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Introduction: Understanding the healing process of dental pulp after tooth autotransplantation (TAT) and regenerative endodontic treatment (RET) of immature teeth is important both clinically and scientifically. This study aimed to characterize the pattern of dental pulp healing in human teeth that underwent TAT and RET using state-of-the-art imaging techniques., Materials and Methods: This study examined 4 human teeth, 2 premolars that underwent TAT, and 2 central incisors that received RET. The premolars were extracted after 1 year (case 1) and 2 years (case 2) due to ankylosis, while the central incisors were extracted after 3 years (cases 3 and 4) for orthodontic reasons. Nanofocus x-ray computed tomography was used to image the samples before being processed for histological and immunohistochemical analysis. Laser scanning confocal second harmonic generation imaging (SHG) was used to examine the patterns of collagen deposition. A maturity-matched premolar was included as a negative control for the histological and SHG analysis., Results: Analysis of the 4 cases revealed different patterns of dental pulp healing. Similarities were observed in the progressive obliteration of the root canal space. However, a striking loss of typical pulpal architecture was observed in the TAT cases, while a pulp-like tissue was observed in one of the RET cases. Odontoblast-like cells were observed in cases 1 and 3., Conclusions: This study provided insights into the patterns of dental pulp healing after TAT and RET. The SHG imaging sheds light on the patterns of collagen deposition during reparative dentin formation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite the fact that external cervical resorption (ECR) is a well-known and rather frequently met condition, the driving force of this phenomenon still remains unclear. Recently, hypoxia has been linked to ECR. Thus, the aim of this work was to investigate the existence of hypoxia in ECR and hypothesize on its role at the time of extraction. This work is a case study of a tooth with ECR. ECR diagnosis was based on clinical and radiographic examination with cone-beam computed tomographic imaging. The extracted tooth was further analyzed by using nanofocus computed tomographic imaging and immunohistology. To investigate the 3-dimensional extent and pattern of ECR, in vivo cone-beam computed tomographic imaging and ex vivo nanofocus computed tomographic imaging were used. Different histologic stains were used to investigate the presence of a hypoxic environment and to gain a better insight into the involved cells, neuronal structures, and remodeling process during ECR. A higher distribution of hypoxia-inducible factor 1a-positive cells was found in the apical part of the resorption area when compared with the coronal area of the resorption. In addition, a similar distribution of hypoxia-inducible factor 1a-positive odontoblasts was observed in the pulp. Three-dimensional analysis of the calcification of the pulp revealed the formation of pulp stones in areas with higher hypoxia. Histology showed that remodeling during ECR can occur according to a layered pattern. This investigation confirms the presence of hypoxia in ECR and shows that there is a gradient of hypoxia within the ECR lesion and surrounding tooth structure. The hypoxic environment within the pulp is also indicated by the formation of pulp stones., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Regenerative endodontic procedures (REP) are a novel treatment modality to restore the function of necrotic pulp tissue via stimulation or transplantation of stem cells into the root canal. This study aimed to investigate the immunohistologic outcome of 3 extracted teeth because of sequelae of trauma and unsatisfactory REP outcomes., Methods: Three immature permanent maxillary central incisors of 3 female patients (6-9 years) were extracted 5.5-22 months after REP. Additionally, 1 sound permanent immature central maxillary incisor of 1 of the included patients was extracted for orthodontic reasons. The teeth were immunohistologically stained with Masson's trichrome, neurofilament (NF), pan cytokeratin, dentin sialophosphoprotein, and Gram+/-., Results: The REP-teeth presented intracanalar vascularized connective/mineralized reparative tissue (RT), which was less organized than the pulp tissue of the sound tooth. Moderate to considerable calcification was observed below the Portland cement used during REP. In 1 case, the RT was NF+; in the 2 other cases, the periodontal ligament and apical granuloma/papilla were NF+. All teeth were Gram+/- negative; nevertheless, inflammatory cells were present in 2 cases. The pan cytokeratin and dentin sialophosphoprotein stainings were not specific enough for 2 cases., Conclusions: This