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- Lipid Antigen Presentation by CD1b and CD1d in Lysosomal Storage Disease PatientsPublication . Pereira, C.; Pérez-Cabezas, B.; Ribeiro, H.; Maia, M.; Cardoso, M.; Dias, A.; Azevedo, O.; Ferreira, M.; Garcia, P.; Rodrigues, E.; Castro-Chaves, P.; Martins, Esmeralda; Aguiar, P.; Pineda, M.; Amraoui, Y.; Fecarotta, S.; Leão-Teles, E.; Deng, S.; Savage, P.; Macedo, M.The lysosome has a key role in the presentation of lipid antigens by CD1 molecules. While defects in lipid antigen presentation and in invariant Natural Killer T (iNKT) cell response were detected in several mouse models of lysosomal storage diseases (LSD), the impact of lysosomal engorgement in human lipid antigen presentation is poorly characterized. Here, we analyzed the capacity of monocyte-derived dendritic cells (Mo-DCs) from Fabry, Gaucher, Niemann Pick type C and Mucopolysaccharidosis type VI disease patients to present exogenous antigens to lipid-specific T cells. The CD1b- and CD1d-restricted presentation of lipid antigens by Mo-DCs revealed an ability of LSD patients to induce CD1-restricted T cell responses within the control range. Similarly, freshly isolated monocytes from Fabry and Gaucher disease patients had a normal ability to present α-Galactosylceramide (α-GalCer) antigen by CD1d. Gaucher disease patients' monocytes had an increased capacity to present α-Gal-(1-2)-αGalCer, an antigen that needs internalization and processing to become antigenic. In summary, our results show that Fabry, Gaucher, Niemann Pick type C, and Mucopolysaccharidosis type VI disease patients do not present a decreased capacity to present CD1d-restricted lipid antigens. These observations are in contrast to what was observed in mouse models of LSD. The percentage of total iNKT cells in the peripheral blood of these patients is also similar to control individuals. In addition, we show that the presentation of exogenous lipids that directly bind CD1b, the human CD1 isoform with an intracellular trafficking to the lysosome, is normal in these patients.
- Effects of a nursing care program on functional outcomes in older acute medical in-patients: protocol for a randomized controlled trialPublication . Rodrigues, Cecília; Mendonça, Denisa; Martins, Maria ManuelaBackground: Hospitalization often leads to long periods of bed rest and inactivity which is associated with an increase in length of hospital stay, loss of capacity for basic self-care and discharge into a nursing home. Objective: This trial aims to verify if a nursing care program centered on basic self-care and predefined physical activity, improves functional outcomes in older hospitalized patients. Methods: This is a 2-group randomized controlled trial with repeated measures: 182 older acute medical patients will be blindly randomly allocated to the control group (n = 91) or intervention group (n = 91). The intervention will consist of nursing care intervention centered on basic self-care that includes a twice daily walking training, plus privileging pre-established trips to the toilet by walking and all daytime meals seated, off the bed. The main outcome was changes in the number of independent activities of daily living from 2 weeks before admission (baseline) to discharge. Trial registration: ClinicalTrials.gov (Identifier NCT03106064). Results: This intervention has the potential to change the outcomes of the older patient in the acute setting. Conclusion: The loss of independence in self-care is determinant in future health care needs. If our hypothesis is correct and demonstrate that this nursing care program centered on basic self-care for older acute medical patients improves functional outcomes, a change in the paradigmatic organization of hospital care may be justifiable.
- Hemangioma of the Internal Auditory Canal and PHACES Syndrome: A Rare Finding in a Rare SyndromePublication . Santos, Mariline; Mendes, Gonçalo J.; Pinto, Ana N.; Coutinho, Miguel B.; Sousa, Cecília A.
