RESUMO
Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.
Assuntos
Infecções por Vírus Epstein-Barr , Interleucina-27 , Receptores de Interleucina , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Alelos , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD8-Positivos/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Finlândia , Frequência do Gene , Herpesvirus Humano 4 , Homozigoto , Mononucleose Infecciosa/complicações , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/terapia , Interleucina-27/imunologia , Interleucina-27/metabolismo , Mutação com Perda de Função , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Resultado do TratamentoRESUMO
ABSTRACT: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αß/CD19 (TCRαß) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαß (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαß and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαß and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαß (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαß, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαß and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαß 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαß. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.
Assuntos
Antígenos CD19 , Ciclofosfamida , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos de Linfócitos T alfa-beta , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Criança , Pré-Escolar , Feminino , Masculino , Lactente , Adolescente , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Adulto Jovem , Depleção Linfocítica , Condicionamento Pré-Transplante/métodos , Antígenos HLA/imunologia , Adulto , Resultado do Tratamento , Recém-NascidoRESUMO
Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma associated with Kaposi Sarcoma-associated herpesvirus (KSHV/HHV8) infection. Lymphoma cells are coinfected with Epstein-Barr virus (EBV) in 60-80% of cases. Tools allowing a reliable PEL diagnosis are lacking. This study reports PEL diagnosis in 4 patients using a Flow-Fluorescence in situ hybridization (FlowFISH) technique that allowed detection of differentially expressed EBV and HHV8 transcripts within the same sample, revealing viral heterogeneity of the disease. Moreover, infected cells exhibited variable expressions of CD19, CD38, CD40, and CD138. Therefore, FlowFISH is a promising tool to diagnose and characterize complex viral lymphoproliferations.
Assuntos
Herpesvirus Humano 4 , Herpesvirus Humano 8 , Hibridização in Situ Fluorescente , Linfoma de Efusão Primária , Humanos , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/isolamento & purificação , Hibridização in Situ Fluorescente/métodos , Linfoma de Efusão Primária/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Infecções por Herpesviridae/virologia , Infecções por Herpesviridae/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Idoso de 80 Anos ou maisRESUMO
Ceftazidime-avibactam is a novel cephalosporin/B-lactamase inhibitor developed in the context of increasing resistance. This case reports the pharmacokinetics of ceftazidime-avibactam in a critically ill child under continuous renal replacement (CRRT) therapy for fluid overload. The patient was a 6-month-old female with sepsis due to bloodstream infection to Stenotrophomonas maltophilia following stem cell transplantation for severe combined immunodeficiency. CRRT was started on Day 2. Concentrations have been monitored using liquid chromatography-tandem mass spectrometry. Treatment was given every 8 h with a 2 h infusion of 30-7,5 mg/kg and did not reach pharmacokinetic/pharmacodynamic targets. Total clearance was respectively 1.7 and 3.02 L/h, with CRRT clearance respectively 28.8%-60% for ceftazidime and 14%-33% for avibactam. Those clearances are higher than reported in adult literature leading to a risk of treatment failure and emerging resistance. This supports the benefit of monitoring antimicrobial therapy under CRRT and the necessity to assess higher dosing or continuous infusion of ceftazidime-avibactam.