immunohistologic study of failed REP cases resulted in bacteria-free intracanalar RT and biomaterial-induced calcification. Nevertheless, the presence of inflammatory cells revealed a persistent inflammation. Hence, the clinical and radiographic signs were decisive for tooth survival and multidisciplinary outcome determination., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Compelling evidence pinpoints that pulp tissue engineering after the transplantation of stem cells is possible. Although intriguing, severe problems regarding clinical feasibility remain. Cell homing has been proposed as a viable alternative in which dentin-derived growth factors in a conducive scaffold may attract resident cells to form pulplike tissue. In this study, an ectopic animal model for in situ dental pulp tissue engineering was developed to evaluate whether pulplike tissue formation in empty root canals after the attraction of stem cells was possible and whether this could be enhanced by dentin-derived growth factors., Methods: Three types of fibrin (custom-made fibrin, fibrin sealant, and plasma rich in growth factors [PRGF]) as well as a self-assembling peptide were evaluated in vivo in a modified tooth root model using human teeth. Root canal dentin was conditioned with EDTA, tooth roots were filled with growth factor-laden scaffolds, and dental pulp stem cells in collagen were placed at the root tip. Constructs were implanted into immunocompromised mice for 4 weeks and subsequently analyzed histologically. Differential interference contrast and second harmonic generation imaging were performed for selected sections., Results: For custom-made fibrin and fibrin sealant with dentin matrix proteins, migration into the roots and the formation of a pulplike tissue were observed, whereas the peptide-based scaffold appeared less suitable. PRGF supported tissue formation regardless of the addition of dentin matrix proteins. In the test groups with dentin matrix proteins and EDTA conditioning, differentiated odontoblastlike cells extended cellular processes into the dentinal tubules, which coincided with the deposition of the newly formed collagenous dentin matrix., Conclusions: This new cell homing model provides evidence that fibrin derivatives make applicable scaffolds and that dentin-derived proteins induce chemotaxis and pulplike tissue formation., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Dental pulp is a highly vascularized and innervated tissue containing a heterogeneous stem cell population with multilineage differentiation potential. Current endodontic treatments focus on the preservation of the pulp tissue and the regeneration of dental pulp after pathological insults. Human dental pulp stem cells (hDPSCs) are currently investigated as stem cell-based therapy for pulp regeneration and for peripheral nerve injury in which neurons and Schwann cells display limited regenerative capacity. We have developed a neuronal differentiation protocol for hDPSCs that requires neurosphere formation before neuronal maturation. Moreover, Schwann cell differentiation of hDPSCs in our group revealed that differentiated hDPSCs have acquired the ability to myelinate and guide neurites from dorsal root ganglia. Besides their dynamic differentiation capacity, hDPSCs were shown to exert a paracrine effect on neural and endothelial cells. Analysis of hDPSC conditioned medium revealed the secretion of a broad spectrum of growth factors including brain-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and glial-derived neurotrophic factor. Application of the conditioned medium to endothelial cells promoted cell migration and tubulogenesis, indicating a paracrine proangiogenic effect. This hypothesis was enforced by the enhanced formation of blood vessels in the chorioallantoic membrane assay in the presence of hDPSCs. In addition, transplantation of 3-dimensional-printed hydroxyapatite scaffolds containing peptide hydrogels and hDPSCs into immunocompromised mice revealed blood vessel ingrowth, pulplike tissue formation, and osteodentin deposition suggesting osteogenic/odontogenic differentiation of hDPSCs. Future studies in our research group will focus on the pulp regeneration capacity of hDPSCs and the role of fibroblasts within the pulp extracellular matrix., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

