countries, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was tasked to provide scientific advice on a tolerable upper intake level (UL) or a safe level of intake for dietary (total/added/free) sugars based on available data on chronic metabolic diseases, pregnancy-related endpoints and dental caries. Specific sugar types (fructose) and sources of sugars were also addressed. The intake of dietary sugars is a well-established hazard in relation to dental caries in humans. Based on a systematic review of the literature, prospective cohort studies do not support a positive relationship between the intake of dietary sugars, in isocaloric exchange with other macronutrients, and any of the chronic metabolic diseases or pregnancy-related endpoints assessed. Based on randomised control trials on surrogate disease endpoints, there is evidence for a positive and causal relationship between the intake of added/free sugars and risk of some chronic metabolic diseases: The level of certainty is moderate for obesity and dyslipidaemia (> 50-75% probability), low for non-alcoholic fatty liver disease and type 2 diabetes (> 15-50% probability) and very low for hypertension (0-15% probability). Health effects of added vs. free sugars could not be compared. A level of sugars intake at which the risk of dental caries/chronic metabolic diseases is not increased could not be identified over the range of observed intakes, and thus, a UL or a safe level of intake could not be set. Based on available data and related uncertainties, the intake of added and free sugars should be as low as possible in the context of a nutritionally adequate diet. Decreasing the intake of added and free sugars would decrease the intake of total sugars to a similar extent. This opinion can assist EU Member States in setting national goals/recommendations.

Feasibility of Early Active Rehabilitation for Concussion Recovery in Youth: A Randomized Trial.

OBJECTIVE: The primary objective is to evaluate the feasibility (safety and acceptability) of implementing early active rehabilitation (AR) for concussion management in youth with symptoms persisting 2 weeks after injury. A secondary and exploratory objective was to estimate the potential efficacy of early AR compared with standard AR. We hypothesize that AR at 2-weeks postconcussion will be safe and acceptable to patients. DESIGN: Randomized clinical trial. SETTING: The Montreal Children's Hospital of the McGill University Health Center (MCH-MUHC), a tertiary care pediatric teaching hospital affiliated with McGill University in Montreal, Canada. PARTICIPANTS: Twenty youth aged 9 to 17 years old with postconcussion symptoms for at least 2 weeks. INTERVENTION: Active rehabilitation (aerobic exercise, coordination drills, visualization, and education/reassurance) was administered by physiotherapists in-person, and then continued as a home program. METHODS: Twenty participants were randomized to either early AR (initiated 2 weeks after injury) or standard AR (initiated 4 weeks after injury). RESULTS: Two adverse events (one in each group) were identified through an online survey more than one-month postconcussion. Postconcussion symptoms decreased over time for both groups. CONCLUSIONS: The results from this pilot study indicate that a full clinical trial estimating the efficacy of early AR (starting 2 weeks after injury) is feasible. Further study is needed to determine the superiority of this strategy over current treatment approaches.

The effects of polydeoxyribonucleotide on wound healing and tissue regeneration: a systematic review of the literature.

Aim: The present study evaluated the effects of polydeoxyribonucleotide (PDRN) on tissue regeneration, paying special attention to the molecular mechanisms that underlie its tissue remodeling actions to better identify its effective therapeutic potential in wound healing. Materials & methods: Strategic searches were conducted through MEDLINE/PubMed, Google Scholar, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials, from their earliest available dates to March 2020. The studies were included with the following eligibility criteria: studies evaluating tissue regeneration, and being an in vitro, in vivo and clinical study. Results: Out of more than 90 articles, 34 fulfilled the eligibility criteria. All data obtained proved the ability of PDRN in promoting a physiological tissue repair through salvage pathway and adenosine A2A receptor activation. Conclusion: Up to date PDRN has proved promising results in term of wound regeneration, healing time and absence of side effects.

3D-printed chitosan scaffolds modified with D-(+) raffinose and enriched with type IV collagen to improve epithelial cell colonization.

