Longitudinal genotype-phenotype analysis in 86 PAX6-related aniridia patients

Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterised by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma and aniridia related keratopathy (ARK). Genotype-phenotype correlations have previously been described, however detailed longitudinal studies of aniridia are less commonly reported. We identified eighty-six patients from sixty-two unrelated families with molecularly confirmed heterozygous PAX6 variants from a United Kingdom (UK)-based single-centre ocular genetics service. They were categorised into mutation groups and retrospective review of baseline to most recent clinical characteristics (ocular and systemic) were recorded. One hundred and seventy-two eyes were evaluated, with a mean follow up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2%, and foveal hypoplasia in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6% and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention varied amongst mutation groups. Overall, the missense mutation sub-group had the mildest phenotype, and surgically naïve eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8%, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the United Kingdom, providing insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features

New combined CFH/MCP mutations and a rare clinical course in atypical haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease due to uncontrolled alternative pathway complement activation. In this report, we discuss the case of a heterozygous carrier of a mutation on both factor H and membrane cofactor protein, who persistently presents haemolytic anaemia without need for blood transfusions, normal platelet count, normal renal function and no signs or symptoms of organ injury due to thrombotic microangiopathy 4 years after the diagnosis of aHUS.info:eu-repo/semantics/publishedVersio

Hypotrophic roots of the upper central incisors – a proposed new dental discrete trait

This paper describes a newly de-fined nonmetric trait in the human dentition, i.e., Hypotrophic Roots of the Upper Central Incisors (HRUCI). Teeth presenting HRUCI are character-ized by abnormally short roots whose crowns exhibit no apparent morphological alterations. The trait was observed in six samples from collec-tive funerary sites in the Iberian Peninsula dated from the Late Neolithic to the Chalcolithic period

The systemic immune response to collagen-induced arthritis and the impact of bone injury in inflammatory conditions

Rheumatoid arthritis (RA) is a systemic disease that affects the osteoarticular system, associated with bone fragility and increased risk of fractures. Herein, we aimed to characterize the systemic impact of the rat collagen-induced arthritis (CIA) model and explore its combination with femoral bone defect (FD). The impact of CIA on endogenous mesenchymal stem/stromal cells (MSC) was also investigated. CIA induction led to enlarged, more proliferative, spleen and draining lymph nodes, with altered proportion of lymphoid populations. Upon FD, CIA animals increased the systemic myeloid cell proportions, and their expression of co-stimulatory molecules CD40 and CD86. Screening plasma cytokine/chemokine levels showed increased tumor necrosis factor-a (TNF-a), Interleukin (IL)-17, IL-4, IL-5, and IL-12 in CIA, and IL-2 and IL-6 increased in CIA and CIA+FD, while Fractalkine and Leptin were decreased in both groups. CIA-derived MSC showed lower metabolic activity and proliferation, and significantly increased osteogenic and chondrogenic differentiation markers. Exposure of control-MSC to TNF-a partially mimicked the CIA-MSC phenotype in vitro. In conclusion, inflammatory conditions of CIA led to alterations in systemic immune cell proportions, circulating mediators, and in endogenous MSC. CIA animals respond to FD, and the combined model can be used to study the mechanisms of bone repair in inflammatory conditions.This research was funded by the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and AO Foundation-Switzerland (project S-15-83S). J.H.T, A.M.S, M.B.G, M.I.A and C.C were supported by FCT-Fundação para a Ciência e a Tecnologia, through the fellowships SFRH/BD/112832/2015, SFRH/BD/85968/2012, PD/BD/135489/2018, DL 57/2016/CP1360/CT0008 and DL 57/2016/CP1360/CT0004, respectively

