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1.
Am J Med Genet A ; 194(6): e63536, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38243380

ABSTRACT

Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.


Subject(s)
Adrenal Insufficiency , DAX-1 Orphan Nuclear Receptor , Child, Preschool , Humans , Male , Adrenal Insufficiency/genetics , Adrenal Insufficiency/pathology , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/congenital , DAX-1 Orphan Nuclear Receptor/genetics , Follow-Up Studies , Genetic Association Studies/methods , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Genetic Diseases, X-Linked/diagnosis , Hypoadrenocorticism, Familial/genetics , Mutation/genetics , Phenotype , Infant, Newborn , Adolescent
2.
Transfus Med ; 34(1): 46-53, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38165014

ABSTRACT

Knowledge regarding the profile of eligible blood donors presenting positive results in laboratory screening is essential for reducing transfusion-transmitted human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). Our study aimed to evaluate the prevalence, incidence, predictor variables and residual risk (RR) of HIV/HBV/HCV in blood bags donated in Minas Gerais, Brazil. This study analysed data retrieved from the records of a large blood bank relating to donations collected at multiple centres within the period 2012-2018, during which 1 991 120 blood bags were screened using immunoassays and nucleic acid tests (NATs). Multilevel modelling was used to investigate the association between sex, civil status and age group with HIV/HBV/HCV. RR was estimated from the incidence values (restricted to negative and positive tests within the study period) and window periods for infections. The prevalence in first time donors, incidence and RR of HCV (223.73 cases per 100 000; 54.84 per 100 000 persons-year and 1.6527 per 100 000, respectively) were higher than those of HIV (172.65 cases per 100 000; 28.25 per 100 000 persons-year and 0.8514 per 100 000) and HBV (168.17 cases per 100 000; 18.54 per 100 000 persons-year and 0.5588 per 100 000). The odds of acquiring infection were greater in male, single and older donors. Sixteen donors were identified as seronegative and NATs+ during the 7-year span of the study. Our study has clarified some spatiotemporal trends regarding HIV/HBV/HCV infections in donated blood in Brazil. The results will contribute to the formulation of directives addressed to high-risk donors.


Subject(s)
HIV Infections , Hepatitis B , Hepatitis C , Male , Humans , Female , Incidence , Hepatitis B/epidemiology , Brazil/epidemiology , Blood Donors , Prevalence , Risk Factors , Hepatitis C/epidemiology , Hepatitis B virus , HIV Infections/epidemiology , Hepacivirus
3.
Caries Res ; : 1-9, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38574474

ABSTRACT

INTRODUCTION: Pediatric dentistry should rely on evidence-based clinical decisions supported by high-quality, unbiased systematic reviews (SRs). Therefore, the purpose of this study was to systematically evaluate the methodological quality and risk of bias of SRs focused on non- and micro-invasive treatment for caries lesions in primary and permanent teeth. METHODS: A comprehensive search was conducted in multiple databases, including MEDLINE/PubMed, Scopus, Web of Science, EMBASE, Epistemonikos, and ProQuest, up to March 2023 to identify relevant systematic reviews (SRs) focused on non- and micro-invasive caries treatment. Two independent reviewers extracted data from the included SRs and assessed the methodological quality and risk of bias using the AMSTAR 2 and ROBIS tools, respectively. RESULTS: A total of 39 SRs were included in the analysis. Among these, 27 SRs (69.2%) were assessed as having critically low methodological quality, 11 SRs (28.2%) were considered to have low methodological quality, and only one SR was rated as high-quality. The primary concern identified was the absence of protocol registration before commencing of the study, observed in 33 SR when using the AMSTAR 2 tool. According to the ROBIS tool, 21 studies (53.8%) were categorized as low risk of bias, 10 (25.6%) as high risk, and eight (20.5%) as unclear risk of bias. CONCLUSION: Our analysis revealed that SRs focused on non- and micro-invasive treatment for caries in children and adolescents had critically low methodological quality according to the AMSTAR 2 tool but demonstrated a low risk of bias based on the ROBIS tool. These findings highlight the importance of emphasizing prospective protocol registration, transparent reporting of statistical analyses, and addressing potential bias implications within this topic. By addressing these issues, we can enhance the quality of SRs and ensure that clinical decisions rely on unbiased and trustworthy evidence.

