Browsing by Author "Maia, L."
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- A case of haemophagocytic syndrome presenting with oculogyric crisesPublication . Taipa, R.; Moreira, B.; França, M.; Maia, L.Haemophagocytic lymphohistiocytosis (HLH), also called haemophagocytic syndrome (HPS), is a rare disorder resulting in abnormal proliferation of histiocytes in tissues and organs, including the CNS. HLH can present as a primary disease or occur as a secondary reactive disease. Clinical features are high fever, splenomegaly, cytopenia of two or more cell lines, hypertriglyceridaemia and haemophagocytosis. CNS involvement varies between 10% and 73%, and clinical manifestations include seizures, decreased sensorium, brainstem symptoms, ataxia or demyelinating peripheral neuropathy.
- Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse modelsPublication . Maia, L.; Kaeser, S.; Reichwald, J.; Lambert, M.; Obermüller, U.; Schelle, J.; Odenthal, J.; Martus, P.; Staufenbiel, M.; Jucker, M.Abnormalities in brains of Alzheimer's disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this 'preclinical AD' stage relies on biomarkers such as decreased levels of the amyloid-β peptide (Aβ) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20-30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new 'preclinical AD' biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.
- Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathyPublication . Coelho, T.; Maia, L.; Martins-Silva, A.; Cruz, M.; Planté-Bordeneuve, V.; Suhr, O.; Conceição, I.; Schmidt, H.; Trigo, P.; Kelly, J.; Labaudinière, R.; Chan, J.; Packman, J.; Grogan, D.Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.
- Metabolic control of T cell immune response through glycans in inflammatory bowel diseasePublication . Dias, A.; Correia, A.; Pereira, M.; Almeida, C.; Alves, I.; Pinto, V.; Catarino, T.; Mendes, N.; Leander, M.; Oliva-Teles, M.; Maia, L.; Delerue-Matos, C.; Taniguchi, N.i; Lima, Margarida; Pedroto, I.; Marcos-Pinto, Ricardo; Lago, P.; Reis, C.; Vilanova, M.; Pinho, S.Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5-/-, MGAT5+/-) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.
- Superficial siderosis: a potential diagnostic marker of cerebral amyloid angiopathy in Alzheimer diseasePublication . Feldman, H.; Maia, L.; Mackenzie, I.; Forster, B.; Martzke, J.; Woolfenden, A.Abstract BACKGROUND AND PURPOSE: Superficial siderosis of the central nervous system results from chronic bleeding in the superficial layers of the cortex and spinal cord. In cerebral amyloid angiopathy (CAA), there is amyloid deposition in meningeal and meningo-cortical arteries and capillaries, predisposing them to rupture. CAA is frequently associated with Alzheimer disease (AD). METHODS: We report a series of 3 AD patients with MRI evidence of superficial siderosis. Two had neuropathological examination confirming superficial siderosis, AD, and CAA. CONCLUSIONS: Superficial siderosis should be recognized within the spectrum of AD with CAA and considered as a possible antemortem diagnostic feature.