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Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair‐associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV‐associated cholesterol was found to promote OPC differentiation predominantly through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance support the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are used for regenerative therapy. Dental pulp MSCs make extracted wisdom teeth a useful resource in humans. Preclinical validation of regenerative therapies requires large animal models such as the sheep. Since stem cells can be retrieved from the dental pulp of ovine incisors, the best age to extract a maximal volume of dental pulp needs to be defined. The objective of this ex vivo study was to quantify incisors dental pulp volume, in sheep of various age. Three jaws were dedicated to histology (one per age group); the others were imaged with a computed tomography scanner [3 years‐old (n = 9), 4 (n = 3) and 6 (n = 5)]. The incisors dental pulp volume was measured after 3D reconstruction. Multiple linear regression showed that dental pulp volume of ovine incisors decreases with age (β‐estimate = −3.3; p < 0.0001) and teeth position from the more central to the more lateral (β‐estimate = −4.9; p = 0.0009). Weight was not a relevant variable in the regression model. The dental pulp volume ranged from 36.7 to 19.6 mm3 in 3‐year‐old sheep, from 23.6 to 11.3 in 4‐year‐old sheep, and from 19.4 to 11.5 in 6‐year‐old sheep. The pulp volume of the most central teeth (first intermediate) was significantly higher than the most lateral teeth (corner). Haematoxylin–Eosin–Safran of the whole incisors, and of isolated dental pulps demonstrated a similar morphology to that in humans. The first intermediate incisor of 3‐year‐old sheep should be selected preferentially in preclinical research to retrieve the highest volume of dental pulp. [ABSTRACT FROM AUTHOR]

Background and Objective: While osseointegration following various dental implant placement protocols has been extensively investigated, the neurohistological integration has received little attention. The primary aim of this study was to compare the myelinated nerve fibers density in peri‐implant bone tissue following various implant placement protocols. The secondary aim assessed the effect of follow‐up on peri‐implant nerve fibers density. Methods: Ten beagle dogs randomly received 68 commercially pure titanium implants in the mandibular premolar or molar region bilaterally following extraction utilizing one of the six treatment protocols: (a) immediate implant placement (IIP) and immediate loading (IL); (b) IIP and delayed loading (DL); (c) IIP and left unloaded (UL); (d) delayed implant placement (DIP) and IL; (e) DIP and DL; and (f) DIP and UL. Histomorphometric analysis of the peri‐implant myelinated nerve fibers was performed in a 300 μm peri‐implant zone at the cervical, middle, and apical level following implant placement. The follow‐up assessment involved longitudinal observation at 3 months following each implant treatment protocol and at 6 months for IIP+IL and IIP+DL protocols. Results: The influence of different treatment protocols, including the fixed effects of implant groups (IIP+IL, IIP+DL, IIP+UL, DIP+IL, DIP+DL, DIP+UL) and regions (cervical, middle, apical), was examined via a linear mixed model. The IIP+IL group showed a significantly higher myelinated nerve density compared to the IIP+UL and DIP+UL group. Peri‐implant nerve re‐innervation was significantly higher (P =.002) in the apical region compared to the cervical region. After immediate implant placement, the IL group showed a significantly (P =.03) higher density of myelinated nerve fibers compared to DL. No significant (P =.19) effect of follow‐up on nerve density was observed. Conclusion: The immediate implant placement and loading protocol showed most beneficial effect on peri‐implant innervation with highest myelinated nerve density in the apical region. A longer loading time had no influence on the peri‐implant nerve density. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the peri‐implant trabecular bone volume and architecture changes with 6‐month follow‐up after local application of platelet‐rich plasma (PRP) and platelet‐poor plasma (PPP) using high‐resolution micro‐CT. Material and methods: Seventy‐two dental implants were placed into healed mandibular sites of 9 beagle dogs. Implants were randomly divided into 4 groups following a split‐mouth design: control I; control II; PPP; and PRP. Primary and secondary stabilities were assessed using resonance frequency analyses. At 1, 3, and 6 months after implant loading, trabecular structural parameters were evaluated at 0.5, 1, and 1.5 mm away from implants using micro‐CT (voxel = 20 μm). Results: Primary and secondary stabilities were equivalent in all conditions. PPP and PRP groups showed higher bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) but lower trabecular separation (Tb.Sp) and total porosity percentage (Po (tot)) at all 3 time points. A significant decrease in BV/TV and Tb.Th was found for the control groups after 3 months of healing, while this was not observed in both the PPP and PRP groups. However, no distinct difference was found between the PRP and PPP groups over time. Moreover, as the investigated distance from the implant surface increased, BV/TV and Po (tot) within the same group and time point stayed the same, yet Tb.Th and Tb.Sp continued to increase. Conclusions: Platelet‐rich plasma and PPP with conventional implant placement lead to similar primary and secondary implant stability, but improved peri‐implant bone volume and structural integration. The present research does not seem to suggest a different bone remodeling pattern when using PRP or PPP. [ABSTRACT FROM AUTHOR]

