Regulation of neurogenesis by calpains: revelance for post-injury brain repair

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016No cérebro adulto dos mamíferos, novos neurónios são continuamente adicionados em duas regiões neurogénicas principais: a zona subventricular, nas paredes dos ventrículos laterais, e a zona subgranular, no giro dentado do hipocampo. As células estaminais neurais presentes nestes nichos têm a capacidade de proliferar e dar origem a neuroblastos em migração, que acabam por se diferenciar em novos neurónios. Curiosamente, no evento de uma lesão cerebral, a proliferação das células estaminais neurais aumenta, possivelmente numa tentativa de reparação do dano cerebral. No entanto, esta reparação é limitada pela redução da migração celular ou pela diminuição da sobrevivência dos novos neurónios. Descobrir como aumentar a eficiência da neurogénese após lesão poderá ser portanto benéfico para a reparação cerebral. Por outro lado, o dano cerebral também pode activar diversas protéases, incluindo as calpaínas. As calpaínas são proteases ubíquas, sabendo-se que estão envolvidas na proliferação, migração e diferenciação celular em diversos sistemas. No cérebro, a inibição das calpaínas tem efeito neuroprotector, mas os seus efeitos na neurogénese permanecem ainda pouco conhecidos. A delecção do inibidor endógeno das calpaínas, a calpastatina, já anteriormente mostrou ser capaz de reduzir as primeiras fases da neurogénese in vivo. No presente trabalho, mostramos que a inibição das calpaínas é capaz de reverter este efeito, implicando-as ainda mais no processo. Uma vez que a inibição das calpaínas parece ser um alvo promissor para o aumento da neurogénese após lesão, avaliámos várias fases do processo neurogénico, bem como a recuperação das alterações do comportamento cognitivo após lesão no hipocampo induzida por crises epilépticas, em murganhos com sobrexpressão de calpastatina. Avaliámos ainda os efeitos da delecção das calpaínas 1 e 2 nas primeiras fases da neurogénese no hipocampo. Observámos que o padrão de aumento da neurogénese após lesão foi mantido em murganhos com sobrexpressão de calpastatina, apesar de alguma recuperação cognitiva indicar algum grau de neuroprotecção, que por si só poderá ter mascarado a influência da inibição das calpaínas na neurogénese. Murganhos com falta de calpaínas, no entanto, não apresentaram alterações das primeiras fases da neurogénese no hipocampo, sugerindo que as calpaínas apenas afectam este processo quando a sua actividade está acima de um certo limite, abaixo do qual a neurogénese não é afectada. Isto significa que a inibição das calpaínas poderá potencialmente ser útil para prevenir a redução da formação de novos neurónios após lesão, caso os níveis de actividade das calpaínas possam ser reduzidos abaixo de um certo limite.New neurons are continuously added in the adult mammalian brain, in two main neurogenic regions: the subventricular zone, in the walls of the lateral ventricles, and the subgranular zone, in the dentate gyrus of the hippocampus. Neural stem cells present in these niches are able to proliferate and originate migrating neuroblasts, which ultimately differentiate into new neurons. Interestingly, in the event of a brain lesion, neural stem cell proliferation increases, possibly in an attempt to repair the damage. However, this repair is limited by impaired cell migration or decreased survival of new neurons. Discovering how to increase the efficiency of post-injury neurogenesis may therefore be beneficial for brain repair. On the other hand, brain damage can also activate several proteases, including calpains. Calpains are ubiquitous proteases known to be involved in cell proliferation, migration and differentiation in several systems. In the brain, calpain inhibition has been shown to be neuroprotective, but their effects on neurogenesis remain elusive. Deletion of the endogenous inhibitor of calpains, calpastatin, has previously been shown to impair early stages of neurogenesis in vivo. In the present work, we show that calpain inhibition is able to reverse this impairment, further implicating them in the process. Since calpain inhibition offers a promising target for the enhancement of post-injury neurogenesis, we evaluated different stages of the process and cognitive behavior recovery after seizure-induced hippocampal lesion in mice overexpressing calpastatin, and also the effects of the absence of conventional calpains on the early stages of hippocampal neurogenesis. We observed that the pattern of enhancement of post-injury neurogenesis was mostly maintained in mice overexpressing calpastatin, though some cognitive recovery indicates some degree of neuroprotection, which by itself may have masked the influence of calpain inhibition on neurogenesis. Mice lacking calpains, however, presented unaltered levels of the early stages of hippocampal neurogenesis, suggesting that calpains only affect this process when their activity is over a certain threshold, under which neurogenesis is not affected. This means that calpain inhibition could potentially be useful to stimulate the formation of new neurons after injury, given that the levels of calpain activity could be reduced under a certain threshold

