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Psoriatic arthritis (PsA) is a very heterogeneous disease with significant impact on health-related quality-of-life (HRQoL). Our objective was to assess and identify predictors of HRQoL in a 3-year follow-up period among PsA patients. Patients with PsA included in the Rheumatic Diseases Portuguese Register (Reuma.pt), with HRQoL data measured by the EuroQoL five Dimensions (EQ-5D) with at least two evaluations throughout a 3-year period, were analysed. Statistics included t- tests, logit and linear mixed models and univariable and multivariable linear regression. PsA patients’ ( n  = 342) mean age 51.0 (12.2) years, 48.5% being female, mean disease duration 11.8 (9.3) years with a follow-up period of 3-years had a mean EQ-5D of 0.53 (0.28), 0.59 (0.29), and 0.58 (0.28) at baseline, 1-year and 3-year evaluations, respectively. During the follow-up period, EQ-5D score and EQ VAS, significantly improved at both time-point assessments, compared to baseline. Poorer HRQoL was significantly associated with older age (β=-0.004; p-value = 0.008), female sex (β=-0.092; p-value = 0.01), non-employment (β=-0.112; p-value = 0.018), higher disease activity (β=-0.005; p-value < 0.001), prior exposure of three or more biologics at baseline and switching of biologic therapy during the study follow-up [(β=-0.182; p-value = 0.04); (β=-0.150; p-value = 0.002), respectively]. Our study provides important insights into the long-term predictors of HRQoL in PsA patients, highlighting the influence of sociodemographic factors, disease activity and therapeutic approach (prior use and switch/cycle of biologic therapies) on HRQoL.

O fim da União das Repúblicas Socialistas Soviéticas desencadeou um vastíssimo conjunto de consequências geopolíticas que causou profundas modificações no equilíbrio de poderes a uma escala global. Como é evidente, o epicentro das maiores mudanças tomou lugar nas repúblicas que outrora integravam o bloco. Uma das que mais sentiu a turbulência dessa nova etapa da história do mundo foi a Geórgia, vizinha da Rússia a sul, já que este novo país contava no território sob sua responsabilidade com duas regiões de aspirações independentistas, a Abecásia e a Ossétia do Sul. Ora esses sentimentos de separatismo foram responsáveis por altos níveis de tensão e conflitualidade violenta que viriam a conhecer o seu apogeu em agosto de 2008, altura em que se registaram confrontações entre georgianos e russos, que se afirmaram apoiantes das pretensões abecásias e ossetas. A presente dissertação irá levar a cabo uma investigação destinada a compreender com clareza as motivações que estiveram no cerne destas discórdias, ao mesmo tempo que procurará compreender o que é um conflito congelado e de que forma pode este conceito enquadrar-se neste tipo de crise.

Post-stroke motor rehabilitation should begin as soon as possible, as the patient's condition is stabilized. As rehabilitation should be intensive and repetitive, this can lead to some problems, such as lack of motivation and willingness on the part of patients during the performance of therapeutic exercises. The present work was elaborated in the scope of the Dissertation of Integrated Masters Degree in Electrotechnical Engineering and of Computers, taught in the Department of Electrical and Computer Engineering of the Faculty of Sciences and Technology of the University of Coimbra, aiming at the creation of a useful tool in virtual reality, exploring the concept of serious game, for the aid to the traditional motor rehabilitation. The objective is to motivate and encourage the patient to perform therapeutic exercises, through a playful activity that will cause him pleasure during his execution. As people have different needs, the game can be customized by a physiotherapist to suit according to the skills and needs of the patient who wants to play it. The game developed was put to the appreciation of a specialist in physiotherapy, in order to prove the validity and usability of it. It was thought and developed in order to stimulate only movements of patients shoulders and arms. Seen this, and after a brief discussion it was suggested the use of an orthosis, which will be placed in the patients arms, thus being able to dissociate the movement only for the arms and shoulders and lead to a elbow stabilization. The feedback obtained was very positive, verifying as valid the game proposed during this dissertation.

