Cervicometria na gravidez: sua relevância na prevenção do parto pré-termo

O parto pré-termo continua a ser a principal causa de mortalidade e morbilidade perinatal, apesar das melhorias na prevenção, no diagnóstico e no tratamento. Várias estratégias têm sido tentadas para diminuir a incidência de parto pré-termo mas, infelizmente, todas elas têm sido ineficazes. No entanto, a existência de uma relação inversa entre o comprimento do colo do útero em mulheres grávidas e o risco de parto pré-termo levou a que a Cervicometria (medição do comprimento cervical uterino) se tornasse o método de rastreio de risco de parto pré-termo mais consensualmente aceite. Neste contexto, a avaliação do colo do útero por ecografia transvaginal, entre as 22 e as 24 semanas de gestação, permite identificar as grávidas com alterações do comprimento (colos curtos <25mm e muito curtos <15mm), associadas a risco de parto pré-termo. A detecção destas grávidas com alto risco de parto pré-termo, permite aplicar medidas adequadas a evitá-lo, tais como a suplementação com Progesterona e a Ciclorrafia (Cérclage), e assim prevenir ou atrasar a ocorrência de parto pré-termo nas populações seleccionadas.Preterm birth remains the leading cause of perinatal mortality and morbility despite improvements in obstetrical prevention, diagnosis and treatment. Various strategies have been tried to reduce the incidence of preterm birth but, unfortunately they all have been ineffective. However, the existence of an inverse relationship between the uterine cervical length in pregnant women and the risk of preterm birth led to the systematic measurement of cervical length that became the most widely used method of screening for preterm birth risk. In this context, the evaluation of the cervix by tranvaginal ultrasound, at 22 and 24 weeks of gestation, allows to detect pregnant women with cervical changes, particularly on the length (short cervix <25mm and very short <15mm) and so to predict an increased risk of preterm birth. The detection of these pregnant women at higher risk for preterm birth (short cervices) allows to initiate the most appropriate measures such as supplementation with Progesterone and Cerclage to prevent or delay the occurrence of preterm birth in the selected populations

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

(This article belongs to the Special Issue Molecular Mechanisms in Lysosomal Storage Diseases: From Pathogenesis to Therapeutic Strategies 2.0)ReviewDespite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures.Funding: This work was partially supported by the Portuguese Society for Metabolic Disorders, SPDM (Bolsa SPDM de apoio à investigação Dr. Aguinaldo Cabral 2018; 2019DGH1629/SPDM2018I&D), Sanfilippo Children’s Foundation (2019DGH1656/SCF2019I&D), and Fundação para a Ciência e a Tecnologia, FCT: EXPL/BTM-SAL/0659/2021; UIDB/00211/2020—Centro de Estudos de Ciência Animal/Center for the Study of Animal Science; LA/P/0059/2020—Laboratório Associado para Ciência Animal e Veterinária/Associate Laboratory for Animal and Veterinary Sciences.info:eu-repo/semantics/publishedVersio

The disease modelling value of baby teeth: A new way to unlock knowledge about a special group of genetic disorders

Mucopolysaccharidoses (MPS), are a group of genetic, metabolic, and rare diseases investigated since the early years of the 20th century. One of the first steps to collect information about the underlying mechanisms of those disorders is the development and analysis of in vitro models. Furthermore, those models provide an appropriate platform for the evaluation of future therapeutics. Among all the possible disease cell models, patient-derived ones are those which allow us to get better disease insights. However, finding the best cell type that recapitulates diseaserelevant features is not always easy: two systems largely involved in MPS pathology are the brain and the musculoskeletal ones, which reflects an issue once both are hard to access. Here, our main goal is to establish an innovative non-invasive method to generate disease-relevant cell models from stem cells from deciduous (baby) teeth (SHED), which may then be differentiated into our MPS-target cell lines. So far, we have already implemented and optimized the protocol for collection, isolation, establishment and cryopreservation of those stem cells. Then, our rationale is simple: for those obtained from MPS patients suffering from multisystemic disease with marked musculoskeletal alterations, we are using a chondrogenesis differentiation protocol. For those derived from patients with neurological pathology, we will establish mixed neuronal/glial cultures. As soon as we can get the SHED-derived differentiated cells, various cellular and molecular processes from our target disorders may be unveiled and used as a target for possible future therapeutics. Acknowledgements This work is partially supported by the Portuguese Society for Metabolic Disorders (SPDM - Bolsa SPDM de apoio à investigação Dr. Aguinaldo Cabral 2018;2019DGH1629/SPDM2018I&D), Sanfilippo Children's Foundation (2019DGH1656/SCF2019I&D) and FCT (EXPL/BTM-SAL/0659/2021).This work is partially supported by the Portuguese Society for Metabolic Disorders (SPDM - Bolsa SPDM de apoio à investigação Dr. Aguinaldo Cabral 2018;2019DGH1629/SPDM2018I&D), Sanfilippo Children's Foundation (2019DGH1656/SCF2019I&D) and FCT (EXPL/BTM-SAL/0659/2021),N/