Assuntos
Compostos Azabicíclicos , Terapia de Substituição Renal Contínua , Sepse , Adulto , Humanos , Feminino , Criança , Lactente , Ceftazidima/farmacocinética , Antibacterianos , Estado Terminal/terapia , Combinação de Medicamentos , Sepse/tratamento farmacológico , Testes de Sensibilidade MicrobianaRESUMO
PURPOSE: To evaluate the oral health-related quality of life (OHRQoL) of individuals diagnosed with Fanconi anemia (FA). METHODS: A cross-sectional study was conducted with FA patients from two Brazilian referral centers. Participants underwent a complete dental, periodontal, and oral mucosa examination, as well as assessment of resting salivary flow. The short version of the Oral Health Impact Profile (OHIP-14) questionnaire was administered. Descriptive and bivariate analyses were performed, followed by multivariate analysis to examine the impact of independent variables on OHRQoL. RESULTS: The study included 20 (57.1%) males and 15 (42.9%) females, with a mean age of 18.9 years. Oral leukoplakia (OL) was found in 18 individuals. The overall OHIP-14 score was 9.9 ± 10.5. Individuals aged ≥ 16 years had higher OHIP-14 scores, indicating worse OHRQoL for physical pain (p = 0.007), psychological discomfort (p = 0.001), physical disability (p = 0.03), psychological disability (p = 0.001), handicap (p = 0.004), and overall score (p = 0.007). Females reported more negative OHRQoL than males for physical pain (p = 0.02), psychological discomfort (p = 0.03), psychological disability (p = 0.009), and overall score (p = 0.02). Individuals with OL had an overall OHIP-14 score 1.83 times higher than those without OL (95% CI: 1.02-3.28; p = 0.04). Lower salivary flow correlated with higher overall OHIP-14 scores (95% CI: 0.14-0.84; p = 0.01). CONCLUSION: This study represents the first attempt to evaluate OHRQoL in individuals with FA. The presence of OL and reduced salivary flow were identified as predictors of a negative impact on OHRQoL. It is imperative to integrate patients' quality of life in the clinical treatment protocols for the FA population.
Assuntos
Anemia de Fanconi , Saúde Bucal , Qualidade de Vida , Humanos , Masculino , Feminino , Estudos Transversais , Adolescente , Adulto Jovem , Anemia de Fanconi/psicologia , Inquéritos e Questionários , Brasil , Adulto , Leucoplasia Oral/psicologia , Criança , Análise MultivariadaRESUMO
OBJECTIVES: Root resorption in permanent teeth is a common pathological process that often follows dental trauma or orthodontic treatment. More rarely, root resorption is a feature of genetic disorders and can help with diagnosis. Thus, the present review aims to determine which genetic disorders could induce pathological root resorptions and thus which mutated genes could be associated with them. METHODS: We conducted a systematic review following the PRISMA guidelines. Articles describing root resorptions in patients with genetic disorders were included from PubMed, Embase, Web of Science, and Google Scholar. We synthesized the genetic disorder, the type, severity, and extent of the resorptions, as well as the other systemic and oral symptoms and histological features. RESULTS: The synthetic analysis included 25 studies among 937 identified records. We analyzed 21 case reports, three case series, and one cohort study. Overall, we highlighted 14 different pathologies with described root resorptions. Depending on the pathology, the sites of resorption, their extent, and their severity showed differences. CONCLUSION: With 14 genetic pathologies suspected to induce root resorptions, our findings are significant and enrich a previous classification. Among them, three metabolic disorders, three calcium-phosphorus metabolism disorders, and osteolysis disorders were identified.
RESUMO
BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.
