Discondroplasia da tíbia como modelo em estudos de mecanobiologia experimental

A discondroplasia da tíbia, consiste numa anomalia espontânea, ou induzida, nas placas de crescimento epifisárias dos ossos longos, das estirpes de rápido crescimento das espécies avícolas, caracterizada pelo aparecimento de uma massa cartilagínea avascular opaca, não calcificada, que se estende até à metáfise, numa zona em que, normalmente, existe osso trabecular. Do ponto de vista citológico, a discondroplasia reflecte alterações na homeostase celular no decurso normal da ossificação endocondral, ou seja, a cartilagem não calcifica e não é substituída por osso endocondral. Deste modo, os processos de proliferação dos condrócitos (que é normal) e de degradação da cartilagem (que não se verifica), não estão em equilíbrio, resultando numa acumulação de matriz extracelular. Com a presente linha de investigação pretende-se, com base em resultados obtidos por um dos autores [Capela e Silva, 2004], designadamente no que diz respeito à expressão das caderinas, e com base noutros trabalhos relativos à expressão de proteínas de stress [Ribeiro e tal., 2004], avaliar da possibilidade de utilização da discondroplasia em estudos de mecanobiologia experimental

Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein

During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z’s misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease

Expressão imunoistoquímica da proteína S-100 na discondroplasia da tíbia

It was compared, by immunohistochemistry, the expression of S-100 protein from normal and tibial dyschondroplasia (TD) growth plates. The results suggest that S-100 may be involved in growth plate homeostasis. The expression of S-100 in dyschondroplastic chondrocytes may be due to a low level of calcium in the lesion and/or compression of chondrocytes by the accumulated matrix. One further possibility is the association between S-100 and the regulation of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). Further studies will be necessary to provide insight into involvement of S-100 in tibial dyschondroplasia development and the precise nature of the pathology

Long COVID Symptoms in Non-Hospitalised Patients: A Retrospective Study

Introduction: The COVID-19 pandemic has presented numerous challenges to healthcare systems. As the number of affected individuals continues to rise, it is crucial to find preventive, diagnostic, and therapeutic approaches. This study aims to describe different COVID-19 sequelae within a Primary Health Care population.Methods: A retrospective cohort study was conducted in adults diagnosed with COVID-19 from March 2020 to April 2022, excluding pregnant women, minors, nursing home residents, hospitalizations, and deaths. Data was gathered from surveillance records on the Trace COVID-19 (R) platform, a pre-set original questionnaire (which included the Portuguese version of the World Health Organization's Quality of Life Assessment Instrument), and, if needed, patient electronic health records. Information on sociodemographic and clinical characteristics of acute COVID-19 was collected along with long COVID symptoms.Results: This study included 284 patients, aged 19 to 99 years old. The five most prevalent acute COVID-19 symptoms were fever (50.0%), tiredness (48.2%), myalgias (44.7%), dry cough (37.7%) and odynophagia (36.3%). Symptoms related to the neurological system (23.2%) and tiredness (22.9%) were the most prevalent in long COVID symptoms. Acute tiredness and arthralgia were associated with all long COVID outcomes. The associations between acute COVID-19 symptoms with long COVID outcomes were stronger for anosmia [OR = 5.07, 95% confidence interval (CI) 2.49 -10.36, p < 0.001] on a neurological chapter, acute tiredness for long lasting tiredness (OR = 4.07, 95% CI 2.07 -8.02, p = 0.041), fatigue for muscles and/or bones chapter (OR = 7.55, 95% CI 3.06 -18.66, p < 0.001), tiredness on an endocrine/hormonal chapter (OR = 6.54, 95% CI 2.37 -18.04, p < 0.001), dyspnea for respiratory symptoms (OR = 5.67, 95% CI 1.92 -16.74, p = 0.002) and fever for stomach or intestine symptoms (OR = 8.06, 95% CI 2.55 -25.47, p < 0.001). Almost all quality of life dimensions were negatively associated with the number of long COVID symptoms.Conclusion: A higher number of acute symptoms, as well as the presence of specific COVID-19 symptoms were associated with reported symptoms = 12 weeks after infection. In the studied population, an increased number of symptoms in both acute and long COVID had a significant negative impact on the perception of overall quality of life. The identification of these relationships could provide a new perspective for post-COVID care

COVID-19 in a Pediatric Cohort—Retrospective Review of Chest Computer Tomography Findings