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures

RNA como alvo terapêutico: desenvolvimento de abordagens inovadoras utilizando oligonucleótidos sintéticos.

Sobre o desenvolvimento de abordagens inovadoras utilizando oligonucleótidos sintéticos - RNA como alvo terapêutico.N/

The 2020s Tooth Fairy: from loose tooth to neuronal cell cultures, an innovative method for in vitro genetic disease modeling of a rare neurological disorder

Abstract disponibilizado: https://www.impsg2022.uevora.pt/wp-content/uploads/2022/06/Livro-de-Abstracts-IIIIMPSG_2022_draft-version.pdfThe development of adequate in vitro disease models is a major issue in Biomedical Genetics. Those models allow for the initial screening of novel therapeutics and help us get an insight on the cellular mechanisms that underly pathology in each case. In fact, one of the best ways to get those insights is the analysis of patient-derived cells. Yet, not every cell holds potential to recapitulate relevant disease features. For neurodegenerative diseases in particular, it is challenging to grow neuronal cultures that accurately represent them because of the obvious inability to access live neurons. This scenario changed significantly when induced pluripotent stem cells (iPSC) were first described. From then on several differentiation protocols to generate neurons from iPSC were developed. Still, iPSC generation is a laborious/expensive protocol with significant limitations in terms of production and subsequent uses. Here we present an alternative to establish patient-derived neuronal cells in a much more expedite way. We are taking advantage of the existence of a population of multipotent stem cells (SC) in human dental pulp, the dental pulp stem cells (DPSC), to establish mixed neuronal and glial cultures for a rare neurological genetic disorder: the Sanfilippo syndrome. Sanfilippo-derived DPSC have never been used for differentiation into specific cell types even though they represent a natural source of SC that may be used to investigate human disease especially for the infantile forms. This is a total innovation in the field and we believe it holds potential to set a new trend for investigating the cellular/gene expression changes that occur in Sanfilippo and other related diseases as it relies on a non-invasive, cost-effective approach that can be set as a routine in any lab with standard cell culture conditions. Ultimately, the same method may be applied for virtually any monogenic disorder with neurological presentation.This work is partially supported by the Portuguese Society for Metabolic Disorders (SPDM - Bolsa SPDM de apoio à investigação Dr. Aguinaldo Cabral 2018; 2019DGH1629/SPDM2018I&D), Sanfilippo Children's Foundation (2019DGH1656/SCF2019I&D) and FCT (EXPL/BTM-SAL/0659/2021).N/

Modeling Lysosomal Storage Disorders in an Innovative Way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidosis Type II Patients

Among the many lysosomal storage disorders (LSDs) that would benefit from the establishment of novel cell models, either patient-derived or genetically engineered, is mucopolysaccharidosis type II (MPS II). Here, we present our results on the establishment and characterization of two MPS II patient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population has been isolated from LSD patient samples obtained from the dental pulp. Taking into account our results on the molecular and biochemical characterization of those cells and the fact that they exhibit visible and measurable disease phenotypes, we consider these cells may qualify as a valuable disease model, which may be useful for both pathophysiological assessments and in vitro screenings. Ultimately, we believe that patient-derived dental pulp stem cells (DPSCs), particularly those isolated from human exfoliated deciduous teeth (SHEDs), may represent a feasible alternative to induced pluripotent stem cells (iPSCs) in many labs with standard cell culture conditions and limited (human and economic) resources

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved