In-vivo repeatability of three intra-oral spectrophotometers.

OBJECTIVE: The objective was to assess the repeatability of three spectrophotometers, based on the CIELCh factors and shadeguide reference measurements. MATERIALS AND METHODS: Color analysis was performed using three devices: Rayplicker, Easyshade 4, and Easyshade V. Five repeated measures were performed by the same operator, on the right central maxillary incisor of 30 patients. The CIELCh factors were retrieved and the intra-class correlation was calculated. The Vita Classical and Vita 3D Master shadeguides were used to evaluate the respective Fleiss' Kappa factors. RESULTS: Rayplicker and Easyshade V demonstrated strong intra-class correlation based on the CIELCh factors: 0.98, 0.99, and 0.91 for Rayplicker, and 0.95, 0.99, and 0.93 for Easyshade V, for the L*, C*, and h* parameters, respectively. Regarding the repeatability of the shadeguide data, while Easyshade 4 had the best repeatability when using the Vita Classical as a reference, Rayplicker and Easyshade V showed better repeatability when using the Vita 3D Master. CONCLUSION: These findings suggest that both Rayplicker and Easyshade V are reliable devices for measuring CIELCh parameters. In terms of shadeguide references, the reliability of spectrophotometers is generally lower compared to the CIELCh measurements. CLINICAL SIGNIFICANCE: Given their good repeatability, both the Rayplicker and the Easyshade V spectrophotometers are reliable tools for prosthetic dental practices.

Intraoral optical impression versus conventional impression for fully edentulous maxilla: an in vivo comparative study.

AIM: The aim of the present in vivo study was to compare the clinical trueness of primary mucostatic impressions obtained either by a classical alginate or an optical intraoral scanner technique in patients with a fully edentulous maxilla. MATERIALS AND METHODS: A total of 30 patients with a fully edentulous maxilla were included in the study and underwent both conventional impressions and intraoral optical impressions (Trios 3). The conventional impressions were casted and the resulting plaster casts were digitized using a desktop scanner (Imetric D104i). These digitized impressions were superimposed over the optical impressions to compare the differences between the two data sets. Statistical analyses were performed to identify relevant deviations. RESULTS: For the 30 intraoral impressions, 80.88% of the surface areas were below the tolerance threshold of 25 µm and were thus considered similar to the areas scanned with the desktop scanner from the reference plaster cast. Interestingly, the differences (19.12% of the surface areas) were localized in depressible areas such as the vestibule, soft palate, incisive papilla, and flabby ridges. These locations were consistent with the mean of positive differences of +22.8 µm, indicating deformation or less compression with the use of the intraoral scanner. CONCLUSIONS: The digital primary impression of the fully edentulous maxilla can be considered similar to the conventional alginate impression except in the depressible areas. Considering the mucostatic objective of such a primary impression, one may consider the optical impression to be more accurate than the conventional one.

Operator versus material influence on film thickness using adhesive resin cement or pre-heated resin composite.

OBJECTIVE: There is a growing interest in using pre-heated composites instead of dual-cured cements when luting indirect restorations. This study evaluated the film thickness obtained from two pre-heated composites and two resin cements, by two different operators. The influence of the materials and the level of expertise of the operator were analyzed. MATERIALS AND METHODS: Forty specimens of human dentin and composite discs were prepared and divided into four groups depending on the luting process. Each group was randomly equally divided to be handled by two operators with different levels of experience. Two of the initial four groups were luted using dual-cured cements and the two remaining groups using light-cured pre-heated composites. Specimen discs were cut after luting, and film thickness was measured using a Digital microscope. Data were analyzed using a 2-way ANOVA with the Holm-Sidak pairwise multiple comparison procedure (p < 0.05). RESULTS: Mean film thickness ranged from 156.16 ± 4.7 to 33.82 ± 0.7 µm. Significant differences (p < 0.001) were noticed between expert and novice results with pre-heated composites. CONCLUSION: Within the limits of this study, using pre-heated composites as a luting cement requires a better level of expertise to achieve a clinically acceptable film thickness. CLINICAL SIGNIFICANCE: Using pre-heated composites as luting agent for indirect restorations requires an experimented skill level to achieve a clinically recommended film thickness.

In vitro comparison of the surface roughness of polymethyl methacrylate and bis-acrylic resins for interim restorations before and after polishing.