4.
Clin Oral Investig ; 28(7): 391, 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38907162

ABSTRACT

OBJECTIVE: To evaluate cytokine levels of interleukin (IL)-1ß, IL-4, IL-6, IL-17a, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in the gingival crevicular fluid (GCF) of periodontal sites in individuals with Down syndrome (DS) and analyze their relationship with clinical periodontal parameters. MATERIALS AND METHODS: A cross-sectional study was conducted with 49 DS patients and 32 individuals without DS (non-DS group). Periodontal probing depth (PPD), clinical attachment level (CAL), bleeding on probing (BoP), and visible plaque index (VPI) were evaluated. The periodontal sites were classified as shallow, moderate, and deep. GCF was collected in all shallow sites and, when present, in moderate and deep sites for the analysis of cytokine levels. The cytokines, IL-1ß, IL-4, IL-6, IL-17a, TNF-α, and IFN-γ, were quantified using the Luminex® automatic analyzer system. RESULTS: The DS group presented greater severity of periodontitis compared to the non-DS group (P = 0.005). The DS group showed a significant direct correlation of IL-1ß and an inverse correlation of IFN-γ and IL-14 with all periodontal variables. In the analysis stratified by periodontal pocket depth, we observed a higher level of IFN-γ, IL-17a, IL-1ß, and IL-6 in the shallow sites, and IL-17a, IL-1ß, and IL-6 in deep pockets of DS group individuals. Multivariate models showed that higher levels of IL-1ß, IL-4, IL-6, and IL-17a were associated with Down syndrome even after adjusting for periodontal status, sex, and age. CONCLUSION: The findings suggest that people with DS have greater periodontal impairment and higher levels of cytokines in GCF, even in sites having clinical periodontal parameters similar to those of individuals without DS. These data reiterate the concept of an altered and less effective immune response in the population with DS in the face of a periodontal microbial challenge. CLINICAL RELEVANCE: Elevated periodontal inflammation burden can be observed with higher cytokine levels in the gingival crevicular fluid of people with Down syndrome, especially IL-1, IL-4, IL-6, and IL-17, regardless of the stage of periodontitis.


Subject(s)
Cytokines , Down Syndrome , Gingival Crevicular Fluid , Periodontal Index , Humans , Gingival Crevicular Fluid/chemistry , Cross-Sectional Studies , Male , Female , Down Syndrome/metabolism , Cytokines/metabolism , Cytokines/analysis , Adult , Dental Plaque Index , Adolescent
5.
Int J Paediatr Dent ; 34(1): 11-25, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37101236

ABSTRACT

BACKGROUND: Fluoride varnish (FV) is widely recommended for caries prevention in preschool children, despite its anticaries benefits being uncertain and modest. Dentists often report using clinical practice guidelines (CPGs) as a source of scientific information. AIM: To identify and analyze recommendations for clinical practice on the use of FV for caries prevention in preschool children and to assess the methodological quality of the CPG on this topic. DESIGN: Two researchers independently used 12 search strategies and searched the first five pages of Google Search™ and three guideline databases for recommendations freely available to health professionals on the use of FV for caries prevention in preschoolers. Then, they retrieved and recorded recommendations that met the eligibility criteria and extracted the data. A third researcher resolved disagreements. Each included CPG was appraised using the AGREE II instrument. RESULTS: Twenty-nine documents were included. Recommendations varied according to age, patients' caries risk, and application frequency. Of the six CPGs, only one scored above 70% in the AGREE II overall assessment. CONCLUSION: Recommendations on the use of FV lacked scientific evidence, and CPGs were of poor quality. Application of FV is widely recommended despite recent evidence showing an uncertain, modest, and possibly not clinically relevant anticaries benefit. Dentists should be aware that it is necessary to critically appraise CPGs since they may be of poor quality.