Purpose To assess bone microarchitecture in maxillary sites grafted with autogenous or xenogenous grafts as well as to demonstrate the usefulness of micro CT in dental implant research. Materials and Methods Samples ( n = 12) consisting of titanium fixation screws covered by at least 0.5-1 mm of human bone were obtained from 17 sites grafted with autogenous or xenogenous materials and prepared for micro CT scanning and conventional histology. Bone histomorphometric parameters were evaluated in three distinct regions (graft region, transitional region, and native bone region). Three-dimensional (3D) bone-to-implant contact ( BIC) calculation was performed using micro CT data. Histological sections were used to calculate two-dimensional (2D) BIC percentages, which were compared with values obtained from 2D micro CT images. Results Histomorphometric parameters varied according to the type of graft used, but sites reconstructed with autogenous bone showed higher mean values in general. In autograft samples, indices for parameters such as Tb.Th and Tb.Sp were significantly different when the native bone region was compared to the graft region. While a higher mean 3D BIC was found in the native bone region for both graft materials, significant BIC differences were absent when graft types were compared. The 2D BIC percentages obtained from histological and micro CT images were similar. Conclusions Autografts outperformed the xenogenous material used in this study concerning the histomorphometric parameters assessed. While graft type did not seem to influence 3D BIC, the native bone region showed the highest BIC percentages when compared to the other regions in both graft groups. In addition, 2D BIC ratios were similar regardless of graft material or image source (histological sections x micro CT slices). Taken together, our findings suggest that micro CT is an effective tool for 2D and 3D histomorphometric and BIC assessments in dental implant research. [ABSTRACT FROM AUTHOR]

Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed. [ABSTRACT FROM AUTHOR]

Objectives To systematically review the available literature on the influence of dental implant placement and loading protocols on peri-implant innervation. Material and methods The database MEDLINE, Cochrane, EMBASE, Web of Science, LILACS, Open Grey and hand searching were used to identify the studies published up to July 2013, with a populations, exposures and outcomes ( PEO) search strategy using Me SH keywords, focusing on the question: Is there, and if so, what is the effect of time between tooth extraction and implant placement or implant loading on neural fibre content in the peri-implant hard and soft tissues? Results Of 683 titles retrieved based on the standardized search strategy, only 10 articles fulfilled the inclusion criteria, five evaluating the innervation of peri-implant epithelium, five elucidating the sensory function in peri-implant bone. Three included studies were considered having a methodology of medium quality and the rest were at low quality. All those papers reported a sensory innervation around osseointegrated implants, either in the bone-implant interface or peri-implant epithelium, which expressed a particular innervation pattern. Compared to unloaded implants or extraction sites without implantation, a significant higher density of nerve fibres around loaded dental implants was confirmed. Conclusions To date, the published literature describes peri-implant innervation with a distinct pattern in hard and soft tissues. Implant loading seems to increase the density of nerve fibres in peri-implant tissues, with insufficient evidence to distinguish between the innervation patterns following immediate and delayed implant placement and loading protocols. Variability in study design and loading protocols across the literature and a high risk of bias in the studies included may contribute to this inconsistency, revealing the need for more uniformity in reporting, randomized controlled trials, longer observation periods and standardization of protocols. [ABSTRACT FROM AUTHOR]