Assuntos
Infecções por Enterovirus , Transplante de Células-Tronco Hematopoéticas , Hepatite , Imunodeficiência Combinada Severa , Viroses , Humanos , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/etiologia , Linfócitos T CD8-Positivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Viroses/etiologia , Hepatite/etiologiaRESUMO
BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
Assuntos
Fosfatidilinositol 3-Quinase , Doenças da Imunodeficiência Primária , Humanos , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases , Antígeno CTLA-4/genética , Mutação , Doenças da Imunodeficiência Primária/genética , Sistema de RegistrosRESUMO
Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the ß-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Mutação em Linhagem Germinativa , beta Catenina/metabolismo , Células Germinativas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteína Axina/genéticaRESUMO
BACKGROUND: Metagenomic next-generation sequencing (mNGS) was used to assess patients with primary or secondary immune deficiencies (PIDs and SIDs) who presented with immunopathological conditions related to immunodysregulation. METHODS: Thirty patients with PIDs or SIDs who presented with symptoms related to immunodysregulation and 59 asymptomatic patients with similar PIDs or SIDs were enrolled. mNGS was performed on organ biopsy. Specific Aichi virus (AiV) reverse-transcription polymerase chain reaction (RT-PCR) was used to confirm AiV infection and screen the other patients. In situ hybridization (ISH) assay was done on AiV-infected organs to identify infected cells. Virus genotype was determined by phylogenetic analysis. RESULTS: AiV sequences were detected using mNGS in tissue samples of 5 patients and by RT-PCR in peripheral samples of another patient, all of whom presented with PID and long-lasting multiorgan involvement, including hepatitis, splenomegaly, and nephritis in 4 patients. CD8+ T-cell infiltration was a hallmark of the disease. RT-PCR detected intermittent low viral loads in urine and plasma from infected patients but not from uninfected patients. Viral detection stopped after immune reconstitution obtained by hematopoietic stem cell transplantation. ISH demonstrated the presence of AiV RNA in hepatocytes (n = 1) and spleen tissue (n = 2). AiV belonged to genotype A (n = 2) or B (n = 3). CONCLUSIONS: The similarity of the clinical presentation, the detection of AiV in a subgroup of patients suffering from immunodysregulation, the absence of AiV in asymptomatic patients, the detection of viral genome in infected organs by ISH, and the reversibility of symptoms after treatment argue for AiV causality.
Assuntos
Kobuvirus , Doenças da Imunodeficiência Primária , Viroses , Humanos , Kobuvirus/genética , Filogenia , PacientesRESUMO
The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Criança , Transplantados , Acetatos , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Malformações do Sistema Nervoso , Humanos , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/tratamento farmacológico , Malformações do Sistema Nervoso/genética , Transdução de Sinais , Testes GenéticosRESUMO
The main target cells for Epstein-Barr virus (EBV) infection and persistence are B lymphocytes, although T and NK cells can also become infected. In this paper, we characterize the EBV present in 21 pediatric and adult patients who were treated in France for a range of diseases that involve infection of T or NK cells. Of these 21 cases, 5 pediatric patients (21%) and 11 adult patients (52%) were of Caucasian origin. In about 30% of the cases, some of the EBV genomes contain a large deletion. The deletions are different in every patient but tend to cluster near the BART region of the viral genome. Detailed investigation of a family in which several members have persistent T or NK cell infection by EBV indicates that the virus genome deletions arise or are selected independently in each individual patient. Genome sequence polymorphisms in the EBV in these T or NK cell diseases reflect the geographic origin of the patient and not a distinct type of EBV (the 21 cases studied included examples of both type 1 and type 2 EBV infection). Using virus produced from type 1 or type 2 EBV genomes cloned in bacterial artificial chromosome (BAC) vectors, we demonstrate infection of T cells in cord blood from healthy donors. Our results are consistent with transient infection of some T cells being part of normal asymptomatic infection by EBV in young children. IMPORTANCE EBV contributes to several types of human cancer. Some cancers and nonmalignant lymphoproliferative diseases involving T or NK cells contain EBV. These diseases are relatively frequent in Japan and China and have been shown sometimes to have deletions in the EBV genome in the disease cells. We identify further examples of deletions within the EBV genome associated with T or NK cell diseases, and we provide evidence that the virus genomes with these deletions are most likely selected in the individual cases, rather than being transmitted between people during infection. We demonstrate EBV infection of cord blood T cells by highly characterized, cloned EBV genomes and suggest that transient infection of T cells may be part of normal asymptomatic infection by EBV in young children.