Tooth reattachment and palatal veneer on a multidisciplinary approach of crown fractures in upper central incisors

Dental trauma is more common in young patients and its sequelae may have great impact on the esthetics, functions, and phonetics. This paper reports a case of trauma in both central incisors in a young 17-year-old patient who was treated using adhesive tooth fragment reattachment on tooth 2.1 and a palatal indirect composite veneer on tooth 1.1. Regarding the available literature and fracture extension, the treatment approach proposed for this case provided good functional and esthetic outcomes. Clinical and radiographic results after 1 year were successful. This case demonstrates the importance of establishing a multidisciplinary approach for successful dental trauma management.info:eu-repo/semantics/publishedVersio

Assessment of the relationship between oral health-related quality of life (OHRQoL) and dental malocclusion in a Portuguese sample

Abstract in proceedings of the Fourth International Congress of CiiEM: Health, Well-Being and Ageing in the 21st Century, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from 3–5 June 2019.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/publishedVersio

Evaluation of the relationship between oral health-related quality of life (OHRQoL) and skeletal malocclusion : a pilot study

Abstract in proceedings of the Fourth International Congress of CiiEM: Health, Well-Being and Ageing in the 21st Century, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from 3–5 June 2019.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/publishedVersio

Relationship between blood and standard biochemistry levels with periodontitis in Parkinson’s disease patients: data from the NHANES 2011–2012

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.People with Parkinson’s Disease (PD) are associated with the presence of periodontitis. We aimed to compare blood and standard biochemical surrogates of PD patients diagnosed with periodontitis with PD individuals without periodontitis. This retrospective cohort study used a sample from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 that underwent periodontal diagnosis (n = 3669). PD participants were identified through specific PD reported medications. Periodontitis was defined according to the 2012 case definition, using periodontal examination data provided. Then, we compared blood levels and standard chemical laboratory profiles of PD patients according to the presence of periodontitis. Multivariable regression was used to explore this dataset and identify relevant variables towards the presence of periodontitis. According to the medication report, 37 participants were eligible, 29 were secure and 8 were unsecure PD medications regimens. Overall, PD cases with periodontitis presented increased levels of White Blood Cells (WBC) (p = 0.002), Basophils (p = 0.045) and Segmented neutrophils (p = 0.009), and also, lower levels of Total Bilirubin (p = 0.018). In the PD secure medication group, a significant difference was found for WBC (p = 0.002) and Segmented neutrophils (p = 0.002) for the periodontitis group. Further, WBC might be a discriminating factor towards periodontitis in the global sample. In the secure PD medication, we found gender, segmented neutrophils and Vitamin D2 to be potential discriminative variables towards periodontitis. Thus, periodontitis showed association with leukocyte levels alterations in PD patients, and therefore with potential systemic changes and predictive value. Furthermore, Vitamin D2 and gender showed to be associated with periodontitis in with secure medication for PD. Future studies should assess in more detail the potential systemic repercussion of the presence of periodontitis in PD patients.info:eu-repo/semantics/publishedVersio

Halitosis self-perception and awareness among periodontal patients : an exploratory study

Communication abstract: Proceedings of the 5th International Congress of CiiEM - Reducing inequalities in Health and Society, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from June 16th to 18th, 2021.This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Halitosis is an unpleasant breath odor that interferes with self-confidence and with people’s professional and social lives. The aim of this exploratory study was to evaluate the self-perception and awareness of oral malodor among patients with periodontitis.info:eu-repo/semantics/publishedVersio

Serum C-Reactive Protein and Periodontitis: A Systematic Review and Meta-Analysis