Tissue regeneration often requires the use of biocompatible resorbable scaffolds to support the ingrowth of cells from neighboring tissues into a localized tissue defect. Such scaffolds must possess surface molecular cues that stimulate cells to populate the device, the first necessary condition for the formation of a healthy tissue. Chitosan is a natural polymer that has long been tested in biomedical applications because of its high biocompatibility, which can be further increased by modifying its formulation, e.g. adding D-(+) raffinose. We used this formulation in an ad hoc designed 3D printer to create regularly ordered scaffolds, which we then enriched with type IV collagen, an isoform of collagen that is exclusively found in basement membranes. Human epithelial A549 cells were then seeded on control scaffolds or on scaffolds coated with collagen, which was precipitated, or on scaffolds first collagenized and then exposed to either UVB or UVC radiation. Observations by the transmission light microscope, confocal microscope after staining with calcein-AM/propidium iodide, and by environmental scanning electron microscope revealed that collagen-enriched UV-treated scaffolds promoted the attachment of a higher number of cells, which covered a more extensive area of the scaffold, as also confirmed by alamar blue viability assay. Together these data confirm that coating 3D-printed scaffolds made of D-(+) raffinose-modified chitosan with type IV collagen and exposing them to UV light sensibly increases the cell compatibility of scaffolds, making them a better candidate to serve as a tool for the regeneration of epithelia.

Sub-Micropillar Spacing Modulates the Spatial Arrangement of Mouse MC3T3-E1 Osteoblastic Cells.

Surface topography is one of the main factors controlling cell responses on implanted devices and a proper definition of the characteristics that optimize cell behavior may be crucial to improve the clinical performances of these implants. Substrate geometry is known to affect cell shape, as cells try to optimize their adhesion by adapting to the irregularities beneath, and this in turn profoundly affects their activity. In the present study, we cultured murine calvaria MC3T3-E1 cells on surfaces with pillars arranged as hexagons with two different spacings and observed their morphology during adhesion and growth. Cells on these highly ordered substrates attached and proliferated effectively, showing a marked preference for minimizing the inter-pillar distance, by following specific pathways across adjacent pillars and displaying consistent morphological modules. Moreover, cell behavior appeared to follow tightly controlled patterns of extracellular protein secretion, which preceded and matched cells and, on a sub-cellular level, cytoplasmic orientation. Taken together, these results outline the close integration of surface features, extracellular proteins alignment and cell arrangement, and provide clues on how to control and direct cell spatial order and cell morphology by simply acting on inter-pillar spacing.

The cellular effects of Pulsed Electromagnetic Fields on osteoblasts: A review.

Electromagnetic fields (EMFs) have long been known to interact with living organisms and their cells and to bear the potential for therapeutic use. Among the most extensively investigated applications, the use of Pulsed EMFs (PEMFs) has proven effective to ameliorate bone healing in several studies, although the evidence is still inconclusive. This is due in part to our still-poor understanding of the mechanisms by which PEMFs act on cells and affect their functions and to an ongoing lack of consensus on the most effective parameters for specific clinical applications. The present review has compared in vitro studies on PEMFs on different osteoblast models, which elucidate potential mechanisms of action for PEMFs, up to the most recent insights into the role of primary cilia, and highlight the critical issues underlying at least some of the inconsistent results in the available literature. Bioelectromagnetics. 2019;9999:XX-XX. © 2019 Bioelectromagnetics Society.

The Use of Pulsed Electromagnetic Fields to Promote Bone Responses to Biomaterials In Vitro and In Vivo.

Implantable biomaterials are extensively used to promote bone regeneration or support endosseous prosthesis in orthopedics and dentistry. Their use, however, would benefit from additional strategies to improve bone responses. Pulsed Electromagnetic Fields (PEMFs) have long been known to act on osteoblasts and bone, affecting their metabolism, in spite of our poor understanding of the underlying mechanisms. Hence, we have the hypothesis that PEMFs may also ameliorate cell responses to biomaterials, improving their growth, differentiation, and the expression of a mature phenotype and therefore increasing the tissue integration of the implanted devices and their clinical success. A broad range of settings used for PEMFs stimulation still represents a hurdle to better define treatment protocols and extensive research is needed to overcome this issue. The present review includes studies that investigated the effects of PEMFs on the response of bone cells to different classes of biomaterials and the reports that focused on in vivo investigations of biomaterials implanted in bone.