- Gastroenteropancreatic Neuroendocrine Neoplasia Characterization in Portugal: Results from the NETs Study Group of the Portuguese Society of Endocrinology, Diabetes and MetabolismPublication . Santos, A.; Vinagre, J.; Soares, P.; Claro, I.; Sanches, A.; Gomes, L.; Fernandes, I.; Catarino, A.; Preto, J.; Pereira, B.; Marques, A.; Rodrigues, F.; Amaral, C.; Rocha, G.; Mellidez, J.; Simões, H.; Lopes, J.; Bugalho, M.Background: The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has been increasing in the last five decades, but there is no large-scale data regarding these tumours in Portugal. We conducted a cross-sectional, multicentric study in main Portuguese centers to evaluate the clinical, pathological, and therapeutic profile of GEP-NENs. Methods: From November, 2012, to July, 2014, data from 293 patients diagnosed with GEP-NENs from 15 centers in Portugal was collected and registered in an online electronic platform. Results: Median age at diagnosis was 56.5 (range: 15-87) years with a preponderance of females (54.6%). The most frequent primary sites were the pancreas (31.1%), jejunum-ileum (24.2%), stomach (13.7%), and rectum (8.5%). Data regarding hormonal status was not available in most patients (82.3%). Stratified by the tumour grade (WHO 2010 classification), we observed 64.0% of NET G1, 24.7% of NET G2, and 11.3% of NEC. Poorly differentiated tumours occurred mainly in older patients (p = 0.017), were larger (p < 0.001), and presented more vascular (p = 0.004) and lymphatic (p = 0.001) invasion. At the time of diagnosis, 44.4% of GEP-NENs presented metastatic disease. Surgery (79.6%) and somatostatin analogues (30.7%) were the most frequently used therapies of GEP-NENs with reported grading. Conclusion: In general, Portuguese patients with GEP-NENs presented similar characteristics to other populations described in the literature. This cross-sectional study represents the first step to establish a national database of GEP-NENs that may aid in understanding the clinical and epidemiological features of these tumours in Portugal. Methods: From November, 2012, to July, 2014, data from 293 patients diagnosed with GEP-NENs from 15 centers in Portugal was collected and registered in an online electronic platform. Results: Median age at diagnosis was 56.5 (range: 15-87) years with a preponderance of females (54.6%). The most frequent primary sites were the pancreas (31.1%), jejunum-ileum (24.2%), stomach (13.7%), and rectum (8.5%). Data regarding hormonal status was not available in most patients (82.3%). Stratified by the tumour grade (WHO 2010 classification), we observed 64.0% of NET G1, 24.7% of NET G2, and 11.3% of NEC. Poorly differentiated tumours occurred mainly in older patients (p = 0.017), were larger (p < 0.001), and presented more vascular (p = 0.004) and lymphatic (p = 0.001) invasion. At the time of diagnosis, 44.4% of GEP-NENs presented metastatic disease. Surgery (79.6%) and somatostatin analogues (30.7%) were the most frequently used therapies of GEP-NENs with reported grading. Conclusion: In general, Portuguese patients with GEP-NENs presented similar characteristics to other populations described in the literature. This cross-sectional study represents the first step to establish a national database of GEP-NENs that may aid in understanding the clinical and epidemiological features of these tumours in Portugal.
- Phakic Intraocular Lens Implantation After Deep Anterior Lamellar Keratoplasty: Retrospective Case Series Analysis With Long-Term Follow-UpPublication . Malheiro, Luisa; Coelho, João; Neves, Miguel Mesquita; Gomes, Miguel; OLIVEIRA, LUISPurpose: To report outcomes of phakic intraocular lens (IOL) implantation after deep anterior lamellar keratoplasty (DALK) to correct high ametropia. Setting: Centro Hospitalar Universitário do Porto, Portugal. Methods: Retrospective case series with 11 eyes submitted to phakic IOL implantation after DALK. Main outcomes measured were uncorrected and corrected distance visual acuity (UDVA and CDVA), refractive error components, tomographic parameters and endothelial cell density (ECD). The minimum follow-up was 3 years for all cases. Results: Mean ECD loss was 8.7±6.7% at 1 year, 13.1±8.6% at 3 years (n=11; p=0.016, p=0.007, respectively) and 14.0±20.4% at 5 years (n=5, p=0.212). Mean logMAR UDVA increased from 1.27±0.90logMAR preoperatively to 0.16±0.15logMAR postoperatively (p≤0.001) and no statistically significant differences were registered during follow-up. All patients gained at least 5 lines of UDVA. 54.5% of the eyes gained 1 line in CDVA postoperative and only one eye lost one CDVA line through follow-up. Efficacy and safety indexes at 1 and 3 years were 1.01-0.97 and 1.24-1.21, respectively. Mean spherical equivalent was reduced from -7.84±4.63 D preoperatively to -1.05±1.07 D postoperatively (p=0.001). Mean percentage of reduction in refractive cylinder and spherical error was 83.8±15.8% and 73.1±31.5%, respectively, p≤0.001 for both. In one eye there was a significantly gradual ECD loss over 5 years follow-up and the patient will be submitted to IOL explant. Conclusion: Phakic IOLs were effective for correction high ametropia after DALK, showing high efficacy and safety indexes with stability over time. However, it was registered a continuing endothelial cell loss postoperatively, which assumed to be higher than those reported in eyes without DALK.
- A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrilsPublication . Saelices, L.; Nguyen, B.; Chung, K.; Wang, Y.; Ortega, A.; Lee, J.; Coelho, T.; Bijzet, J.; Benson, M.; Eisenberg, D.The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloid-driving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach.