Purpose To develop a method for characterizing trabecular bone microarchitecture using cone beam computed tomography ( CBCT) and to evaluate trabecular bone changes after rehabilitation using immediate versus delayed implant protocols. Materials and Methods Six mongrel dogs randomly received 27 titanium implants in the maxillary incisor or mandibular premolar areas, following one of four protocols: (1) normal extraction socket healing; (2) immediate implant placement and immediate loading; (3) delayed implant placement and delayed loading; (4) delayed implant placement and immediate loading. The animals were euthanized at 8 weeks, and block biopsies were scanned using high resolution CBCT. Standard bone structural variables were assessed in coronal, middle, and apical levels. Results Coronal and middle regions had more compact, more platelike, and thicker trabeculae. Protocols (2), (3), and (4) had significantly higher values ( p < 0.001) than protocol (1) for bone surface density, bone surface volume ratio, and connectivity density, while significantly lower values ( p < 0.001) were found for trabecular separation and fractal dimension. However, protocols (2), (3), and (4) did not show significantly different bone remodeling. Conclusions Compared with normal extraction healing, the implant protocols have an improved bone structural integration. Results do not suggest a different bone remodeling pattern when a delayed versus an immediate implant protocol is used. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the differentiation potential of human dental pulp stem cells (hDPSCs) toward Schwann cells, together with their functional capacity with regard to myelination and support of neurite outgrowth in vitro. Successful Schwann cell differentiation was confirmed at the morphological and ultrastructural level by transmission electron microscopy. Furthermore, compared to undifferentiated hDPSCs, immunocytochemistry and ELISA tests revealed increased glial marker expression and neurotrophic factor secretion of differentiated hDPSCs (dhDPSCs), which promoted survival and neurite outgrowth in 2-dimensional dorsal root ganglia cultures. In addition, neurites were myelinated by d-hDPSCs in a 3-dimensional collagen type I hydrogel neural tissue construct. This engineered construct contained aligned columns of d-hDPSCs that supported and guided neurite outgrowth. Taken together, these findings provide the first evidence that hDPSCs are able to undergo Schwann cell differentiation and support neural outgrowth in vitro, proposing them to be good candidates for cell-based therapies as treatment for peripheral nerve injury.--Martens, W., Sanen, K., Georgiou, M., Struys, T., Bronckaers, A., Ameloot, M., Phillips, J., Lambrichts, I. Human dental pulp stem cells can differentiate into Schwann cells and promote and guide neurite outgrowth in an aligned tissue-engineered collagen construct in vitro. [ABSTRACT FROM AUTHOR]

Aim: To determine the human anatomic variability of the nasopalatine canal and determine its characteristics using an anatomical, histological and computed tomography (CT) scan evaluation. Materials and Methods: Measurements for the canal characteristics were carried out on 163 dry human skulls and 120 upper jaw spiral CT scans, taken from patients for pre-operative planning purposes of implant placement in the incisor region. Furthermore, four human cadaver specimens were imaged using a high-resolution magnetic resonance imaging (HR-MRI) unit. Afterwards, these specimens were serially sectioned for histological examination to evaluate the nasopalatine canal region and its content. Results: The nasopalatine canal anatomy showed a large variability in morphology and dimensions, with the canal branching in up to four canals at the level of the nose. The canal diameter was on average 3.3 mm (±0.9 mm SD), and typically enlarged by age and male gender ( p<0.05). HR-MRI and histological sections enabled to identify the neurovascular structures within the canals. Conclusions: The large anatomic variations, the increased canal dimensions with age and the neurovascular canal content are all factors favouring a thorough three-dimensional planning before surgery, such as implant placement, of the anterior maxillary region. [ABSTRACT FROM AUTHOR]

Oligodendrocytes are glial cells responsible for the synthesis and maintenance of myelin in the central nervous system (CNS). Oligodendrocytes are vulnerable to damage occurring in a variety of neurological diseases. Understanding oligodendrocyte biology is crucial for the dissemination of de- and remyelination mechanisms. The goal of the present study is the construction of a protein database of mature rat oligodendrocytes. Post-mitotic oligodendrocytes were isolated from mature Wistar rats and subjected to immunocytochemistry. Proteins were extracted and analyzed by means of two-dimensional gel electrophoresis and two-dimensional liquid chromatography, both coupled to mass spectrometry. The combination of the gel-based and gel-free approach resulted in confident identification of a total of 200 proteins. A minority of proteins were identified in both proteomic strategies. The identified proteins represent a variety of functional groups, including novel oligodendrocyte proteins. The results of this study emphasize the power of the applied proteomic strategy to study known or to reveal new proteins and to investigate their regulation in oligodendrocytes in different disease models. [ABSTRACT FROM AUTHOR]

Background: Computer-assisted preoperative implant planning and transfer toward the patient allow the production of a prosthesis prior to surgery. This implies that the prosthesis can be installed immediately following implant insertion. An inherent disadvantage of this is a cumulated error, which can lead to prosthesis misfit owing to topographic deviations of the planned versus the installed implants. Purpose: The aim of this study was to determine whether prosthesis misfit is compromising the osseointegration of immediately versus delayed loaded implants and whether freshly installed implants adapt to the prosthesis. Materials and Methods: In each of five New Zealand White rabbits, two experimental conditions were compared. One tibia harbored the so-called test implant, which originally showed a vertical misfit of about 500 Am with the prosthesis to which it was tightened immediately after implant installation. The control implant was installed in the other tibia and was allowed to heal during 9 weeks before the prosthesis with the vertical misfit of about 500 Am was connected to it. The prostheses were left in place for 12 weeks, after which the animals were sacrificed. Results: All implants healed uneventfully. There were no statistically significant differences between the biologic responses of test and control implants. With a three-dimensional laser scanner, significantly more displacement of the test implants toward the prostheses was observed compared with the control implants. This led to a significant decrease in prosthesis misfit for the test implants compared with the control implants. Conclusions: This study indicates that prosthesis misfit does not per se lead to biologic failure of immediately loaded or of already osseointegrated implants. In addition, immediately loaded implants seem to topographically adapt to the prosthesis, thereby minimizing the existing misfit. [ABSTRACT FROM AUTHOR]