Osteoblasts preferentially adhere to peaks on micro-structured titanium.

The aim of the study was to investigate cell adhesion to micro-structured titanium. Osteoblastic MC3T3 cells were cultured on smooth (P) or sand-blasted/acid-etched (SLA) titanium discs and were observed at scanning electron microscope/focused ion beam (SEM/FIB). Myosin II and actin microfilaments were labelled for epifluorescence microscopy. FIB revealed that cell adhesion initiated centrally and expanded to the cell periphery and that cells attached on the substrate by bridging over the titanium irregularities and adhering mostly on surface peaks. Gaps were visible between concave areas and cytoplasm and areas around ridges represented preferred attachment points for cells. A different myosin distribution was observed between samples and myosin inhibition affected cell responses. Taken together our data indicate that cells attach on micro-rough titanium by bridging over its irregularities. This is likely mediated by myosin II, whose distribution is altered in cells on SLA discs.

Performance and antrhropometric characteristics of Elite Rugby Players.

BACKGROUND AND AIM OF THE STUDY: Physical performance is the result of a complex combination of several factors such as genetic and anthropometric aspects, nutrition and hormonal status. In the past few years many studies have considered the impact of vitamin D on muscular strength and athletic performance.The aim of the present study was to assess the anthropometric measures impacting on physical performance in a group of professional rugby athletes.  As a secondary aim we investigated a possible relationship between baseline vitamin D status and athletic performance status in these subjects. METHODS: All rugby players completed a test-retest reliability study on performance measures, as 70kg jump squat and body weight (BW) jump squat to assess musculoskeletal performance. Additionally at the time point we collected a blood sample of every athletes for the assessment of serum vitamin D. RESULTS: We found that lean mass was an important independent predictor of performance score in 70kg jump squat (p=0.007, R2=0.74) and BW jump squat (p=0.010, R2=0.66) in these well trained athletes. No statistically significant association was present between performance score and serum vitamin D in this specific setting. CONCLUSIONS: We demonstrate a positive interaction between lower limb lean mass and performance score, but we have not been able to identify any statistically significant association between worsening in performance measures and decrease of serum 25 OH Vitamin D.

The integration of orthodontic miniscrews under mechanical loading: a pre-clinical study in rabbit.

INTRODUCTION: Orthodontic miniscrews are an increasingly popular choice to achieve absolute anchorage. The temporary use of miniscrews and their recent introduction have limited the debate over the biological aspect of the materials to that of the surface that permeates the field of dental implants. The aim of the present study was to investigate the integration of grade 5 titanium mini-implants with machined or sand blasted acid etched surface (SAE) under mechanical load in a rabbit tibia model of implant integration. METHODS: A total of 64 miniscrews (Ti6Al4V) of 1.5 mm diameter and 6.5 mm length were inserted in the proximal medial surface of each tibia in eight male rabbits aged 6 months. Each tibia received four miniscrews. A 100 g nickel-titanium coil spring (Neosentalloy) was applied between two miniscrews along the main axis while two miniscrews were left unloaded. The removal torque was measured for loaded and unloaded miniscrews after 12 weeks. Two miniscrews were harvested for histology. RESULTS: Removal torque was significantly higher for SAE mini-implants than for machined screws, under both loading conditions. Although no difference in bone to implant contact was observed among the groups, cortical area significantly decreased with both surfaces under loading. CONCLUSIONS: Our data indicate that SAE miniscrews have higher bone retention than MA miniscrews, although the effects of mechanical loading of these devices on cortical bone require further investigations.

"Over-inlay" block graft and differential morphometry: a novel block graft model to study bone regeneration and host-to-graft interfaces in rats.