- [Evaluation of Bispectral Index time delay in response to anesthesia induction: an observational study]Publication . Ferreira, Ana Isabel Leitão; Mendes, Joaquim Gabriel; Nunes, Catarina Sofia; Amorim, PedroBackground and objectives: According to the manufacturer, the Bispectral Index (BIS) has a processing time delay of 5-10s. Studies addressing this have suggested longer delays. We evaluated the time delay in the Bispectral Index response. Methods: Based on clinical data from 45 patients, using the difference between the predicted and the real BIS, calculated during a fixed 3minutes period after the moment the Bispectral Index dropped below 80 during the induction of general anesthesia with propofol and remifentanil. Results: The difference between the predicted and the real BIS was in average 30.09±18.73s. Conclusion: Our results may be another indication that the delay in BIS processing may be much longer than stated by the manufacture, a fact with clinical implications.
- Real-world retrospective comparison of 0.19 mg fluocinolone acetonide and 0.7 mg dexamethasone intravitreal implants for the treatment of diabetic macular edema in vitrectomized eyesPublication . Coelho, João; Malheiro, Luisa; Melo Beirão, João; Meireles, Angelina; Pessoa, BernardetePurpose: The aim of this study was to evaluate the long-term real-world effectiveness of FAc and DEX implants in vitrectomized DME eyes in a real-world setting. Methods: This was a non-interventional, retrospective, comparative study of 46 vitrectomized eyes in 33 patients with persistent or recurrent DME quantified best-corrected visual acuity (BCVA), central foveal thickness (CFT) and intraocular pressure (IOP) over up to 37 months. Results: Both FAc and DEX treatment led to statistically and clinically significant improvements in BCVA and CFT. FAc >10-letter improvement on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart over months 3-24 and a sustained ~200 µm CFT reduction over months 1-24; DEX: >5-letter improvement on the ETDRS chart at months 1 and 3 and >100 µm CFT reduction at month 1. FAc demonstrated sustained, stable and predictable effects on BCVA and CFT over 24 months and also improved BCVA and decreased CFT in a cohort of DME eyes that was refractory to DEX over 6 months. Conclusion: This real-world study demonstrates long-term effectiveness of FAc in vitrectomized DME eyes and sustained effectiveness in DME eyes that did not respond to DEX therapy.
- Guselkumab for the treatment of psoriasis - evidence to datePublication . Nogueira, Miguel; Torres, T.Psoriasis is a chronic, immune-mediated, inflammatory, and debilitating skin disease with significant impact on patients' quality of life. Its pathogenesis is complex and not yet fully understood. However, the IL-23/IL-17 axis is currently considered the main pathogenic pathway in psoriasis. Guselkumab is a fully human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that binds to the p19 subunit of IL-23. It is the first of its class, already approved by the US Food and Drug Administration (FDA), as well as the European Medicines Agency (EMA) for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for either systemic therapy or phototherapy. Several clinical trials have demonstrated potential benefits of guselkumab over other already approved immunomodulators in terms of safety and efficacy. The results of the head-to-head trial ECLIPSE were recently released and are addressed in this review. They contribute to the increasing confidence in guselkumab, demonstrating great potential for long-term treatment of psoriasis. However, further long-term data and additional comparative studies will be essential for positioning guselkumab in the therapeutic armamentarium for psoriasis.
- Enzymatic vitreolysis for the treatment of tractional diabetic macular edemaPublication . Pessoa, Bernardete; Coelho, João; Coelho, Constança; Monteiro, Sílvia; Abreu, Carolina; Figueira, João; Meireles, Angelina; Beirão, JoãoBackground: A new approach to address focal vitreomacular adhesion in patients with diabetic macular edema may control and stabilize diabetic macular edema with fewer anti-vascular endothelial growth factor injections. Objectives: The aim of this study was to demonstrate that diabetic macular edema can be improved by inducing the release of a vitreomacular adhesion, with less than 2500 μm, with enzymatic vitreolysis. Methods: From a retrospective analysis of clinical records from patients with diabetic retinopathy, patients with diabetic macular edema and vitreomacular adhesion <2500 μm were selected for a single-arm prospective study. The primary endpoint was to control diabetic macular edema with fewer anti-vascular endothelial growth factor injections after an observed vitreomacular adhesion release. A statistical subanalysis was performed for the following two groups: the group with vitreomacular adhesion release (group 1) and the group without vitreomacular adhesion release (group 2). Results: A total of 23 eyes from 19 patients were included. A reduction of the median number of injections was achieved in group 1 (p = 0.006). Adverse events were mild and transitory. Conclusion: Release of vitreomacular adhesion <2500 μm through enzymatic vitreolysis contributed to the control and stabilization of diabetic macular edema with fewer anti-vascular endothelial growth factor injections, reducing the burden and the risks related to these invasive and frequently chronic treatments.