STATEMENT OF PROBLEM: Polymethyl methacrylate and bis-acrylic based resins are widely used for interim restorations. Their initial surface roughness is important because it determines their aesthetic properties and the potential for biofilm adhesion. PURPOSE: The purpose of this in vitro study was to assess the surface roughness and morphology of 6 bis-acrylic and 2 polymethyl methacrylate resins widely used for interim dental restorations, both before and after polishing. MATERIAL AND METHODS: Specimens made of different bis-acrylic resins (Protemp 4, Luxatemp Star, Systemp, Telio, Structur Premium, Structur 3) or of polymethyl methacrylate (Unifast Trad, Unifast 3) were polished using a 2-step polishing system (Diatech). The average surface roughness before and after polishing (10 seconds at low speed in dry conditions) was measured by optical profilometry. Atomic force microscopy and scanning electron microscopy were used to analyze surface morphology. The Mann-Whitney and Kruskal-Wallis tests were used to evaluate the differences in roughness among specimens (α=.05), and the Pearson r correlation was computed to assess the relationship between fillers and average surface roughness. RESULTS: In the 8 groups evaluated, the roughness significantly increased (P<.001) for Protemp 4 (from 0.12 to 0.50 µm), Luxatemp Star (0.17 to 1.19 µm), Unifast 3 (0.40 to 1.00 µm), Systemp (0.46 to 1.51 µm), Structur 3 (0.85 to 1.06 µm), Structur Premium (1.00 to 1.74 µm), and Telio (1.13 to 1.21 µm), except for Unifast Trad (9.20 to 2.59 µm). Pairwise multiple comparisons identified Protemp 4 as having the smoothest surface before and after polishing, while Unifast Trad was the roughest in both. Atomic force microscopy and scanning electron microscopy observations showed that the surface roughness of bis-acrylic resins was related to their surface morphology and average filler sizes. A positive relation between fillers and roughness was assessed (r=0.345, P<.001). CONCLUSIONS: For the bis-acrylic interim resins, the surface roughness after polishing was correlated to the material used and its filler sizes. Nanofiller-based resins showed the smoothest surfaces. For the polymethyl methacrylate-based resins, the recently marketed Unifast 3 had the lowest overall roughness values.

A comparative in vivo study of new shade matching procedures.

AIM: The aim of the present study was to compare six different methods of in vivo color matching: visual shade matching (3D-Master Linearguide shade guide) performed by 1) a novice practitioner, 2) an expert practitioner, 3) the new Rayplicker spectrometer, 4) the Trios III intraoral scanner, and 5) the Omnicam intraoral scanner compared with 6) the Easyshade V spectrophotometer, which was considered as the reference. MATERIALS AND METHODS: Color matching was performed using the 3D-Master references on the sound maxillary right central incisors of 40 subjects. The study first compared the number of colors found using each of the six methods. The references were then converted to the Commission Internationale de l'Eclairage (CIE) L*a*b* values, from which the difference ?E between either two methods ?was derived. Finally, the L* value was used to compare the luminosity measured by each of the six methods. RESULTS: The Rayplicker showed the smallest ?E compared with the Easyshade V. The expert found a closer color to the Easyshade V than did the novice, and both were closer to the Easyshade V than the two intraoral scanners. The intraoral scanners showed notable differences compared with the Easyshade V. The intraoral scanners also offered a reduced choice of colors and recorded the highest luminosities compared with the other methods. CONCLUSION: Within the limitations of this study, the color matching by the Rayplicker was closest to that of the Easyshade V. The good performance of this new device means that it is a challenging competitor for the Easyshade V. Finally, the new methods based on intraoral scanners were less reliable than the spectrophotometers and the visual shade matching.

The prion protein is critical for DNA repair and cell survival after genotoxic stress.

The prion protein (PrP) is highly conserved and ubiquitously expressed, suggesting that it plays an important physiological function. However, despite decades of investigation, this role remains elusive. Here, by using animal and cellular models, we unveil a key role of PrP in the DNA damage response. Exposure of neurons to a genotoxic stress activates PRNP transcription leading to an increased amount of PrP in the nucleus where it interacts with APE1, the major mammalian endonuclease essential for base excision repair, and stimulates its activity. Preventing the induction of PRNP results in accumulation of abasic sites in DNA and impairs cell survival after genotoxic treatment. Brains from Prnp(-/-) mice display a reduced APE1 activity and a defect in the repair of induced DNA damage in vivo. Thus, PrP is required to maintain genomic stability in response to genotoxic stresses.