PURPOSE: The aim of this study was to present new a model that allows the study of the bone healing process, with an emphasis on the biological behavior of different graft-to-host interfaces. A standardized "over-inlay" surgical technique combined with a differential histomorphometric analysis is presented in order to optimize the use of critical-size calvarial defects in pre-clinical testing. METHODS: Critical-size defects were created into the parietal bone of 8 male Wistar rats. Deproteinized bovine bone (DBBM) blocks were inserted into the defects, so that part of the block was included within the calvarial thickness and part exceeded the calvarial height (an "over-inlay" graft). All animals were sacrificed at 1 or 3 months. Histomorphometric and immunohistochemical evaluation was carried out within distinct regions of interest (ROIs): the areas adjacent to the native bone (BA), the periosteal area (PA) and the central area (CA). RESULTS: The animals healed without complications. Differential morphometry allowed the examination of the tissue composition within distinct regions: the BA presented consistent amounts of new bone formation (NB), which increased over time (24.53%±1.26% at 1 month; 37.73%±0.39% at 3 months), thus suggesting that this area makes a substantial contribution toward NB. The PA was mainly composed of fibrous tissue (71.16%±8.06% and 78.30%±2.67%, respectively), while the CA showed high amounts of DBBM at both time points (78.30%±2.67% and 74.68%±1.07%, respectively), demonstrating a slow remodeling process. Blood vessels revealed a progressive migration from the interface with native bone toward the central area of the graft. Osterix-positive cells observed at 1 month within the PA suggested that the periosteum was a source of osteoprogenitor elements. Alkaline phosphatase data on matrix deposition confirmed this observation. CONCLUSIONS: The present model allowed for a standardized investigation of distinct graft-to-host interfaces both at vertically augmented and inlay-augmented sites, thus possibly limiting the number of animals required for pre-clinical investigations.

CeF3-ZnO scintillating nanocomposite for self-lighted photodynamic therapy of cancer.

We report on the synthesis and characterization of a composite nanostructure based on the coupling of cerium fluoride (CeF3) and zinc oxide (ZnO) for applications in self-lighted photodynamic therapy. Self-lighted photodynamic therapy is a novel approach for the treatment of deep cancers by low doses of X-rays. CeF3 is an efficient scintillator: when illuminated by X-rays it emits UV light by fluorescence at 325 nm. In this work, we simulate this effect by exciting directly CeF3 fluorescence by UV radiation. ZnO is photo-activated in cascade, to produce reactive oxygen species. This effect was recently demonstrated in a physical mixture of distinct nanoparticles of CeF3 and ZnO [Radiat. Meas. (2013) 59:139-143]. Oxide surface provides a platform for rational functionalization, e.g., by targeting molecules for specific tumors. Our composite nanostructure is stable in aqueous media with excellent optical coupling between the two components; we characterize its uptake and its good cell viability, with very low intrinsic cytotoxicity in dark.

Comparison of Environmental Scanning Electron Microscopy in Low Vacuum or wet mode for the investigation of cell biomaterial interactions.

AIM: The aim of the present study was to investigate the efficacy of environmental scanning electron microscopy (ESEM), in low vacuum mode (LV-ESEM) and in wet mode (wet-ESEM) in the assessment of cell-material interactions. METHODS: Mouse calvaria MC3T3 cells (ATCC) were seeded on commercially pure machined titanium discs of 10 mm diameter in Dulbecco modified MEM, 10% Fetal Bovine Serum, 1% Penicillin and Streptomycin and 1% Glutamine. Samples were then processed for microscope observation by rinse in Phosphate Buffer saline and fixation in 4.5% Glutaraldehyde. Samples were then rinsed in Sodium Cacodylate buffer and observed or dehydrated in alcohol prior to LV-ESEM observation. Fresh samples in 0.9% NaCl solution were observed in wet- ESEM. RESULTS: No significant loss of detail was observed when dehydrated or non dehydrated samples were analysed at LV-ESEM.The observation of fresh samples in wet-ESEM however proved difficult for the need to eliminate water which forms a layer covering the sample, thus hiding cell surface details. When reducing the vapor pressure in the chamber, the layer evaporated and NaCl immediately started to precipitate and cells collapsed, thus no further investigation was possible. CONCLUSIONS: The use of low vacuum-ESEM after cell fixation, but without dehydration or gold sputter coating proved a viable alternative to traditional high vacuum SEM observation.