In previous studies exposing animals to Cd caused oxidative stress and kidney damage. Mostly high doses were applied, often by injection. In the present study mice were exposed up to 23 weeks to low Cd concentrations (10 and 100 mg CdCl2/l) in the drinking water. Antioxidant gene expression levels as well as glutathione, ascorbate and lipid peroxidation levels were measured. Metallothionein 1 and 2 were upregulated from 1 week of exposure on. An early induction of the Prdx2 gene suggested that peroxiredoxin might be involved in the early response as well. After 8 weeks Cd reduced antioxidant expression of Bcl2, Prdx2 and Sod1 which might indicate a toxic effect. No significant effect was seen on lipid peroxidation however, and the overall redox status remained in balance throughout the whole experiment. Levels of reduced glutathione and ascorbate and of transcription of Sod2 remained stable. This suggested that the energy maintenance in mitochondria was under control. A second response was observed after 23 weeks. Interestingly, the expression of renal NADPH oxidase 4 (Nox4) increased. Nox4 has not been studied yet in Cd nephrotoxicity. The antioxidants catalase, glutathione peroxidase 4 and heme oxygenase 1 also responded. In conclusion our study reveals a two-step oxidative stress response in the kidney. Clearly the kidney was in control of Cd-induced oxidative stress after exposure to low Cd concentrations. [ABSTRACT FROM AUTHOR]

A core component of the α-proteobacterial general stress response (GSR) is the extracytoplasmic function (ECF) sigma factor EcfG, exclusively present in this taxonomic class. Half of the completed α-proteobacterial genome sequences contain two or more copies of genes encoding σ(EcfG) -like sigma factors, with the primary copy typically located adjacent to genes coding for a cognate anti-sigma factor (NepR) and two-component response regulator (PhyR). So far, the widespread occurrence of additional, non-canonical σ(EcfG) copies has not satisfactorily been explained. This study explores the hierarchical relation between Rhizobium etli σ(EcfG1) and σ(EcfG2) , canonical and non-canonical σ(EcfG) proteins, respectively. Contrary to reports in other species, we find that σ(EcfG1) and σ(EcfG2) act in parallel, as nodes of a complex regulatory network, rather than in series, as elements of a linear regulatory cascade. We demonstrate that both sigma factors control unique yet also shared target genes, corroborating phenotypic evidence. σ(EcfG1) drives expression of rpoH2, explaining the increased heat sensitivity of an ecfG1 mutant, while katG is under control of σ(EcfG2) , accounting for reduced oxidative stress resistance of an ecfG2 mutant. We also identify non-coding RNA genes as novel σ(EcfG) targets. We propose a modified model for GSR regulation in R. etli, in which σ(EcfG1) and σ(EcfG2) function largely independently. Based on a phylogenetic analysis and considering the prevalence of α-proteobacterial genomes with multiple σ(EcfG) copies, this model may also be applicable to numerous other species., (© 2013 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Aim: To determine the human anatomic variability of the nasopalatine canal and determine its characteristics using an anatomical, histological and computed tomography (CT) scan evaluation., Materials and Methods: Measurements for the canal characteristics were carried out on 163 dry human skulls and 120 upper jaw spiral CT scans, taken from patients for pre-operative planning purposes of implant placement in the incisor region. Furthermore, four human cadaver specimens were imaged using a high-resolution magnetic resonance imaging (HR-MRI) unit. Afterwards, these specimens were serially sectioned for histological examination to evaluate the nasopalatine canal region and its content., Results: The nasopalatine canal anatomy showed a large variability in morphology and dimensions, with the canal branching in up to four canals at the level of the nose. The canal diameter was on average 3.3 mm (+/-0.9 mm SD), and typically enlarged by age and male gender (p<0.05). HR-MRI and histological sections enabled to identify the neurovascular structures within the canals., Conclusions: The large anatomic variations, the increased canal dimensions with age and the neurovascular canal content are all factors favouring a thorough three-dimensional planning before surgery, such as implant placement, of the anterior maxillary region.