Lack of a p21waf1/cip -dependent G1/S checkpoint in neural stem and progenitor cells after DNA damage in vivo.

The cyclin-dependent kinase inhibitor p21(waf1/cip) mediates the p53-dependent G1/S checkpoint, which is generally considered to be a critical requirement to maintain genomic stability after DNA damage. We used staggered 5-ethynyl-2'deoxyuridine/5-bromo-2'-deoxyuridine double-labeling in vivo to investigate the cell cycle progression and the role of p21(waf1/cip) in the DNA damage response of neural stem and progenitor cells (NSPCs) after exposure of the developing mouse cortex to ionizing radiation. We observed a radiation-induced p21-dependent apoptotic response in migrating postmitotic cortical cells. However, neural stem and progenitor cells (NSPCs) did not initiate a p21(waf1/cip1) -dependent G1/S block and continued to enter S-phase at a similar rate to the non-irradiated controls. The G1/S checkpoint is not involved in the mechanisms underlying the faithful transmission of the NSPC genome and/or the elimination of critically damaged cells. These processes typically involve intra-S and G2/M checkpoints that are rapidly activated after irradiation. p21 is normally repressed in neural cells during brain development except at the G1 to G0 transition. Lack of activation of a G1/S checkpoint and apoptosis of postmitotic migrating cells after DNA damage appear to depend on the expression of p21 in neural cells, since substantial cell-to-cell variations are found in the irradiated cortex. This suggests that repression of p21 during brain development prevents the induction of the G1/S checkpoint after DNA damage.

Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death.

Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death.

XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors.

XLF/Cernunnos is a component of the ligation complex used in classical non-homologous end-joining (cNHEJ), a major DNA double-strand break (DSB) repair pathway. We report neurodevelopmental delays and significant behavioral alterations associated with microcephaly in Xlf-/- mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is associated with a low level of apoptosis of neural cells and premature neurogenesis, which consists of an early shift of neural progenitors from proliferative to neurogenic divisions during brain development. We show that premature neurogenesis is related to an increase in chromatid breaks affecting mitotic spindle orientation, highlighting a direct link between asymmetric chromosome segregation and asymmetric neurogenic divisions. This study reveals thus that XLF is required for maintaining symmetric proliferative divisions of neural progenitors during brain development and shows that premature neurogenesis may play a major role in neurodevelopmental pathologies caused by NHEJ deficiency and/or genotoxic stress.

Fanconi DNA repair pathway is required for survival and long-term maintenance of neural progenitors.

Although brain development abnormalities and brain cancer predisposition have been reported in some Fanconi patients, the possible role of Fanconi DNA repair pathway during neurogenesis is unclear. We thus addressed the role of fanca and fancg, which are involved in the activation of Fanconi pathway, in neural stem and progenitor cells during brain development and adult neurogenesis. Fanca(-/-) and fancg(-/-) mice presented with microcephalies and a decreased neuronal production in developing cortex and adult brain. Apoptosis of embryonic neural progenitors, but not that of postmitotic neurons, was increased in the neocortex of fanca(-/-) and fancg(-/-) mice and was correlated with chromosomal instability. In adult Fanconi mice, we showed a reduced proliferation of neural progenitor cells related to apoptosis and accentuated neural stem cells exhaustion with ageing. In addition, embryonic and adult Fanconi neural stem cells showed a reduced capacity to self-renew in vitro. Our study demonstrates a critical role for Fanconi pathway in neural stem and progenitor cells during developmental and adult neurogenesis.

Digital evaluation of dental bleaching using a new methodology: an in vivo study.