Na artrite reumatoide, os danos cardiovascular e ósseo são importantes fontes de morbilidade, incapacidade e mortalidade. No passado, a osteoporose e a aterosclerose eram consideradas duas patologias, independentes uma da outra. No entanto, hoje em dia, existe uma evidência crescente duma ligação epidemiológica e fisiopatológica entre as duas doenças.As doenças cardiovasculares (DCVs) são uma das principais causas de morte em doentes com artrite reumatoide e a avaliação do risco cardiovascular (CV) nestes doentes ainda é uma questão por esclarecer. Nesta tese, pesquisámos a presença de isquemia miocárdica silenciosa em doentes com artrite reumatoide estabelecida, e a sua associação a múltiplas variáveis antropométricas e clínicas, ao peptídeo natriurético cerebral (BNP) e a biomarcadores ósseos e de ateroma [osteoprotegerina (OPG) e ligando do recetor ativador do fator nuclear-kappa B (RANKL), assim como a sua razão; dickkopf-1 (DKK-1) e esclerostina, inibidores conhecidos da via Wnt/β-catenina canónica]. O score de cálcio coronário (SCC), avaliado por tomografia computadorizada, tem sido associado ao prognóstico da artrite reumatoide. Neste trabalho, avaliamos também o SCC em doentes com artrite reumatoide e investigámos as suas associações com os mesmos parâmetros que escolhemos para o estudo de cintigrafia de perfusão miocárdica, acrescentando as avaliações do dano ósseo.A cintigrafia de perfusão miocárdica sob stresse com adenosina revelou para os 189 doentes com artrite reumatoide, assintomáticos para DCV, revelou defeitos de perfusão miocárdica (summed stress score, SSS≥4) em 47 (25%) doentes, defeitos ligeiros em 35 (18,5%), moderados em 10 (5,3%) e graves em 2 (1%). Os defeitos apresentaram um summed difference score(SDS) médio de 4,1±3 e uma extensão no stresse de 2,5±3,6%, tendo sido reversíveis em repouso em 31 (16%) casos. A fração de ejeção do ventrículo esquerdo foi inferior a 45% em 9 (4,76%) doentes, apresentando-se com um valor médio de 63,7±9,8%. Os defeitos de perfusão eram únicos (25/47, 53%) ou múltiplos (22/47, 47%), sem distribuição preferencial pelos diferentes territórios coronários. Os defeitos de perfusão associaram-se a valores de BNP≥100pg/mL [odds ratio (OR)=5,68; intervalo de confiança (IC) 95%: 2,038-15,830], ao quarto quartil do logaritmo da razão OPG/RANKL (OR=2,88; IC 95%: 1,091-7,622) e a valores de DKK-1≥133pmol/L (OR=2,69; IC 95%: 1,058-6,840). Associações similares foram confirmadas, quer nos doentes com PCR>3mg/L, quer nos com valores ≤3mg/L. Não se encontraram associações com a maioria dos fatores de risco CV tradicionais nem com variáveis da doença. Assim, os nossos resultados sustentaram a hipótese de que a cintigrafia de perfusão miocárdica poderia revelar uma disfunção CV subclínica, apoiaram a utilidade do doseamento do BNP como instrumento de rastreio dos doentes e colocaram em perspectiva o potencial interesse de utilizar outras abordagens complementares na avaliação do risco CV em doentes com artrite reumatoide.Além disso, em 78 doentes com artrite reumatoide, também assintomáticos para DCV, tivemos a oportunidade de medir o cálcio das artérias coronárias.