A major conceptual breakthrough in cell signaling has been the finding of EV as new biomarker shuttles in body fluids. Now, one of the major challenges in using these nanometer-sized biological entities as diagnostic marker is the development of translational methodologies to profile them. SPR offers a promising label-free and real time platform with a high potential for biomarker detection. Therefore, we aimed to develop a uniform SPR methodology to detect specific surface markers on EV derived from patient with CHD. EVs having an approximate size range between 30 and 100 nm (~48.5%) and 100-300 nm (~51.5%) were successfully isolated. The biomarker profile of EV was verified using immunogold labeling, ELISA and SPR. Using SPR, we demonstrated an increased binding of EV derived from patients with CHD to anti-ICAM-1 antibodies as compared to EV from healthy donors. Our current findings open up novel opportunities for in-depth and label-free investigation of EV., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the influence of the number of basis images and the orientation of the skull on the evaluation of cortical alveolar bone in cone beam computed tomography (CBCT)., Study Design: Eleven skulls with a total of 59 anterior teeth were selected. CBCT images were acquired by using 4 protocols, by varying the rotation of the tube-detector arm and the orientation of the skull (protocol 1: 360°/0°; protocol 2: 180°/0°; protocol 3: 180°/90°; protocol 4: 180°/180°). Observers evaluated cortical bone as absent, thin, or thick. Direct observation of the skulls was used as the gold standard. Intra- and interobserver agreement, as well as agreement of scoring between the 3 bone thickness classifications, were calculated by using the κ statistic. The Wilcoxon signed-rank test was used to compare the 4 protocols., Results: For lingual cortical bone, protocol 1 showed no statistical difference from the gold standard. Higher reliability was found in protocol 3 for absent (κ = 0.80) and thin (κ = 0.47) cortices, whereas for thick cortical bone, protocol 2 was more consistent (κ = 0.60). In buccal cortical bone, protocol 1 obtained the highest agreement for absent cortices (κ = 0.61), whereas protocol 4 was better for thin cortical plates (κ = 0.38) and protocol 2 for thick cortical plates (κ = 0.40)., Conclusions: No consistent effect of the number of basis images or head orientation for visual detection of alveolar bone was detected, except for lingual cortical bone, for which full rotation scanning showed improved visualization., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction., Methods: Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot., Results: After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression., Conclusion: Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hydrogels have emerged as promising biomaterials for regenerative medicine. Despite major advances, tissue engineers have faced challenges in studying the complex dynamics of cell-mediated hydrogel remodelling. Second harmonic generation (SHG) microscopy has been a pivotal tool for non-invasive visualization of collagen type I hydrogels. By taking into account the typical polarization SHG effect, we recently proposed an alternative image correlation spectroscopy (ICS) model to quantify characteristics of randomly oriented collagen fibrils. However, fibril alignment is an important feature in many tissues that needs to be monitored for effective assembly of anisotropic tissue constructs. Here we extended our previous approach to include the orientation distribution of fibrils in cellular hydrogels and show the power of this model in two biologically relevant applications. Using a collagen hydrogel contraction assay, we were able to capture cell-induced hydrogel modifications at the microscopic scale and link these to changes in overall gel dimensions over time. After 24h, the collagen density was about 3 times higher than the initial density, which was of the same order as the decrease in hydrogel area. We also showed that the orientation parameters recovered from our automated ICS model match values obtained from manual measurements. Furthermore, regions axial to cellular processes aligned at least 1.5 times faster compared with adjacent zones. Being able to capture minor temporal and spatial changes in hydrogel density and collagen fibril orientation, we demonstrated the sensitivity of this extended ICS model to deconstruct a complex environment and support its potential for tissue engineering research., Statement of Significance: It is generally accepted that looking beyond bulk hydrogel composition is key in understanding the mechanisms that influence the mechanical and biological properties of artificial tissues. In this manuscript, we performed label-free non-invasive imaging and extended a robust automated analysis method to characterize the microstructural organisation of cellular hydrogel systems. We underpin the sensitivity of this technique by capturing minor changes in collagen density and fibril orientation in biologically relevant systems over time. Therefore, we believe that this method is applicable in fundamental cell-matrix research and has high-throughput potential in screening arrays of hydrogel scaffolds, making it an interesting tool for future tissue engineering research., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: This study assesses the incidence of neuropathic pain after orthognathic surgery at our center and briefly reports the cases found., Study Design: All records of orthognathic surgical patients between 2001 and 2011 were exported from the hospital information system into a Portable Document Format platform (Adobe Acrobat) to simplify keyword searching. Records of patients that developed debilitating chronic pain were isolated and examined., Results: Records included 982 bilateral sagittal split osteotomies, 536 LeFort I procedures, and 335 surgically assisted rapid palatal expansion procedures. Six records were identified that described cases in which patients developed debilitating chronic neuropathic pain after orthognathic surgery (mean age at surgery, 43 years)., Conclusions: The exposure of the inferior alveolar nerve or partial axonal injury together with a disruption of the bony environment of the inferior alveolar nerve is a risk factor after bilateral sagittal split osteotomy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Perioperative navigation is a recent addition to orthognathic surgery. This study aimed to evaluate the accuracy of anatomical landmarks-based registration., Materials and Methods: Eighty-five holes (1.2 mm diameter) were drilled in the surface of a plastic skull model, which was then scanned using a SkyView cone beam computed tomography scanner. DICOM files were imported into BrainLab ENT 3.0.0 to make a surgical plan. Six anatomical points were selected for registration: the infraorbital foramena, the anterior nasal spine, the crown tips of the upper canines, and the mesial contact point of the upper incisors. Each registration was performed five times by two separate observers (10 times total)., Results: The mean target registration error (TRE) in the anterior maxillary/zygomatic region was 0.93 ± 0.31 mm (p < 0.001 compared with other anatomical regions). The only statistically significant inter-observer difference of mean TRE was at the zygomatic arch, but was not clinically relevant., Conclusion: With six anatomical landmarks used, the mean TRE was clinically acceptable in the maxillary/zygomatic region. This registration technique may be used to access occlusal changes during bimaxillary surgery, but should be used with caution in other anatomical regions of the skull because of the large TRE observed., (Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the outcome of cone beam computed tomography (CBCT)-based surgical planning and transfer technique for tooth autotransplantation versus conventional autotransplantation., Study Design: The study material comprised 40 pediatric subjects in whom 48 teeth were transplanted following a case-control design. While the study group (mean age 11 years) underwent CBCT imaging for surgical planning and transfer via stereolithographic tooth replica fabrication, the historical control group (mean age 12 years) was subjected to conventional autotransplantation., Results: The CBCT-based preoperative planning and the use of a tooth replica decreased the extra-alveolar time and reduced the number of positioning trials with the donor tooth. In the control group, 6 patients showed 1 or more complications, while this was noticed for only 2 study patients., Conclusion: CBCT-based surgical planning of tooth autotransplantation may benefit from a shorter surgical time, while being a less invasive technique, causing fewer failures than a conventional approach., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: The objectives of this study were to analyze outcomes with miniplates in orthognathic surgery and define risk factors resulting in plate removal., Study Design: Clinical files of 570 orthognathic surgery patients operated between 2004 and 2009 were reviewed: 203 had a bimaxillary operation, 310 a lower jaw osteotomy, and 57 an upper jaw osteotomy. Age, sex, and jaw movement were analyzed. Reasons for hardware removal were recorded., Results: Hardware was removed in 157 patients (27.5%). Seventy-eight patients (13.7%) needed removal because of plate-related infection; 66 (11.6%) because of clinical irritation; 5 (0.9%) for dental implant placement; and 8 (1.4%) for other reasons. Average time between operation and removal was 9.9 months. More women (31.7%) than men (20.3%) had plates removed, but age was not a factor except with infection., Conclusions: More than a quarter of patients developed complications from plates and screws, necessitating their removal, and infection occurred in 13.7%. Prompt removal constituted adequate management., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objectives: The objectives of this study were to determine the incidence of bad splits in sagittal split osteotomies (SSOs), performed at the same