OBJECTIVE: The objective of the present study was to assess the progress and efficiency of at-home bleaching protocols with 10% carbamide peroxide using a new methodology based on dental photography. MATERIALS AND METHODS: A 4-week overnight at-home bleaching protocol using whitening trays and 10% carbamide peroxide was performed on 52 patients. The tooth color was analyzed using standardized photographs taken every week for 4 weeks and at 4 months posttreatment. The values of the color evolution (ΔE00), L*, a*, and b* were also measured and used to assess the evolution of the chroma, luminosity, and hue using the CIEDE2000 formula. The statistical analyses were conducted at a significance level of P < 0.05 by means of a repeated measures analysis of variance (ANOVA). RESULTS: The tooth color changed the most, and thus the highest ΔE00 was observed, after the first week of treatment. The color continued to change but to a lesser degree during the following weeks. After 4 weeks, the treatment proved to be very effective. Four months after the end of treatment, a color relapse was observed, though it was hardly perceptible to the human eye. The luminosity (L') changed significantly between the beginning and the end of treatment, affecting the maxilla to a greater extent. The chroma evolution showed a high variance and a low relapse for both jaws. The hue was not affected significantly during the treatment and the stabilization. CONCLUSIONS: Within the limitations of the present study, the authors were able to assess the progress and efficiency of at-home bleaching with 10% carbamide peroxide in terms of chroma, luminosity, and hue using a new methodology based on dental photography. CLINICAL SIGNIFICANCE: This new method is effective and enables a reliable analysis of the evolution of a dental bleaching treatment, turning dental photo-graphy into an even more powerful tool for analysis and communication. It can also be used as a proof-of-concept, paving the way for further research on objective monitoring and evaluation of dental treatments using dental photography.

Treatment of Tooth Wear Using Direct or Indirect Restorations: A Systematic Review of Clinical Studies.

Tooth wear is considered a well-developed issue in daily clinical practice; however, there is no standard protocol for treatment. The aim of this manuscript was to systematically review the literature to evaluate the clinical outcomes of direct or indirect restorations for treating tooth wear. A literature search was conducted through the PubMed MedLine, Scopus, ISI Web of Science, Scielo, and EMBASE databases up to 29 April 2022. Clinical studies evaluating the clinical performance of direct or indirect restorations for treating tooth wear for a minimum follow-up of 6 months were included in the review. A total of 2776 records were obtained from the search databases. After full-text reading, 16 studies were included in the qualitative analysis. Considering the high heterogenicity of the studies included, a meta-analysis could not be performed. All studies included the rehabilitation of anterior and posterior teeth with extensive wear, using both indirect and direct restorations for a maximum follow-up of 10 years. Restoration materials included ceramo-metal crowns, full gold crowns, lithium disilicate ceramic, zirconia, polymer infiltrated ceramic networks, and resin composites. Most of the reports assessed the survival rate of the restorations and the clinical features using the United States Public Health Service (USPHS) Evaluation System criteria. Contradictory discoveries were perceived concerning the type of restoration with better clinical performance. Considering the current literature available, there is no evidence in the superiority of any restoration technique to ensure the highest clinical performance for treating tooth wear.

Esthetic mock-ups: a clinical study of reproducibility.

The mock-up technique is a widely used clinical method to achieve successful esthetic and functional treatments. Several methods have been described to fabricate the mock-up, either directly in the mouth or indirectly using a silicone index or CAD/CAM options. The mock-up mainly serves as a guide during the preparation stage, but it is also a useful communication and validation tool. Based on the controlled depth preparation concept, the mock-up ensures a specific restoration thickness sufficient for the ceramic and respectful of the enamel tissue. Any error in fabricating the mock-up may cause debonding complications and have a negative impact on the esthetic result. Currently, most mock-ups are created indirectly using a silicone index injected with a temporary resin that mimics the final esthetic project. The present article reports on the protocol involved in a clinical study conducted to validate the precision of reproducibility of this indirect method. Two different options for creating the silicone index were investigated. Twenty mock-ups were realized on the same subject by the same operator. Each mock-up was 3D scanned to compare its reproducibility using the superimposition of 3D meshes. The results show that the reproducibility of indirect mock-ups is clinically acceptable (~ 100 µm), regardless of the fabrication method used. However, a combination of standard silicone and a rigid tray produces better results than hard silicone alone.

Dentine disorders and adhesive treatments: A systematic review.