Mesenchymal stromal cells (MSC) hold great promise for tissue engineering and cell-based therapies due to their multilineage differentiation potential and intrinsic immunomodulatory and trophic activities. Over the past years, increasing evidence has proposed extracellular vesicles (EVs) as mediators of many of the MSC-associated therapeutic features. EVs have emerged as mediators of intercellular communication, being associated with multiple physiological processes, but also in the pathogenesis of several diseases. EVs are derived from cell membranes, allowing high biocompatibility to target cells, while their small size makes them ideal candidates to cross biological barriers. Despite the promising potential of EVs for therapeutic applications, robust manufacturing processes that would increase the consistency and scalability of EV production are still lacking. In this work, EVs were produced by MSC isolated from different human tissue sources [bone marrow (BM), adipose tissue (AT), and umbilical cord matrix (UCM)]. A serum-/xeno-free microcarrier-based culture system was implemented in a Vertical-WheelTM bioreactor (VWBR), employing a human platelet lysate culture supplement (UltraGROTM-PURE), toward the scalable production of MSC-derived EVs (MSC-EVs). The morphology and structure of the manufactured EVs were assessed by atomic force microscopy, while EV protein markers were successfully identified in EVs by Western blot, and EV surface charge was maintained relatively constant (between −15.5 ± 1.6 mV and −19.4 ± 1.4 mV), as determined by zeta potential measurements. When compared to traditional culture systems under static conditions (T-flasks), the VWBR system allowed the production of EVs at higher concentration (i.e., EV concentration in the conditioned medium) (5.7-fold increase overall) and productivity (i.e., amount of EVs generated per cell) (3-fold increase overall). BM, AT and UCM MSC cultured in the VWBR system yielded an average of 2.8 ± 0.1 × 1011, 3.1 ± 1.3 × 1011, and 4.1 ± 1.7 × 1011 EV particles ( n = 3), respectively, in a 60 mL final volume. This bioreactor system also allowed to obtain a more robust MSC-EV production, regarding their purity, compared to static culture. Overall, we demonstrate that this scalable culture system can robustly manufacture EVs from MSC derived from different tissue sources, toward the development of novel therapeutic products.

The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, and blood vessels. This leads to a significant pathophysiological overlap between neurodegenerative and cerebrovascular diseases. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease whose pathogenesis is still to be unveiled but has mostly been explored under the light of the amyloid-cascade hypothesis. Either as a trigger, bystander, or consequence of neurodegeneration, vascular dysfunction is an early component of the pathological conundrum of AD. The anatomical and functional substrate of this neurovascular degeneration is the BBB, a dynamic and semi-permeable interface between blood and the central nervous system that has consistently been shown to be defective. Several molecular and genetic changes have been demonstrated to mediate vascular dysfunction and BBB disruption in AD. The isoform ε4 of Apolipoprotein E is at the same time the strongest genetic risk factor for AD and a known promoter of BBB dysfunction. Low-density lipoprotein receptor–related protein 1 (LRP-1), P-glycoprotein, and receptor for advanced glycation end products (RAGE) are examples of BBB transporters implicated in its pathogenesis due to their role in the trafficking of amyloid-β. This disease is currently devoid of strategies that change the natural course of this burdening illness. This unsuccess may partly be explained by our misunderstanding of the disease pathogenesis and our inability to develop drugs that are effectively delivered to the brain. BBB may represent a therapeutic opportunity as a target itself or as a therapeutic vehicle. In this review, we aim to explore the role of BBB in the pathogenesis of AD including the genetic background and detail how it can be targeted in future therapeutic research.

Robust methods to compute tissue displacements in optical coherence elastography (OCE) data are paramount, as they play a significant role in the accuracy of tissue elastic properties estimation. In this study, the accuracy of different phase estimators was evaluated on simulated OCE data, where the displacements can be accurately set, and on real data. Displacement (∆d) estimates were computed from (i) the original interferogram data (Δφori) and two phase-invariant mathematical manipulations of the interferogram: (ii) its first-order derivative (Δφd) and (iii) its integral (Δφint). We observed a dependence of the phase difference estimation accuracy on the initial depth location of the scatterer and the magnitude of the tissue displacement. However, by combining the three phase-difference estimates (Δdav), the error in phase difference estimation could be minimized. By using Δdav, the median root-mean-square error associated with displacement prediction in simulated OCE data was reduced by 85% and 70% in data with and without noise, respectively, in relation to the traditional estimate. Furthermore, a modest improvement in the minimum detectable displacement in real OCE data was also observed, particularly in data with low signal-to-noise ratios. The feasibility of using Δdav to estimate agarose phantoms’ Young’s modulus is illustrated.