Role of prostaglandin E2 in the modulation of Wnt canonical signaling in cells on microstructured titanium surfaces.

BACKGROUND: Rough surface topography enhances the activation of Wnt canonical signaling, a pathway required for osteoblast differentiation. The present study investigated the effects of the modulation of prostaglandin E2 (PGE2) signaling on osteoblastic differentiation on titanium surfaces for endosseous implants with different topographies. METHODS: C2C12 cells were plated on polished or acid-etched/sand-blasted (SLA) titanium discs and stimulated with 1 µM PGE2 or 100 nM cyclooxygenase inhibitor indomethacin. Activation of Wnt canonical signaling was measured with a reporter system. Gene expression was measured in the same cell system by real-time polymerase chain reaction (RT-PCR). Osteoblastic MC3T3 cells were then plated on polished or SLA titanium discs with or without indomethacin, and their proliferation and the expression of osteoblast-specific genes was assessed by RT-PCR. Cell morphology was furthermore studied on SEM, and cell adhesion was assessed by fluorescent labeling of focal adhesion. RESULTS: PGE2 decreased Wnt signaling stimulation in cells growing on polished or SLA surfaces, while indomethacin increased the expression of Wnt target genes in C2C12 and MC3T3 cells, by reporter assay. Moreover, indomethacin increased the expression of early differentiation marker alkaline phosphatase in MC3T3 cells on polished discs and of late marker osteocalcin in cells on SLA titanium. CONCLUSIONS: Prostaglandin signaling affects the activation of Wnt canonical pathway in osteoblastic and mesenchymal cells on microstructured surfaces.

The diffusion-weighted imaging and 11-C-methionine positron emission tomography depiction of an endodermal cyst at the cervico-medullary junction.

A case of a 52-year-old male with left-sided neck pain, vertigo and gait instability is reported. A MRI scan revealed an intra-dural mass at the cervico-medullary junction, further characterised by diffusion-weighted imaging and 11-C-methionine positron emission tomography. Pathological diagnosis was endodermal cyst. The clinico-surgical relevance of the imaging findings is discussed.

Chitosan-based scaffold modified with D-(+) raffinose for cartilage repair: an in vivo study.

BACKGROUND: Osteochondral defects significantly affect patients' quality of life and represent challenging tissue lesions, because of the poor regenerative capacity of cartilage. Tissue engineering has long sought to promote cartilage repair, by employing artificial scaffolds to enhance cell capacity to deposit new cartilage. An ideal biomaterial should closely mimic the natural environment of the tissue, to promote scaffold colonization, cell differentiation and the maintenance of a differentiated cellular phenotype. The present study evaluated chitosan scaffolds enriched with D-(+) raffinose in osteochondral defects in rabbits. Cartilage defects were created in distal femurs, both on the condyle and on the trochlea, and were left untreated or received a chitosan scaffold. The animals were sacrificed after 2 or 4 weeks, and samples were analysed microscopically. RESULTS: The retrieved implants were surrounded by a fibrous capsule and contained a noticeable inflammatory infiltrate. No hyaline cartilage was formed in the defects. Although defect closure reached approximately 100% in the control group after 4 weeks, defects did not completely heal when filled with chitosan. In these samples, the lesion contained granulation tissue at 2 weeks, which was then replaced by fibrous connective tissue by week 4. Noteworthy, chitosan never appeared to be integrated in the surrounding cartilage. CONCLUSIONS: In conclusion, the present study highlights the limits of D-(+) raffinose-enriched chitosan for cartilage regeneration and offers useful information for further development of this material for tissue repair.