Subject(s)
Dental Caries , Fluorides , Humans , Child, Preschool , Fluorides, Topical/therapeutic use , Cariostatic Agents/therapeutic use , Dental Caries Susceptibility , Dental Caries/prevention & control , Dental Caries/drug therapy
6.
BMC Oral Health ; 24(1): 474, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38641652

ABSTRACT

BACKGROUND: Important evidence has been constantly produced and needs to be converted into practice. Professional consumption of such evidence may be a barrier to its implementation. Then, effective implementation of evidence-based interventions in clinical practice leans on the understanding of how professionals value attributes when choosing between options for dental care, permitting to guide this implementation process by maximizing strengthens and minimizing barriers related to that. METHODS: This is part of a broader project investigating the potential of incorporating scientific evidence into clinical practice and public policy recommendations and guidelines, identifying strengths and barriers in such an implementation process. The present research protocol comprises a Discrete Choice Experiment (DCE) from the Brazilian oral health professionals' perspective, aiming to assess how different factors are associated with professional decision-making in dental care, including the role of scientific evidence. Different choice sets will be developed, either focusing on understanding the role of scientific evidence in the professional decision-making process or on understanding specific attributes associated with different interventions recently tested in randomized clinical trials and available as newly produced scientific evidence to be used in clinical practice. DISCUSSION: Translating research into practice usually requires time and effort. Shortening this process may be useful for faster incorporation into clinical practice and beneficial to the population. Understanding the context and professionals' decision-making preferences is crucial to designing more effective implementation and/or educational initiatives. Ultimately, we expect to design an efficient implementation strategy that overcomes threats and potential opportunities identified during the DCEs, creating a customized structure for dental professionals. TRIAL REGISTRATION: https://osf.io/bhncv .


Subject(s)
Evidence-Based Practice , Pediatric Dentistry , Child , Humans , Research Design , Dental Care , Brazil
7.
Am J Med Genet A ; 191(2): 592-598, 2023 02.
Article in English | MEDLINE | ID: mdl-36416214

ABSTRACT

Ovotesticular disorders of sex development (OT-DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY-negative 46,XX DSD, OT-DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737-kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes.


Subject(s)
Mosaicism , Ovotesticular Disorders of Sex Development , Male , Female , Humans , Ovotesticular Disorders of Sex Development/diagnosis , Ovotesticular Disorders of Sex Development/genetics , Ovotesticular Disorders of Sex Development/pathology , Siblings , Ovary/pathology , Germ Cells/pathology , SOXB1 Transcription Factors/genetics
8.
Eur J Clin Microbiol Infect Dis ; 42(7): 899-902, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37126131

ABSTRACT

The aim of this study was to evaluate the prevalence of latent Mycobacterium tuberculosis infection in hematopoietic stem cell transplantation candidates, using tuberculin skin test and QuantiFERON-TB Gold-Plus, in a high-burden tuberculosis country. Adult candidates for hematopoietic stem cell transplantation performed both tests before and those submitted to transplantation were followed up for 12 months. The prevalence of latent Mycobacterium tuberculosis infection was 17.1% and a moderate agreement between QuantiFERON-TB Gold-Plus and tuberculin skin test was observed in this population. Previous tuberculosis exposure was a risk factor for latent Mycobacterium tuberculosis infection. No cases of tuberculosis were diagnosed during follow-up period.