Assuntos
Infecções por Vírus Epstein-Barr , Deleção de Genes , Genoma Viral , Herpesvirus Humano 4 , Transtornos Linfoproliferativos , Adulto , Infecções Assintomáticas , Criança , Herpesvirus Humano 4/genética , Humanos , Células Matadoras Naturais/virologia , Transtornos Linfoproliferativos/virologia , Linfócitos T/virologiaRESUMO
AIM: Oligodontia (OD) is a rare developmental condition characterized by the absence of six or more teeth. Dental implant placement may be challenging due to anatomical factors. This study aims to evaluate the alveolar bone dimensions in OD patients compared with controls. MATERIALS AND METHODS: On maxillary and mandibular cone-beam computed tomography (CBCT), bone height and width were measured at every tooth and edentulous site. The distance to the inferior alveolar nerve was also measured. Fifty-three OD patients (40 maxillary and 32 mandibular CBCT) and 82 controls (51 maxillary and 31 mandibular CBCT) were compared using mixed models. RESULTS: Compared with those in OD patients, maxillary permanent teeth and edentulous sites showed significantly higher mean height in control patients (incisive-canine site height: +2.12 mm; edentulous incisive-canine site height: +4.46 mm [p > .001]). For the mandibular permanent teeth, mean height was higher in controls than in OD patients at the incisive-canine (+3.82 mm [p > .001]) and premolar areas (+2.06 mm [p > .001]). Only edentulous incisive-canine sites were significantly different between controls and OD patients (mean: +0.52 mm [p > .001]). Changes in alveolar nerve position were observed in case of molar agenesis. CONCLUSION: Maxillary and mandibular bone dimensions are reduced in OD patients compared with controls both in sites with permanent teeth and in edentulous areas.
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Boca Edêntula , Tomografia Computadorizada de Feixe Cônico Espiral , Humanos , Estudos Retrospectivos , Mandíbula/diagnóstico por imagem , Tomografia Computadorizada de Feixe Cônico/métodos , Maxila/diagnóstico por imagemRESUMO
OBJECTIVE: To investigate the role of phosphatase and tensin homolog (PTEN) in dental pulp cells (hDPs) and adipose-derived mesenchymal stem cells (hADSCs). MATERIALS AND METHODS: Genetic variant was identified with exome sequencing. The hDPs isolated from a patient with Cowden syndrome were investigated for their proliferation, osteogenesis, adipogenesis, and gene expression compared with controls. The normal hDPs and hADSCs were treated with the PTEN inhibitor, VO-OHpic trihydrate (VOT), to investigate the effect of PTEN inhibition. RESULTS: A heterozygous nonsense PTEN variant, c.289C>T (p.Gln97*), was identified in the Cowden patient's blood and intraoral lipomas. The mutated hDPs showed significantly decreased proliferation, but significantly upregulated RUNX2 and OSX expression and mineralization, indicating enhanced osteogenic ability in mutated cells. The normal hDPs treated with VOT showed the decreases in proliferation, colony formation, osteogenic marker genes, alkaline phosphatase activity, and mineral deposition, suggesting that PTEN inhibition diminishes proliferation and osteogenic potential of hDPs. Regarding adipogenesis, the VOT-treated hADSCs showed a reduced number of cells containing lipid droplets, suggesting that PTEN inhibition might compromise adipogenic ability of hADSCs. CONCLUSIONS: PTEN regulates proliferation, enhances osteogenesis of hDPs, and induces adipogenesis of hADSCs. The gain-of-function PTEN variant, p.Gln97*, enhances osteogenic ability of PTEN in hDPs.