hospital, and if the occurrence was reduced over time because of technical progress and/or surgical experience. Bad splits were defined as buccal or lingual plate fractures., Study Design: The files of all patients (n = 1008) who underwent bilateral or unilateral SSO between October 1989 and October 2009 were reviewed retrospectively., Results: A bad split occurred in 14 SSO sites (14 of 2005 sites). No bilateral bad splits occurred. There was no notable decrease of bad splits over the 20 years. All bad splits were resolved perioperatively by plate-osteosynthesis without the additional need of intermaxillary fixation. All patients with a bad split had a good and functional occlusion 6 months postoperatively. No infections occurred at the site of the bad splits. No bad splits occurred in patients younger than 20 years. No particular type of dental-facial deformity, or skeletal class according to the Angle's classification could be correlated with cases of bad splits as a predisposing risk factor., Conclusion: Even if precautions are taken, a bad split can occur during SSO of the mandible. This complication is manageable because of its low incidence (0.7 % of all SSOs) and uneventful healing. A significant decrease in incidence did not occur during the 20-year period, and neither technical progress nor the surgeon's experience further reduced the incidence of bad splits., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Background Aims: This study investigated whether neonatal rat cardiomyocytes (NRCM), when co-cultured, can induce transdifferentiation of either human mesenchymal stromal cells (MSC) or hematopoietic stem cells (HSC) into cardiomyocytes. Stem cells were obtained from patients with ischemic heart disease., Methods: Ex vivo-expanded MSC or freshly isolated HSC were used to set-up a co-culture system between NRCM and MSC or HSC. 5-azacytidin (5-aza) or dimethylsulfoxide (DMSO) was used as differentiation-inducing factor. Co-cultured stem cells were separated from NRCM by flow sorting, and cardiac gene expression was analyzed by reverse transcriptase-polymerase chain reaction. Cellular morphology was analyzed by immunofluorescence and transmission electron microscopy (TEM)., Results: Co-culturing MSC induced expression of troponin T and GATA-4. However, no expression of alpha-actinin, myosin heavy chain or troponin I was detected. In the case of HSC, only expression of troponin T could be induced. Immunofluorescence and TEM confirmed the absence of sarcomeric organization in co-cultured MSC and HSC. Adding 5-aza or DMSO to the co-cultures did not influence differentiation., Conclusions: This in vitro co-culture study obtained no convincing evidence of transdifferentiation of either MSC or HSC into functional cardiomyocytes. Nevertheless, induction of troponin T was observed in MSC and HSC, and GATA-4 in MSC. However, no morphologic changes could be detected by immunofluorescence or by TEM. These data could explain why only limited functional improvement was reported in clinical stem cell trials.

The main target organ for cadmium (Cd) is the kidney, and more specifically the proximal tubular cells. Little is known about the effects of a long-term Cd exposure on the ultrastructure of the kidney and the involvement in tubulointerstitial fibrosis. Therefore, mice were exposed to Cd concentrations varying from 10 to 500 mg CdCl(2)/l in the drinking water during 4, 16 and 23 weeks. Ultrastructural changes were studied by means of light- and electron microscopical analyses. Furthermore, the expression of the extracellular matrix (ECM) proteins collagen I and fibronectin, and the myofibroblast/epithelial-to-mesenchymal transition (EMT) marker alfa-smooth muscle actin (alpha-SMA) were studied by means of immunohistochemistry. The histopathological changes caused by Cd varied considerably from one animal to another, and from one individual cell to another. An exposure to Cd concentrations up to 100mg CdCl(2)/l elicited only minor changes that were restricted to increasing amounts of lysosomes and vacuolisation. When higher Cd concentrations were applied, the changes became more pronounced and featured mitochondrial damage, cellular swelling and loss of basal invaginations. An overproduction of the interstitial matrix component fibronectin and the expression of the myofibroblasts/EMT marker alpha-SMA in kidneys of mice exposed to 100mg CdCl(2)/l clearly indicated that an exposure to relatively low Cd doses might lead ultimately to renal fibrosis. Increasing the Cd dose (up to 500 mg CdCl(2)/l) evoked an increased immunoreactivity for fibrotic markers. In conclusion we may state that concentrations up to 100mg CdCl(2)/l evoked minor changes, although the expression of fibrotic markers was increased. Changes became more pronounced when exposing to higher Cd concentrations.