OBJECTIVES: A better understanding of the microstructure and mechanical properties of enamel and dentine may enable practitioners to apply the current adhesive dentistry protocols to clinical cases involving dentine disorders (dentinogenesis imperfecta or dentine dysplasia). DATA/SOURCES: Publications (up to June 2020) investigating the microstructure of dentine disorders were browsed in a systematic search using the PubMed/Medline, Embase and Cochrane Library electronic databases. Two authors independently selected the studies, extracted the data in accordance with the PRISMA statement, and assessed the risk of bias with the Critical Appraisal Checklist. A Mann-Whitney U test was computed to compare tissues damage related to the two dentine disorders of interest. STUDY SELECTION: From an initial total of 642 studies, only 37 (n = 164 teeth) were included in the present analysis, among which 18 investigating enamel (n = 70 teeth), 15 the dentine-enamel junction (n = 62 teeth), and 35 dentine (n = 156 teeth). Dentine is damaged in cases of dentinogenesis imperfecta and osteogenesis imperfecta (p = 2.55E-21 and p = 3.99E-21, respectively). These studies highlight a reduction in mineral density, hardness, modulus of elasticity and abnormal microstructure in dentine disorders. The majority of studies report an altered dentine-enamel junction in dentinogenesis imperfecta and in osteogenesis imperfecta (p = 6.26E-09 and p = 0.001, respectively). Interestingly, enamel is also affected in cases of dentinogenesis imperfecta (p = 0.0013), unlike to osteogenesis imperfecta (p = 0.056). CONCLUSIONS: Taking into account all these observations, only a few clinical principles may be favoured in the case of adhesive cementation: (i) to preserve the residual enamel to enhance bonding, (ii) to sandblast the tooth surfaces to increase roughness, (iii) to choose a universal adhesive and reinforce enamel and dentine by means of infiltrant resins. As these recommendations are mostly based on in vitro studies, future in vivo studies should be conducted to confirm these hypotheses.

Microguided endodontics: Accuracy evaluation for access through intraroot fibre-post.

In this work, we intended to assess the reliability of guided endodontic technique to remove a bonded fibre-post when there are artefacts in the cone-beam computed tomography (CBCT) images caused by composite dental materials. We mounted natural posterior teeth on ten simulated models. Forty fibre-post and composite-core restorations were inserted in the teeth. We merged a pre-operative CBCT and optical surface scan on the BlueskyplanTM software to digitally design and subsequently 3D-printed the guides. Two operators initiated endodontic access into the fibre-post restorations using the template to guide the drill. Post-operative CBCT was taken and merged onto the pre-operative plan to measure the deviations at the coronal and apical segments. The mean deviation between the planned and actual drill paths were, respectively, of 0.39 ± 0.14 mm coronally and 0.40 ± 0.19 mm apically. Microguided endodontics is a predictable and accurate method to remove fibre-post restorations efficiently.

An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development.

We developed an Xrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4-deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy the Nhej1-/- (known as Xlf -/-) setting with a minor impact on the development of the adaptive immune system. The core non-homologous end-joining (NHEJ) DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast, Xrcc4M61R mice crossed on Paxx-/-, Nhej1-/-, or Atm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in Xlf-Paxx and Xlf-Atm double Knock Out (DKO) settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of Xrcc4M61R -Nhej1-/- double mutants. These in vivo results reveal new functional interplays between XRCC4 and PAXX, ATM and Xlf in mouse development and provide new insights into the understanding of the clinical manifestations of human XRCC4-deficient condition, in particular its absence of immune deficiency.

Microgap between zirconia abutments and titanium implants.

PURPOSE: The aim of this study was to evaluate in vitro the microgap between different zirconia abutments and their titanium implants. MATERIALS AND METHODS: Four systems were evaluated: Procera zirconia (Nobel Biocare) (Nb), Cercon Balance Anterior (Dentsply Friadent) (Ba), ZirDesign (Astratech) (Zd), and Straumann Cares ceramic (Straumann) (Ca). Five assemblies were assessed for each system. The assemblies were embedded in epoxy, cut along their long axes, and polished. Scanning electron microscopic observations were made along the first 100 microm of the gap on each side at maximal magnification. Images were combined and gap measurements were made 10 microm apart. A two-way analysis of variance was performed on the data. RESULTS: Scanning electron micrographs showed a mean marginal microgap of 0.89 microm (SD 1.67) for all assemblies. Significant differences (P < .001) were observed between mean (+/- SD) microgap measurements of the four tested systems: Ba = 0.38 +/- 0.28 microm; Zd = 0.55 +/- 0.23 microm; Nb = 1.83 +/- 3.21 microm; Ca = 0.90 +/- 0.59 microm. The mean microgap of the first 20 microm of the outer region (1.66 microm) was significantly (P < .001) larger than the mean microgap (0.56 microm) of the inner region (30 to 100 microm). CONCLUSIONS: Within the limitations of this study, the mean microgap observed for all tested systems was less than 2 microm. For each system, the microgap decreased quickly from the outer region to the inner. The mean gap was larger for flat-to-flat connection systems, compared to internal-connection systems with a conical interface. These results demonstrate smaller microgaps compared to those described in the literature for titanium abutments. The precise fit of these abutments could lead to better biologic and biomechanical behavior.