Subject(s)
Hematopoietic Stem Cell Transplantation , Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis , Adult , Humans , Interferon-gamma Release Tests , Tuberculin Test , Prevalence , Latent Tuberculosis/diagnosis , Latent Tuberculosis/epidemiology , Latent Tuberculosis/microbiology , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Hematopoietic Stem Cell Transplantation/adverse effects
9.
Semin Dial ; 36(1): 3-11, 2023 01.
Article in English | MEDLINE | ID: mdl-35934871

ABSTRACT

Pregnancy in chronic kidney disease (CKD) women is relatively rare, and the less risky choice of hemodialysis is unknown. The objective of this systematic review was to identify, systematically evaluate and summarize the available evidence on the efficacy and safety of hemodialysis strategies for pregnant CKD women. Sensitive search strategies were applied to six databases without data or language restrictions. Comparative (randomized and non-randomized) studies were prioritized. Two reviewers independently selected, extracted, and critically evaluated data from studies. The risk of bias assessment was performed using the ROBINS-I tool, considering the study design (non-randomized comparative observational studies). The certainty of the evidence was assessed using the GRADE approach. From 7210 references identified, six retrospective cohort studies were included (576 women). The effects of intensive hemodialysis (over 20 h/week) are uncertain for maternal and neonatal mortality (Peto odds ratio [OR] 0.85; 95% confidence interval [95% CI] 0.26-2.80), miscarriage (Peto OR 0, 38; 95% CI 0.12-1.23), stillbirths (Peto OR 0, 56; 95% CI 0.13-2.31), preterm birth (Peto OR 0.87; 95% CI 0.33-2.28), low birth weight (Peto OR 0.71; 95% CI 0.20-2.50) and congenital anomalies rates. The certainty of the evidence was very low due to studies methodological limitations and effect estimates imprecision. The uncertainty about intensive versus conventional hemodialysis effects for pregnant women with CKD and the imprecision in the estimated effects precludes any recommendation. The strategy choice must consider treatment availability, costs, and maternal social aspects until future studies provide more reliable evidence. PROSPERO CRD42021259237.


Subject(s)
Pregnant Women , Premature Birth , Pregnancy , Female , Infant, Newborn , Humans , Retrospective Studies , Renal Dialysis/adverse effects
10.
J Thromb Thrombolysis ; 56(2): 253-263, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37227652

ABSTRACT

Inflammatory phenomena have a direct impact on the prognosis of orthotopic liver transplantation (OLT). Neutrophil extracellular traps (NETs) contribute to OLT inflammation and hemostasis imbalance in OLT. The association between NETosis, clinical outcomes and transfusion requirements is not determined. To evaluate NETs release during OLT and the effect of NETosis ontransfusion requirements and adverse outcomes in a prospective cohort of patients submitted to OLT. We quantified citrullinated histones (cit-H3) and circulating-free-DNA (cf-DNA) in ninety-three patients submitted to OLT in three periods: pre-transplant, after graft reperfusion and before discharge. NETs markers were compared between these periods using ANOVA test. The association of NETosis and adverse outcomes was evaluated using regression models adjusted for age, sex and corrected MELD. We observed a peak of circulating NETs following reperfusion, evidenced by a 2.4-fold increase in cit-H3 levels in the post-graft reperfusion period (median levels of cit-H3 pre transplant: 0.5 ng/mL, after reperfusion: 1.2 ng/mL and at discharge 0.5 ng/mL, p < 0.0001). We observed an association between increased levels of cit-H3 and in-hospital death (OR = 1.168, 95% CI 1.021-1.336, p = 0.024). No association was found between NETs markers and transfusion requirements. There is a prompt release of NETs after reperfusion that is associated with poorer outcomes and death. Intraoperative NETs release seems to be independent of transfusion requirements. These findings highlight the relevance of inflammation promoted by NETS and its impact on OLT adverse clinical outcomes.


Subject(s)
Extracellular Traps , Liver Transplantation , Humans , Neutrophils , Prospective Studies , Hospital Mortality , Histones , Inflammation , DNA
11.
Drug Chem Toxicol ; 46(4): 665-676, 2023 Nov.
Article in English | MEDLINE | ID: mdl-35635136