Recomendação de Curvas de Crescimento para Crianças Nascidas Pré-Termo

Em 2013, a Secção de Neonatologia da Sociedade Portuguesa de Pediatria, face à existência de várias curvas de avaliação de crescimento para crianças nascidas pré-termo e à falta de homogeneidade de critérios na sua escolha, nomeou um grupo de peritos que procedeu à revisão crítica das curvas disponíveis e recomenda as que considera mais adequadas para utilização na prática clínica em fases específicas da vida: ao nascimento (Fenton 2013), durante o internamento na unidade de Neonatologia (Fenton 2013 e Ehrenkranz 1999) e a longo prazo (OMS 2006). As decisões foram tomadas com base na classificação sistemática do nível de evidência e do grau de recomendação. A presente recomendação: é válida enquanto não forem publicados os resultados do estudo do consórcio multicêntrico INTERGROWTH-21st, recentemente incumbido da construção de valores de referência, mais próximos do padrão, de crianças nascidas pré-termo; tem o propósito de auxiliar os clínicos na decisão clínica, mas não ser o único instrumento de avaliação do crescimento das crianças nascidas pré-termo; pode não proporcionar elementos suficientes para orientação do crescimento de todas estas crianças

The neural basis of fatigue in multiple sclerosis: A multimodal MRI approach

BACKGROUND: Fatigue is a frequent disabling symptom in multiple sclerosis (MS), but its pathophysiology remains incompletely understood. This study aimed to explore the underlying neural basis of fatigue in patients with MS. METHODS: We enrolled 60 consecutive patients with MS and 60 healthy controls (HC) matched on age, sex, and education. Fatigue was assessed using the Portuguese version of the Modified Fatigue Impact Scale (MFIS). All participants underwent 3T brain MRI (conventional and diffusion tensor imaging [DTI] sequences). White matter (WM) focal lesions were identified and T1/T2 lesion volumes were computed. Tract-based spatial statistics were applied for voxel-wise analysis of DTI metrics fractional anisotropy and mean diffusivity (MD) on normal-appearing WM (NAWM). Using Freesurfer software, total and regional volumes of cortical and subcortical gray matter (GM) were calculated. RESULTS: Compared to HC, patients with MS scored significantly higher on MFIS (33.8 ± 19.7 vs 16.5 ± 15.1, p < 0.001). MFIS scores were not significantly correlated with T1/T2 lesion volumes, total GM volume, or any regional volume of cortical and subcortical GM. Significant correlations were found between global scores of MFIS and MD increase of the NAWM skeleton, including corona radiata, internal capsule, external capsule, corticospinal tract, cingulum, corpus callosum, fornix, superior longitudinal fasciculus, superior fronto-occipital fasciculus, sagittal stratum, posterior thalamic radiation, cerebral peduncle, and uncinate fasciculus. CONCLUSIONS: In this study, fatigue was associated with widespread NAWM damage but not with lesion load or GM atrophy. Functional disconnection, caused by diffuse microstructural WM damage, might be the main neural basis of fatigue in MS.info:eu-repo/semantics/publishedVersio

Onstage and off: The shifting relevance of gender in women’s prisons

uncorrected proofEven though international research on men’s prisons is no longer oblivious to gender, approaches to women’s prisons have tended to be more gender-bound as a whole. Besides having informed a specific reflexive agenda of representation, the angle of gender has presided to most research issues as an analytical overall parti pris: from the gendered nature of prison regimes to the gendered character of prison cultures, socialities and ‘pains of imprisonment’. This more ‘gendercentric’ agenda is however becoming more diversified for theoretical and empirical reasons alike. These involve a recognition of the diversity of women prisoners’ experiences and identities, and an attention to a wider variety of aspects of carceral life. Drawing on field approaches to the Portuguese carceral world spanning three decades, I propose to take this debate further by focusing on contextual shifts in the actual saliency of gender as a category of identity and social life in women’s prisons.(undefined)(undefined)info:eu-repo/semantics/publishedVersio

As biografias educativas como fonte de pesquisa e estudo no campo da forma??o docente : notas iniciais para uma discuss?o te?rico/metodol?gica.