Assuntos
Adipogenia , Células-Tronco Mesenquimais , Humanos , Adipogenia/genética , Diferenciação Celular/genética , Tecido Adiposo , Osteogênese/genética , Polpa Dentária , Células-Tronco Mesenquimais/metabolismo , Proliferação de Células/genética , Células Cultivadas , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/farmacologiaRESUMO
OBJECTIVE: Oral malignant infiltrations (OMI) are relevant for the diagnosis and prognosis of leukemia/lymphoma. This study analysed the oral health status and OMI of individuals with leukemia/lymphoma. MATERIALS AND METHODS: A retrospective analysis (2010-2021) of data from individuals seen at a specialized hospital-based dental service in Brazil. RESULTS: A total of 781 cases of leukemia/lymphoma were surveyed. Acute lymphoblastic leukemia (30.1%), acute myeloid leukemia (AML; 26.0%), and non-Hodgkin lymphoma (22.2%) were the most common diagnoses. The first (21.3%) and second (19.3%) decades of life were the most affected. Overall, dental caries (36.7%) and periodontal changes (34.6%) were the most frequent oral conditions. OMI occurred in 25 (3.2%) individuals. Lesions mainly involved the gingiva (80%) and patients diagnosed with AML (64%). Death (p < 0.001) and worse periodontal condition (p = 0.036) were more frequent among adults with OMI than among those without OMI. Death (p = 0.002) was more frequent among paediatric individuals with OMI than among those without OMI. When controlling for underlying disease, no association was observed between OMI and these outcomes. CONCLUSION: Oral status of individuals with leukemia, particularly those with acute leukemia or lymphoma, should be closely monitored since one or multiple conditions may occur, including OMI, which may influence disease outcomes.
Assuntos
Cárie Dentária , Leucemia Mieloide Aguda , Linfoma , Adulto , Humanos , Criança , Brasil/epidemiologia , Estudos Retrospectivos , Linfoma/epidemiologia , Leucemia Mieloide Aguda/epidemiologiaRESUMO
OBJECTIVES: Minipigs present advantages for studying oral bone regeneration; however, standardized critical size defects (CSD) for alveolar bone have not been validated yet. The objectives of this study are to develop a CSD in the mandibular alveolar bone in Aachen minipigs and to further investigate the specific role of periosteum. MATERIALS AND METHODS: Three female Aachen minipigs aged 17, 24, and 84 months were used. For each minipig, a split-mouth design was performed: an osteotomy (2 cm height × 2.5 cm length) was performed; the periosteum was preserved on the left side and removed on the right side. Macroscopic, cone beam computed tomography (CBCT), microcomputed tomography (µCT), and histological analyses were performed to evaluate the bone defects and bone healing. RESULTS: In both groups, spontaneous healing was insufficient to restore initial bone volume. The macroscopic pictures and the CBCT results showed a larger bone defect without periosteum. µCT results revealed that BMD, BV/TV, and Tb.Th were significantly lower without periosteum. The histological analyses showed (i) an increased osteoid apposition in the crestal area when periosteum was removed and (ii) an ossification process in the mandibular canal area in response to the surgical that seemed to increase when periosteum was removed. CONCLUSIONS: A robust model of CSD model was developed in the alveolar bone of minipigs that mimics human mandibular bone defects. This model allows to further investigate the bone healing process and potential factors impacting healing such as periosteum. CLINICAL RELEVANCE: This model may be relevant for testing different bone reconstruction strategies for preclinical investigations.
Assuntos
Regeneração Óssea , Periósteo , Animais , Feminino , Suínos , Humanos , Periósteo/cirurgia , Porco Miniatura , Projetos Piloto , Microtomografia por Raio-X , Regeneração Óssea/fisiologia , Mandíbula/diagnóstico por imagem , Mandíbula/cirurgia , Mandíbula/patologiaRESUMO
STATEMENT OF PROBLEM: Cleft lip and palate are the most frequent congenital anomalies of the face and are often linked with lateral incisor agenesis. The therapeutic decision on whether and how to replace the lateral incisors is not straightforward, and a decision-making tree is needed. PURPOSE: The purpose of this systematic review was to evaluate the available literature reporting on treatments for the replacement of missing lateral incisors in cleft areas. By analyzing the success and survival rates of these treatments, a decision-making tree was developed. MATERIAL AND METHODS: The literature search was performed on the PubMed (MEDLINE), Web of Science, Cochrane, EMBASE, Dentistry of Oral and Science Source, and Google Scholar databases and was based on the question: Which treatment for patients with lateral incisor agenesis and cleft lip and palate has a good success rate? RESULTS: Twenty-six articles were included in this systematic review. A meta-analysis was performed on 14 articles (20 case series, 6 case controls). The estimated overall 5-year survival rates were 96.4% for implant-supported prostheses. CONCLUSIONS: Different treatment options are available, depending on the clinical situation. If the patient meets the conditions for implant placement, this treatment remains a preferred solution. If the prosthetic space is reduced, orthodontic space closure and composite resin restorations are possible. When these options are not possible, a resin-bonded fixed partial denture is the preferred option. If the teeth adjacent to the edentulous area require extensive restorations, a fixed partial denture may be a suitable alternative.