Oxidative stress is believed to participate in the early processes of cadmium (Cd)-induced proximal tubular kidney damage. Mice were chronically exposed up to 23 weeks to low Cd concentrations (10 and 100 mg CdCl(2)/l) via the drinking water. Pro- and antioxidant gene expression levels, glutathione, ascorbate and lipid peroxidation levels were measured. Our study provided evidence for an early and a late stress response in the kidney. Metallothioneins were upregulated from 1 week of exposure on and they stayed important during the whole exposure period. After 8 weeks the expression of Bcl2 (anti-apoptotic), Prdx2 and cytosolic superoxide dismutase (Sod1) was reduced in the group exposed to 100 mg CdCl(2)/l, which might indicate a response to Cd-stress. However glutathione, ascorbate and lipid peroxidation levels did not significantly change, and the overall redox balance remained stable. Stable Sod2 transcriptional levels suggested that an increased formation of superoxide anions, which can arise upon Cd-induced mitochondrial free radical generation, was not appearing. A second defence activation was observed after 23 weeks: i.e. an increase of catalase (Cat), glutathione peroxidase 4 (Gpx4) and heme oxygenase 1 (Hmox1), together with NADPH oxidase 4 (Nox4), of which the role has not been studied yet in Cd nephrotoxicity. These findings were in contrast with previous studies, where Cd-induced oxidative stress was detrimental when high Cd concentrations were applied. In conclusion our study provided evidence that a chronic exposure to low Cd concentrations triggered a biphasic defence activation in the kidney that might lead to adaptation and survival.

The anterior jaw bones are often considered relatively safe surgical sites. Nonetheless, the increasing rate of surgical interventions in that area, such as oral implant placement and bone grafting, has highlighted the potential risks and has raised the reported complications. A careful documentation of all anatomic variations in anterior jaw bone neurovascularization has thus become necessary. The present report attempts to revisit jaw bone neurovascularization, addressing typical anatomic appearances and variations. We summarize the results of various microanatomical studies carried out by high-resolution magnetic resonance imaging (HR-MRI) of the human anterior jaw bones. These studies reveal that edentulous and dentate anterior jaws present significant variation in the occurrence of the mandibular incisive canal and genial spinal foramina, as well as the maxillary nasopalatine canal. All of these canal structures contain a neurovascular bundle, whose diameter may be large enough to cause clinically significant trauma. A careful presurgical radiographic analysis of the anterior jaw bones is therefore advised.

Microglia are dispersed throughout the central nervous system. Under physiological circumstances they display a 'ramified' resting phenotype. In different neuropathologies microglia reversibly transform into the activated form, an amoeboid phagocyte with a broad spectrum of immune effector functions. In this study, a coculture of porcine microglia and the pig renal epithelial cell line LLC-PK1 was used to investigate microglial cell biology. The morphology of the cocultures was elucidated as well as the functionality of the microglia cells by proliferation, superoxide and phagocytosis assays. Our results demonstrate that direct intercellular contact between the two cell types was necessary for microglia to acquire a ramified morphology. Moreover, the conditioned medium of the renal cells promoted proliferation of microglia, inhibited giant cell formation and stimulated microglia to retain their capability to generate superoxide and to perform phagocytosis. In conclusion, we have constructed a cell culture system showing differentiation of microglia in vitro and keeping them in optimal conditions.

Mice were exposed to cadmium (Cd) concentrations ranging from 0 to 100mg CdCl(2)/l in the drinking water for 1, 4, 8, 16 and 23 weeks. Urine samples were taken regularly, Cd content was determined in blood, liver, kidney and urine and histological analyses of the kidney were performed. Kidney cortex Cd content increased linearly with time and dose, while blood levels reached a plateau at 8 weeks and liver at 16 weeks in mice exposed to 100mg CdCl(2)/l after which both started to decrease. Urinary Cd levels were not correlated with the kidney Cd content. A multivariate regression model taking into account the actual Cd intake, calculated from the volume of water taken in by each animal and the exposure concentration, confirmed that blood is an indicator of acute exposure, while kidney Cd content is a reliable indicator of chronic exposure. The urinary protein content was significantly increased from 16 weeks on in mice exposed to 100mg CdCl(2)/l (p<0.05), while other signs of proximal tubular damage (glucosuria, enzymuria) were not detected. Histologically more vacuoles and lysosomes were present in the proximal tubule cells with increasing time and dose. The results indicate that chronic exposure to low doses of Cd induced functional and histological signs of early damage at concentrations in or below the ones generally accepted as safe. Our study does not corroborate the statement that urine Cd levels are a reliable indicator of total Cd body burden, at least when the body burden is low.