ABSTRACT

Notwithstanding the advances in molecular target-based drugs, chemotherapy remains the most common cancer treatment, despite its high toxicity. Consequently, effective anticancer therapies with fewer adverse effects are needed. Therefore, this study aimed to determine the anticancer activity of the dichloromethane fraction (DCMF) isolated from Arrabidae brachypoda roots, whose components are three unusual dimeric flavonoids. The toxicity of DCMF was investigated in breast (MCF-7), prostate (DU145), and cervical (HeLa) tumor cells, as well as non-tumor cells (PNT2), using sulforhodamine B (cell viability), Comet (genotoxicity), clonogenicity (reproductive capacity) and wound healing (cell migration) assays, and atomic force microscopy (AFM) for ultrastructural cell membrane alterations. Molecular docking revealed affinity between albumin and each rare flavonoid, supporting the impact of fetal bovine serum in DCMF antitumor activity. The IC50 values for MCF7, HeLa, and DU145 were 2.77, 2.46, and 2.51 µg/mL, respectively, and 4.08 µg/mL for PNT2. DCFM was not genotoxic to tumor or normal cells when exposed to twice the IC50 for up to 24 h, but it inhibited tumor cell migration and reproduction compared to normal cells. Additionally, AFM revealed alterations in the ultrastructure of tumor nuclear membrane surfaces, with a positive correlation between DCMF concentration and tumor cell roughness. Finally, we found a negative correlation between roughness and the ability of DCMF-treated tumor cells to migrate and form colonies with more than 50 cells. These findings suggest that DCFM acts by causing ultrastructural changes in tumor cell membranes while having fewer toxicological effects on normal cells.


Subject(s)
Flavonoids , Neoplasms , Male , Humans , Flavonoids/pharmacology , Flavonoids/chemistry , Molecular Docking Simulation , HeLa Cells , Cell Membrane , Cell Survival , Cell Line, Tumor
12.
Int J Paediatr Dent ; 33(5): 431-449, 2023 Sep.
Article in English | MEDLINE | ID: mdl-36695007

ABSTRACT

BACKGROUND: Fluoride varnish (FV) is a convenient way of professionally applying fluoride in preschoolers. However, its modest anticaries effect highlights the need for economic evaluations. AIM: To assess economic evaluations reporting applications of FV to reduce caries incidence in preschoolers. DESIGN: We included full economic evaluations with preschool participants, in which the intervention was FV and the outcome was related to dentin caries. We searched in CENTRAL; MEDLINE via PubMed; WEB OF SCIENCE; EMBASE; SCOPUS; LILACS; BBO; and BVS Economia em saúde, OpenGrey, and EconoLit. Clinical trial registers, thesis and dissertations, and meeting abstracts were hand searched, as well as 11 dental journals. Risk of bias in the included studies was assessed using the Philips' and Drummond's (full and simplified) tools. RESULTS: Titles and abstracts of 2871 articles were evaluated, and 200 were read in full. Eight cost-effectiveness studies were included: five modeling and three within-trial evaluations. None of the studies gave sufficient information to allow a thorough assessment using the bias tools. We did not combine the results of the studies due to the great heterogeneity among them. Four studies reported that FV in preschool children was a cost-effective measure, but in one of these studies, sealants and fluoride toothpaste were more cost-effective measures than the varnish, and three studies used limited data that compromised the generalizability of their results. The other four studies showed a large increase in costs due to the application of varnish and/or low cost-effectiveness. CONCLUSION: We did not find convincing overall evidence that applying FV in preschoolers is an anticaries cost-effective measure. The protocol of this systematic review is available at Open Science Framework (https://osf.io/xw5va/).


Subject(s)
Dental Caries , Fluorides , Humans , Child, Preschool , Cariostatic Agents/therapeutic use , Fluorides, Topical , Cost-Benefit Analysis , Dental Caries/prevention & control , Pit and Fissure Sealants
13.
Clin Immunol ; 242: 109092, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35944882

ABSTRACT

Vaccines induce antibodies, but T cell responses are also important for protection against Coronavirus disease 2019. Here, we analyzed the frequency of memory T cells in infected and/or vaccinated individuals and observed a decrease in central memory T cells in individuals who were vaccinated following COVID-19 infection.


Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 Vaccines , COVID-19 , Antibodies, Viral , CD8-Positive T-Lymphocytes/cytology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Memory T Cells/cytology , Vaccination
14.
Clin Genet ; 102(6): 537-542, 2022 12.
Article in English | MEDLINE | ID: mdl-36029130

ABSTRACT

Biallelic loss-of-function variants in the TBC1D2B gene were recently reported as a cause of a neurodevelopmental disorder with seizures and gingival overgrowth. Here, we report two male siblings with the similar clinical characteristics. They started with gingival overgrowth and bilateral growth of soft tissues in the malar region at 3 years of age, which evolved with significant maxillary hypertrophy and compression of the brainstem due to fibrous dysplasia of facial bones. After disease evolution, they presented with mental deterioration, limb tremors, and gait ataxia. One of them also presented with seizures. Whole exome sequencing revealed a novel biallelic frameshift variant [c.595del; p.(Val199Trpfs*22)] in the TBC1D2B gene in both patients, which was confirmed and found in heterozygous state in each of their parents. There are strong similarities in clinical characteristics, age of onset, and evolution between the patients described here and cases reported in the literature, including cherubism-like phenotype with progressive gingival overgrowth and seizures. This is the fourth family in the world in which a biallelic loss-of-function variant in the TBC1D2B gene is associated with this phenotype. These results support that loss of TBC1D2B is the cause of this rare condition.


Subject(s)
Cognitive Dysfunction , Gingival Overgrowth , Humans , Male , Cognitive Dysfunction/genetics , Frameshift Mutation , Gingival Overgrowth/genetics , Pedigree , Seizures/genetics , Siblings
15.
Mol Psychiatry ; 26(6): 2633-2650, 2021 06.
Article in English | MEDLINE | ID: mdl-32350390

ABSTRACT

Calcium, the most versatile second messenger, regulates essential biology including crucial cellular events in embryogenesis. We investigated impacts of calcium channels and purinoceptors on neuronal differentiation of normal mouse embryonic stem cells (ESCs), with outcomes being compared to those of in vitro models of Huntington's disease (HD). Intracellular calcium oscillations tracked via real-time fluorescence and luminescence microscopy revealed a significant correlation between calcium transient activity and rhythmic proneuronal transcription factor expression in ESCs stably expressing ASCL-1 or neurogenin-2 promoters fused to luciferase reporter genes. We uncovered that pharmacological manipulation of L-type voltage-gated calcium channels (VGCCs) and purinoceptors induced a two-step process of neuronal differentiation. Specifically, L-type calcium channel-mediated augmentation of spike-like calcium oscillations first promoted stable expression of ASCL-1 in differentiating ESCs, which following P2Y2 purinoceptor activation matured into GABAergic neurons. By contrast, there was neither spike-like calcium oscillations nor responsive P2Y2 receptors in HD-modeling stem cells in vitro. The data shed new light on mechanisms underlying neurogenesis of inhibitory neurons. Moreover, our approach may be tailored to identify pathogenic triggers of other developmental neurological disorders for devising targeted therapies.


Subject(s)
Huntington Disease , Neural Stem Cells , Adenosine Triphosphate , Animals , Calcium/metabolism , Calcium Channels, L-Type/metabolism , Calcium Signaling , Cell Differentiation , Embryonic Stem Cells/metabolism , GABAergic Neurons/metabolism , Huntington Disease/genetics , Mice , Neural Stem Cells/metabolism , Neurogenesis
16.
Neuroendocrinology ; 112(11): 1039-1045, 2022.
Article in English | MEDLINE | ID: mdl-35066497

ABSTRACT

COVID-19 is an intriguing infectious condition with multisystemic manifestations and variable outcomes that are influenced by the concomitant presence of non-communicable diseases, such as obesity, diabetes, and cardiovascular disease, which were previously well established epidemics and therefore are considered global syndemics. Although an enormous progress towards understanding mechanisms of SARS-CoV-2 infection leading to COVID-19 has been made, there are still many areas of uncertainty to clarify. Systemic diseases are characterized by common links that allow integrating apparently unrelated disease manifestations. The authors launch the provocative hypothesis that serotonin is the putative mediator linking the lung, gut, cardiac, neurological, and other systemic manifestations that characterize severe COVID-19 in individuals with diabetes and obesity. In support of a role for serotonin in the mechanisms leading to disease severity are the similarities between acute and post-acute COVID-19 manifestations and neuroendocrine tumors presenting with carcinoid syndrome. Scientific discussion is set by highlighting the available clues that support this working hypothesis to trigger future research aimed at unravelling the molecular pathways underlying SARS-CoV-2 infection that are still far from being fully disclosed.