Background: Radiological features of the novel 2019 coronavirus disease (COVID-19) have been mainly described in adults. Available literature states that imaging findings in children are similar but less pronounced. The aim of this study is to describe and illustrate the chest computer tomography (CT) features of pediatric COVID-19. Results: This retrospective study was based on the review of all the chest CTs performed in pediatric patients with confirmed COVID-19 disease between March 8th and May 26th 2020 (n = 24). The presence of comorbidities and coinfection was assessed, as well as timing of CT examination in relation to the onset of symptoms. CT findings were categorized as typical, indeterminate, atypical, and negative for COVID-19 according to International Expert Consensus Statement on Chest Imaging in Pediatric COVID-19 Patient Management. This study found that CT findings were abnormal in 17 (71%) patients, with 5 (21%), 9 (38%), and 3 (13%) patients considered to have typical, indeterminate, and atypical findings, respectively. The most common CT patterns were multiple ground-glass opacities (58%), followed by consolidations (50%). Six patients showed predominantly peripheral distribution of parenchymal abnormalities. A halo sign was identified in 3 patients and a perilobular pattern was identified in one of the cases with typical findings. Conclusions: Chest CT findings in children infected with SARS-CoV-2 can be subtle or absent. Besides recognizing typical findings, radiologists should be able to identify features that favor different or concomitant diagnosis.info:eu-repo/semantics/publishedVersio

Supplemental selenium source on gut health: Insights on fecal microbiome and fermentation products of growing puppies

Selenium is an essential trace element that can modulate the gut microbiome with an impact on host health. The present study aimed to evaluate the effects of organic (selenium-enriched yeast) vs inorganic (sodium selenite) selenium source on fecal end-fermentation products and gut microbiome of puppies from 20 to 52 weeks of age. Alpha and beta diversity of the gut bacterial community were affected by age but not by gender or selenium source. The relative abundance of taxa was differently affected by age, and the DNA concentration of all selected bacterial groups increased with age, although total volatile fatty acids (VFA), acetate, propionate, caproate and lactate concentrations decreased. Organic selenium was associated with a higher concentration of total VFA, propionate and butyrate, a higher number of DNA copies of Lactobacillus, and a trend to lower DNA copies of Escherichia coli. Effects on fecal microbiome during growth differed with selenium source. Females had higher fecal end-fermentation products related to protein degradation, whereas males had higher DNA concentration of Bifidobacterium. Organic selenium might be beneficial over inorganic for dog food supplementation due to the positive modulation of the gut microbiome observed in puppies

Anti-tumour necrosis factor therapy for Dupuytren's Disease: a randomised dose response proof of concept phase 2a clinical trial

Background Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Methods Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. Interpretation In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease

A new European coastal flood database for low–medium intensity events

Coastal flooding is recognized as one of the most devastating natural disasters, resulting in significant economic losses. Therefore, hazard assessment is crucial to support preparedness and response to such disasters. Toward this, flood map databases and catalogues are essential for the analysis of flood scenarios, and furthermore they can be integrated into disaster risk reduction studies. In this study and in the context of the European Coastal Flood Awareness System (ECFAS) project (GA 101004211), which aimed to propose the European Copernicus Coastal Flood Awareness System, a catalogue of flood maps was produced. The flood maps were generated from flood models developed with LISFLOOD-FP for defined coastal sectors along the entire European coastline. For each coastal sector, 15 synthetic scenarios were defined focusing on high-frequency events specific to the local area. These scenarios were constructed based on three distinct storm durations and five different total-water-level (TWL) peaks incorporating tide, mean sea level, surge and wave setup components. The flood model method was extensively validated against 12 test cases for which observed data were collated using satellite-derived flood maps and in situ flood markers. Half of the test cases represented well the flooding with hit scores higher than 80 %. The synthetic-scenario approach was assessed by comparing flood maps from real events and their closest identified scenarios, producing a good agreement and global skill scores higher than 70 %. Using the catalogue, flood scenarios across Europe were assessed, and the biggest flooding occurred in well-known low-lying areas. In addition, different sensitivities to the increase in the duration and TWL peak were noted. The storm duration impacts a few limited flood-prone areas such as the Dutch coast, for which the flooded area increases more than twice between 12 and 36 h storm scenarios. The influence of the TWL peak is more global, especially along the Mediterranean coast, for which the relative difference between a 2- and 20-year return period storm is around 80 %. Finally, at a European scale, the expansion of flood areas in relation to increases in TWL peaks demonstrated both positive and negative correlations with the presence of urban and wetland areas, respectively. This observation supports the concept of storm flood mitigation by wetlands.</p

Projected sensitivity of the LUX-ZEPLIN experiment to the 0νββ decay of Xe 136

The LUX-ZEPLIN (LZ) experiment will enable a neutrinoless double β decay search in parallel to the main science goal of discovering dark matter particle interactions. We report the expected LZ sensitivity to Xe136 neutrinoless double β decay, taking advantage of the significant (&gt;600 kg) Xe136 mass contained within the active volume of LZ without isotopic enrichment. After 1000 live-days, the median exclusion sensitivity to the half-life of Xe136 is projected to be 1.06×1026 years (90% confidence level), similar to existing constraints. We also report the expected sensitivity of a possible subsequent dedicated exposure using 90% enrichment with Xe136 at 1.06×1027 years