Este artigo busca analisar uma tend?ncia te?rica, mas sobretudo metodol?gica, que vem se constituindo como um campo rico de estudos e pesquisas na ?rea da forma??o docente: as narrativas biogr?ficas, os estudos de mem?rias de forma??o elaboradas pelos professores em exerc?cio ou em forma??o. Recorrem na escrita de memoriais que podem ser percebidos como uma ferramenta de reflex?o biogr?fica a respeito da forma??o inicial e continuada, momento em que s?o expostos os desafios, as dificuldades e as crises da vida profissional, a partir de lembran?as sobre o passado escolar e das reflex?es sobre o presente e o devir. Sem pretender fazer um balan?o da bibliografia j? existente e muito menos esgotar o tema, pretende-se com esta discuss?o inicial situar o debate sobre os estudos biogr?ficos como fonte te?rico-metodol?gica e suas contribui??es na forma??o docente

Profiling the circulating miRnome reveals a temporal regulation of the bone injury response

Bone injury healing is an orchestrated process that starts with an inflammatory phase followed by repair and remodelling of the bone defect. The initial inflammation is characterized by local changes in immune cell populations and molecular mediators, including microRNAs (miRNAs). However, the systemic response to bone injury remains largely uncharacterized. Thus, this study aimed to profile the changes in the plasma miRnome after bone injury and determine its biological implications. Methods: A rat model of femoral bone defect was used, and animals were evaluated at days 3 and 14 after injury. Non-operated (NO) and sham operated animals were used as controls. Blood and spleen were collected and peripheral blood mononuclear cells (PBMC) and plasma were separated. Plasma miRnome was determined by RT-qPCR array and bioinformatics Ingenuity pathway analysis (IPA) was performed. Proliferation of bone marrow mesenchymal stem/stromal cells (MSC) was evaluated by Ki67 staining and high-throughput cell imaging. Candidate miRNAs were evaluated in splenocytes by RT-qPCR, and proteins found in the IPA analysis were analysed in splenocytes and PBMC by Western blot. Results: Bone injury resulted in timely controlled changes to the miRNA expression profile in plasma. At day 3 there was a major down-regulation of miRNA levels, which was partially recovered by day 14 post-injury. Interestingly, bone injury led to a significant up-regulation of let-7a, let-7d and miR-21 in plasma and splenocytes at day 14 relative to day 3 after bone injury, but not in sham operated animals. IPA predicted that most miRNAs temporally affected were involved in cellular development, proliferation and movement. MSC proliferation was analysed and found significantly increased in response to plasma of animals days 3 and 14 post-injury, but not from NO animals. Moreover, IPA predicted that miRNA processing proteins Ago2 and Dicer were specifically inhibited at day 3 post-injury, with Ago2 becoming activated at day 14. Protein levels of Ago2 and Dicer in splenocytes were increased at day 14 relative to day 3 post-bone injury and NO animals, while in PBMC, levels were reduced at day 3 (albeit Dicer was not significant) and remained low at day 14. Ephrin receptor B6 followed the same tendency as Ago2 and Dicer, while Smad2/3 was significantly decreased in splenocytes from day 14 relative to NO and day 3 post-bone injury animals. Conclusion: Results show a systemic miRNA response to bone injury that is regulated in time and is related to inflammation resolution and the start of bone repair/regeneration, unravelling candidate miRNAs to be used as biomarkers in the monitoring of healthy bone healing and as therapeutic targets for the development of improved bone regeneration therapies.This work was funded by project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and AO Foundation-Switzerland (project S-15-83S). AMS, MIA, CC and JHT were supported by FCT-Fundação para a Ciência e a Tecnologia, through fellowships SFRH/BD/ 85968/2012, SFRH/BPD/91011/2012, SFRH/BDP/ 87071/2012 and SFRH/BD/112832/2015, respecttively. Work in Dr. Calin's laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NIH/NCI grant 1R01CA182905-01, a U54 grant-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Ladies Leukemia League grant, a CLL Moonshot Flagship project, a SINF 2017 grant, and the Estate of C. G. Johnson, J