RESUMO
Several primary immunodeficiencies are caused by defects in the general DNA repair machinery as exemplified by the T-B- radiosensitive SCID condition owing to impaired resolution of programmed DNA double-strand breaks introduced by RAG1/2 during V(D)J recombination. The genome instability generally associated with these conditions results in an increased propensity to develop malignancies requiring genotoxic-based anti-cancer treatments. Moreover, the extent of immune deficiency often calls for hematopoietic stem cell transplantation as a definitive treatment, also requiring genotoxic-based conditioning regimen prior to transplantation. In both cases, the underlying general DNA repair defect may result in catastrophic iatrogenic consequences. It is, therefore, of paramount importance to assess the functionality of the DNA repair apparatus prior to any genotoxic treatment when the exact molecular cause of the disease is unknown. For this purpose, two simple assays can be used on patients derived peripheral blood lymphocytes: (1) the PROMIDISα biomarker, based on the next-generation sequencing analysis of the TCRα repertoire, will highlight specific signatures of DNA repair deficiencies; (2) direct analysis of the sensitivity of peripheral lymphocytes to ionizing radiation will formally identify patients at risk to develop toxicity toward genotoxic-based treatments.
Assuntos
Dano ao DNA , Síndromes de Imunodeficiência , Reparo do DNA/genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Recombinação V(D)JRESUMO
The indirect immobilisation of Jagged-1 (Jagged-1) promoted osteogenic differentiation of human dental pulp cells (hDPs). Furthermore, the analysis of the Reactome pathway of RNA sequencing data indicates the upregulated genes involved with the extracellular matrix (ECM). Hence, our objective was to investigate the effects of Jagged-1 on proteomic profiles of human dental pulp stem cells (hDPSC). hDPSCs were cultured on the surface coated with human IgG Fc fragment (hFc) and the surface coated with rhJagged1/Fc recombinant protein-coated surface. Cells were differentiated to the osteogenic lineage using an osteogenic differentiation medium (OM) for 14 days, and cells cultured in a growth medium were used as a control. The protein component of the cultured cells was extracted into the cytosol, membrane, nucleus, and cytoskeletal compartment. Subsequently, the proteomic analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS). Metascape gene list analysis reported that Jagged-1 stimulated the expression of the membrane trafficking protein (DOP1B), which can indirectly improve osteogenic differentiation. hDPSCs cultured on Jagged-1 surface under OM condition expressed COL27A1, MXRA5, COL7A1, and MMP16, which played an important role in osteogenic differentiation. Furthermore, common matrisome proteins of all cellular components were related to osteogenesis/osteogenic differentiation. Additionally, the gene ontology categorised by the biological process of cytosol, membrane, and cytoskeleton compartments was associated with the biomineralisation process. The gene ontology of different culture conditions in each cellular component showed several unique gene ontologies. Remarkably, the Jagged-1_OM culture condition showed the biological process related to odontogenesis in the membrane compartment. In conclusion, the Jagged-1 induces osteogenic differentiation could, mainly through the regulation of protein in the membrane compartment.