Periodontitis has been associated with low-grade inflammation as assessed by C-reactive protein (CRP) levels and its treatment can decrease CRP serum levels. The aim of this systematic review was to critically appraise the evidence comparing CRP serum levels (standard and high-sensitivity [hs]) of otherwise healthy patients suffering from periodontitis when compared to controls. The impact of intensive and non-intensive nonsurgical periodontal treatment (NSPT) on hs-CRP was also investigated. Four electronic databases (Pubmed, The Cochrane Central Register of Controlled Trials [CENTRAL], EMBASE and Web of Science) were searched up to February 2021 and the review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No. CRD42020167454). Observational and intervention studies that: 1) evaluated CRP and hs-CRP serum levels in patients with and without periodontitis, and; 2) hs- CRP levels after NSPT were included. Following risk of bias appraisal, both qualitative and quantitative analyses were performed. Pooled estimates were rendered through ratio of means (RoM) random-effects meta-analyses. After screening 485 studies, 77 case-control studies and 67 intervention trials were included. Chronic and aggressive periodontitis diagnoses were consistently associated with higher levels of CRP and hs-CRP (p<0.001). Patients with aggressive periodontitis exhibited on average more than 50% higher levels of CRP (RoM [95% confidence interval [CI]]: 1.56 [1.15; 2.12], p=0.0039) than patients with chronic periodontitis. Intensive NSPT induced an immediate increase of hs-CRP followed by a progressive decrease whilst non-intensive NSPT consistently decreased hs-CRP after treatment up to 180 days (p<0.001). These findings provide robust evidence that periodontitis is associated with systemic inflammation as measured by serum CRP levels. Periodontitis treatment induces a short-term acute inflammatory increase when performed in an intensive session, whilst a progressive reduction up to 6 months was demonstrated when performed in multiple visits

Fine-tuning multilevel modeling of risk factors associated with nonsurgical periodontal treatment outcome

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This retrospective study evaluated the influence of known risk factors on nonsurgical periodontal treatment (NSPT) response using a pocket depth fine-tuning multilevel linear model (MLM). Overall, 37 patients (24 males and 13 females) with moderate-to-severe chronic periodontitis underwent NSPT. Follow-up visits at 3, 6, and 12 months included measurements of several clinical periodontal parameters. Data were sourced from a previously reported database. In a total of 1416 initially affected sites (baseline PD ≥ 4 mm) on 536 teeth, probing depth (PD) and clinical attachment loss (CAL) reductions after NSPT were evaluated against known risk factors at 3 hierarchical levels (patient, tooth, and site). For each post-treatment follow-up, the variance component models fitted to evaluate the 3-level variance of PD and CAL decrease revealed that all levels contributed significantly to the overall variance (p < 0.001). Patients who underwent NSPT and were continually monitored had curative results. All 3 hierarchical levels included risk factors influencing the degree of PD and CAL reduction. Specifically, the type of tooth, surfaces involved, and tooth mobility site-level risk factors had the strongest impact on these reductions and were highly relevant for the success of NSPT.info:eu-repo/semantics/publishedVersio

Partial recording protocols performance on the assessment of Periodontitis severity and extent: bias magnitudes, sensibility, and specificity

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objectives: This study aimed to assess bias magnitudes, sensibility, and specificity of particular partial-mouth recording protocols (PRPs) to estimate periodontal clinical measurements and periodontal status. Methods: Estimates of mean clinical attachment loss (MCAL) and mean probing depth (MPD) were calculated for 15 different PRPs and were compared to full-mouth recording protocol (FRP) data from 402 Portuguese. Biases, relative biases and intra-class correlations for all PRPs were evaluated. Bland–Altman plots and Receiver Operating Characteristic / Area Under the Curve (ROC/AUC) analysis were used to assess the sensitivity and specificity for each PRP periodontal diagnosis. Results: Regarding MPD, Half RD6 UR/LL and RD6 UL/LR had the lowest bias observed with 0.00 mm (-0.22% and 0.22%, respectively) and all full-mouth PRPs significantly produce an underestimation. Concerning MCAL, the Half MB-B-DL UR/LR had the lowest bias observed with 0.01 mm (0.16%). Excluding CPITN, Full-Mouth PRPs outperforms in average Half Mouth PRPs correlations. The Half RD6 UR/LL had the highest AUC (0.96) with 95.5 and 97.1% of sensitivity and specificity, respectively. Conclusions: Three half-mouth PRPs (Half MB-B-DL UR/LR, Half RD6 UR/LL and Half RD6 UL/ LR) protocols can be used to estimate periodontal clinical measurements with limited bias, and high sensitivity, specificity, and concordance. All full-mouth PRPs failed to estimate pocket depth means, and for clinical attachment loss, they present less ability then half-mouth partial protocols, despite presenting high sensitivity levels.info:eu-repo/semantics/publishedVersio

The prevalence of patients with rheumatic diseases and its periodontal condition : data from a population-based study in the Lisbon Metropolitan Area

Abstract in proceedings of the Fourth International Congress of CiiEM: Health, Well-Being and Ageing in the 21st Century, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from 3–5 June 2019.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/publishedVersio