Higher chromosome stability in embryonic neural stem and progenitor cells than in fibroblasts in response to acute or chronic genotoxic stress.

High fidelity of genetic transmission in neural stem and progenitor cells (NSPCs) has been long time considered to be crucial for brain development and homeostasis. However, recent studies have identified recurrent DSB clusters in dividing NSPCs, which may underlie the diversity of neuronal cell types. This raised the interest in understanding how NSPCs sense and repair DSBs and how this mechanism could be altered by environmental genotoxic stress caused by pollutants or ionizing radiation. Here, we show that embryonic mouse neural stem and progenitor cells (NSPCs) have significantly higher capacity than mouse embryonic fibroblasts (MEFs) to maintain their chromosome stability in response to acute (γ-radiation) and chronic (tritiated thymidine -3H-T- incorporation into DNA) genotoxic stress. Cells deficient for XLF/Cernunnos, which is involved in non-homologous end joining DNA (NHEJ) repair, highlighted important variations in fidelity of DNA repair pathways between the two cell types. Strikingly, a progressive and generalized chromosome instability was observed in MEFs cultured with 3H-T at long-term, whereas NSPCs cultured in the same conditions, preserved their chromosome stability thanks to higher DNA repair activity further enhanced by an adaptive response and also to the elimination of damaged cells by apoptosis. This specific DNA damage response of NSPCs may rely on the necessity for preservation of their genome stability together with their possible function in creating neuronal genetic diversity.

Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells.

Neurogenesis persists in the adult brain subventricular zone where neural stem/progenitor cells (NSPCs) lie close to brain endothelial cells (BECs). We show in mouse that BECs produce bone morphogenetic proteins (BMPs). Coculture of embryonic and adult NSPCs with BECs activated the canonical BMP/Smad pathway and reduced their proliferation. We demonstrate that coculture with BECs in the presence of EGF and FGF2 induced a reversible cell cycle exit of NSPCs (LeX+) and an increase in the amount of GFAP/LeX-expressing progenitors thought to be stem cells. Levels of the phosphatidylinositol phosphatase PTEN were upregulated in NSPCs after coculture with BECs, or treatment with recombinant BMP4, with a concomitant reduction in Akt phosphorylation. Silencing Smad5 with siRNA or treatment with Noggin, a BMP antagonist, demonstrated that upregulation of PTEN in NSPCs required BMP/Smad signaling and that this pathway regulated cell cycle exit of NSPCs. Therefore, BECs may provide a feedback mechanism to control the proliferation of NSPCs.

Adult T-type lymphoblastic lymphoma presenting as hypercalcemic crisis and aplastic anemia: a case report.

BACKGROUND: Hypercalcemia and aplastic anemia are two uncommon presentations of non-Hodgkin lymphoma that potentially worsen the disease prognosis. Although hypercalcemia has been reported in the B-cell subtypes and some T-cell subtypes of non-Hodgkin lymphoma, it has not been described in T-cell lymphoblastic lymphoma. The same applies to aplastic anemia, which is also not described in T-type lymphomas. CASE PRESENTATION: We report a case of a 52-year-old Cameroonian man with acute kidney injury who presented with confusion, abdominal pain, constipation, polyuria, polydipsia, calciphylaxis, enlarged lymph nodes, tachycardia, and a blood pressure of 170/88 mmHg. Laboratory investigations revealed hypercalcemia (total/ionized 199.5/101.75 mg/L), normal serum phosphorus (40.20 mg/L), and a low intact parathyroid hormone (9.70 pg/ml). Complete blood count revealed pancytopenia. Peripheral blood smear confirmed thrombocytopenia but showed neither blasts nor flower cells. Bone marrow aspirate revealed hypocellularity with no blasts or fibrosis. Lymph node biopsy was suggestive of T-cell precursor lymphoma. T-lymphoblastic lymphoma presenting with hypercalcemic crisis and aplastic anemia was diagnosed, and the patient received the cyclophosphamide-doxorubicin-vincristine-prednisone protocol of chemotherapy together with filgrastim and whole-blood transfusion for aplastic anemia. The short-term outcome was fatal, however. CONCLUSIONS: Severe hypercalcemia and aplastic anemia are potential paraneoplastic syndromes of adult T-type lymphoblastic lymphoma, with fatal short-term outcome.