Subject(s)
COVID-19 , Diabetes Mellitus , Humans , COVID-19/complications , SARS-CoV-2 , Serotonin , Diabetes Mellitus/epidemiology , Obesity/complications , Obesity/epidemiology
17.
Lupus ; 31(9): 1067-1077, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35612283

ABSTRACT

Background: Thrombotic risk in antiphospholipid syndrome (APS) is conferred by the association of antiphospholipid (aPL) antibodies (first hit) with additional pro-coagulant stimulus (second hit), such as inflammation. Among inflammatory responses, the production of large amounts of interferon (IFN)-I by plasmacytoid dendritic cells (pDCs) is at the basis of the pathophysiology of systemic autoimmune disorders, which raises the hypothesis that this mechanism could also be associated with vascular manifestations of APS. Purpose: Here, we determined the association of pDCs and IFN-I production with thrombotic APS. Research design: Patients with thrombotic primary (t-PAPS) and secondary APS (t-SAPS), asymptomatic aPL carriers and individuals without thrombosis (controls) were included. Data collection and analysis: Circulating pDCs and IFN-α intracellular expression (in the presence or not of oligodeoxynucleotides (CP) stimulus) were quantified by flow cytometry. The expression of five IFN-I inducing genes: ISG15, OASL, Ly6E, MX1, and OAS1 in mononuclear cells was determined by qPCR. Between-group differences were evaluated using chi-square or Kruskal-Wallis tests. Results: A total of 50 patients with t-PAPS, 50 patients with t-SAPS, 20 aPL carriers, and 50 individuals without thrombosis (controls) were included. Intracellular expression of IFN-α was increased after CPG stimulation in both t-SAPS (1.56%; IQR 1.07-2.02) and t-PAPS (0.96%; IQR 0.55-1.24), when compared to aPL carriers (0.71%; IQR 0.42-0.93) and controls (0.48%; IQR 0.24-0.78; p < .0001). ISG15, OASL, Ly6E, MX1, and OAS1 mRNA expressions were higher in t-SAPS (but not in t-PAPS) than in aPL carriers and controls. The expression of proteins and mRNA related to IFN-I response was similar between the triple aPL-positive profile and other aPL profiles. Conclusion: Our results indicate an association of IFN-I response and t-APS. Since IFN-I expression was not increased in aPL carriers or associated with a higher-risk aPL profile, this mechanism does not appear to be related to the presence of aPL alone. IFN-I response could possibly constitute a complementary mechanism for triggering clinical manifestations in APS.


Subject(s)
Antiphospholipid Syndrome , Lupus Erythematosus, Systemic , Thrombosis , Antibodies, Antiphospholipid , Antiphospholipid Syndrome/complications , Antiviral Agents , Dendritic Cells/metabolism , Humans , Interferons , Lupus Erythematosus, Systemic/complications , RNA, Messenger/genetics , Thrombosis/complications
18.
Lasers Med Sci ; 37(9): 3363-3377, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36201144

ABSTRACT

Tissue injuries that affect the skin and/or adjacent tissues and are usually over a bony prominence are called pressure injuries. The prevalence of these dysfunctions remains high, and despite technological advances, there is no consensus on the most appropriate treatment. The objective of this review was to evaluate the efficacy of photobiomodulation (PBM), ultrasound, and high-frequency electrophysical agents in the healing of pressure injuries in adults and the elderly. The search was conducted in the PubMed, Embase, Cochrane Library, Web of Science, and PEDro databases; in clinical trial records, a list of references of the selected articles, as well as through manual search (Google), of the last 5 years in humans in English and Portuguese. Nine thousand and sixty-seven studies were identified, 13 pre-selected, and 6 were included in this systematic review. PBM showed similar efficacy to other technologies indicated in other studies in healing pressure injuries. PBM with red wavelength (660 nm) in stages 2 and 3 pressure injuries effectively promoted healing compared to standard care. It was observed that the use of PBM accelerates tissue repair in pressure injuries; therapeutic ultrasound showed similar efficacy to other electrophysical agents but was effective in reducing the area of pressure injuries when comparing pre- and post-intervention. No clinical studies using the high-frequency electrophysical agent have been described in the last 5 years.


Subject(s)
Crush Injuries , Pressure Ulcer , Wound Healing , Adult , Aged , Humans
19.
J Wound Care ; 31(1): 92-98, 2022 Jan 02.
Article in English | MEDLINE | ID: mdl-35077205

ABSTRACT

OBJECTIVE: A pressure injury (PI) is a localised area of damage to the skin and/or underlying soft tissue as a result of a sustained mechanical loading. There are three key aetiological mechanisms to PI formation-direct cell deformation, inflammatory oedema and ischaemic damage-which are typically activated sequentially to drive a spiral of injury. This article discusses the role of the perioperative prone position as a rational approach to reducing the recurrence of pelvic PI after reconstructive surgery. METHOD: Patients with deep PI in the pelvic region, who were operated on from 2011 to 2019, were retrospectively evaluated. The protocol of care included training in the prone position, followed by maintenance of the prone position for 4-6 weeks postoperatively. The reconstruction was performed with fasciocutaneous and myocutaneous local or regional flaps. RESULTS: The study evaluated a total of 26 patients. The rate of recurrence of PIs was 15.4% (4/26) in the mean follow-up of 54 months. Regarding postoperative complications, four cases of partial dehiscence of the suture occurred. CONCLUSION: This perioperative protocol of maintaining a prone position seems to be safe for the patient, and it can be used to prevent or reduce the recurrence of deep PIs on the pelvic region after reconstructive surgery.


Subject(s)
Perforator Flap , Plastic Surgery Procedures , Pressure Ulcer , Humans , Pelvis , Pressure Ulcer/prevention & control , Pressure Ulcer/surgery , Prone Position , Recurrence , Retrospective Studies , Treatment Outcome
20.
Odontology ; 110(4): 619-633, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35445361

ABSTRACT

This systematic review aimed to assess if the use of fiber posts reinforces weakened immature teeth. A systematic review was conducted of laboratory studies that evaluated the fracture resistance of simulated immature teeth restored with fiber posts compared to teeth restored exclusively with resin. An electronic search was performed using the following databases: PubMed/MEDLINE, Web of Science, Scopus and LILACS, BBO, and grey literature. Two independent researchers screened the titles and abstracts of the retrieved studies for relevance to the research question. Subsequently, the full texts of potentially relevant studies were screened based on the exclusion criteria. Ten out of 1792 unique records were included in this systematic review. Risk of bias was assessed using an adapted tool based on the Cochrane risk of bias tool. The laboratory studies included in this systematic review were performed on both human and bovine teeth. Eight studies concluded that fiber posts reinforce the structure of weakened roots, and two studies reported that fiber posts did not strengthen the radicular structure compared to teeth exclusively restored with resin composite. The highly heterogeneous data made it challenging to synthesize the results into a summary estimate, and thus no meta-analysis was undertaken. A summary effect could not be estimated without a meta-analysis. Although the laboratory literature suggests that fiber posts reinforce the structure of immature teeth, the results should be interpreted with caution, as most of the studies had an unclear or high risk of bias.


Subject(s)
Post and Core Technique , Tooth Fractures , Tooth, Nonvital , Animals , Cattle , Composite Resins , Dental Stress Analysis , Humans , Tooth Fractures/prevention & control , Tooth Root
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