Cerebrovascular disease is a common comorbidity in patients with Alzheimer’s disease (AD) and other dementias. Accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Additionally, common variants in COL4A1 and rare variants in HTRA1 , NOTCH3 , COL4A1 , and CST3 have been associated with AD pathogenesis. We aimed to search for rare genetic variants in genes associated with monogenic small vessel disease in a cohort of Portuguese early-onset AD patients. We performed whole-exome sequencing in 104 thoroughly studied patients with early-onset AD who lacked known pathogenic variants in the genes associated with AD or frontotemporal dementia. We searched for rare (minor allele frequency < 0.001) non-synonymous variants in genes associated with small vessel disease: NOTCH3 , HTRA1 , COL4A1 , COL4A2 , CSTA , GLA , and TREX1 . We identified 12 rare variants in 18 patients (17.3% of the cohort). Three male AD patients carried a pathogenic GLA variant (p.Arg118Cys). One of these patients had a definite neuropathological study, confirming the diagnosis of AD and showing concomitant Fabry pathology in CA1-CA4 and the subiculum. We also found several rare variants in other genes associated with cSVD ( NOTCH3 , COL4A2 and HTRA1 ), corroborating previous studies and providing further support for the possibility that cSVD genes may play a role in AD pathogenesis. The presence of the same GLA variant in 3 early-onset AD patients, with no other genetic cause for the disease, together with the colocalization of Fabry disease pathology in areas relevant for AD pathogenesis, suggest GLA may have a role in its pathophysiology, possibly parallel to that of GBA in Parkinson’s disease, meriting further studies.

This paper presents a clinical case study investigating the pattern of a saxophonist’s embouchure as a possible origin of orofacial pain. The rehabilitation addressed the dental occlusion and a fracture in a metal ceramic bridge. To evaluate the undesirable loads on the upper teeth, two piezoresistive sensors were placed between the central incisors and the mouthpiece during the embouchure. A newly fixed metal ceramic prosthesis was placed from teeth 13 to 25, and two implants were placed in the premolar zone corresponding to teeth 14 and 15. After the oral rehabilitation, the embouchure force measurements showed that higher stability was promoted by the newly fixed metal-ceramic prosthesis. The musician executed a more symmetric loading of the central incisors (teeth 11 and 21). The functional demands of the saxophone player and consequent application of excessive pressure can significantly influence and modify the metal-ceramic position on the anterior zone teeth 21/22. The contribution of engineering (i.e., monitoring the applied forces on the musician’s dental structures) was therefore crucial for the correct assessment and design of the treatment plan.

Introduction/objectivesTo evaluate rituximab (RTX) effectiveness and safety in patients with interstitial lung disease (ILD) related to connective tissue diseases (CTD).MethodsRetrospective multicenter cohort study, including patients with CTD-ILD, followed in six Portuguese rheumatology departments until November 2018. ILD diagnosis was based on high-resolution CT (HRCT) and/or lung biopsy. Results of HRCT, pulmonary function tests, and 6-min walking test before and after RTX were compared using the Wilcoxon matched pair test. Safety, including adverse events during treatment and reasons for RTX discontinuation, was also analyzed.ResultsA total of 49 patients were included, with rheumatoid arthritis being the commonest CTD (61.2%). The median interval between CTD onset and ILD diagnosis was 4 years (IQR 1–9.5) and median ILD duration at first RTX administration was 1 year (IQR 0–4). The median RTX treatment duration until the last follow-up was 3 years (IQR 1–6). Usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) were the commonest patterns, occurring in 20 and 18 patients, respectively. One year after RTX first administration, there was a stabilization in carbon monoxide diffusing capacity (DLCO; mean + 5.4%, p = 0.12) and improvement in forced vital capacity (FVC; mean + 4.3%, p = 0.03), particularly in patients with NSIP. Patients with UIP had less promising results, but at 1 year, pulmonary function tests remained stable (DLCO + 2.5%, p = 0.77; FVC + 4.2%, p = 0.16). Infection was the main reason for RTX discontinuation and led to two deaths.ConclusionsRTX seems to be a promising treatment for CTD-ILD patients, particularly when NSIP pattern is present.Key points• The use of rituximab in patients with interstitial lung disease related to connective tissue disease is associated with long-standing disease stability in a wide range of systemic rheumatic diseases.• Efficacy results were particularly impressive in patients with non-specific interstitial pneumonia pattern, although in a subgroup of patients with usual interstitial pneumonia pattern, disease progression was also hold with this treatment.• In a large number of patients, rituximab was used in monotherapy and as first-line treatment.