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Background Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse–remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis. Methods CSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student’s t test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches. Results Analysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain—containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease. Conclusions The model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.

Family tree depicting genetic and phenotypic status of the family members. [...]other neurological and systemic signs should carefully sought, as they can help to localise and narrow the differential diagnosis. [...]clinicians must take a clear and accurate personal, medical and family history and perform comprehensive physical and neurological examination. Table 1 The progressive myoclonic epilepsies (according to refs 3 8) Progressive myoclonic epilepsy Gene Inheritance pattern Unverricht-Lundborg disease CSTB Autosomal recessive Lafora body disease EPM2A or EPM2B (NHLRC1) Autosomal recessive Action myoclonus renal failure SCARB2 Autosomal recessive Progressive myoclonus epilepsy-ataxia syndrome PRICKLE1 Autosomal recessive North Sea progressive myoclonus epilepsy GOSR2 Autosomal recessive Myoclonus epilepsy and ragged-red fibres Various mtDNA point mutations Maternal Neuronal ceroid lipofuscinosis CLN1 to CLN14 Autosomal recessive DRPLA DRPLA Autosmal dominant Sialidosis NEU1 Autosomal recessive GM2 gangliosidosis (Tay-Sachs disease) HEXA, HEXB and GM2A Autosomal recessive Gaucher’s disease Numerous mutations Autosomal recessive Myoclonus epilepsy and ataxia due to pathogenic variants in the potassium channel KCNC1 Autosmal dominant DRPLA, dentatorubral–pallidoluysian atrophy.

Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD.

Positional vertigo poses a diagnostic challenge in people with multiple sclerosis (MS). The characteristics of positional nystagmus and its response to repositioning manoeuvres are usually sufficient to diagnose benign paroxysmal positional vertigo (BPPV). However, certain BPPV variants respond poorly to repositioning manoeuvres and their nystagmus pattern can resemble that of central positional vertigo caused by infratentorial demyelination. This diagnostic difficulty is particularly challenging if positional vertigo occurs during an MS relapse. We describe a woman with MS who developed a sixth nerve palsy and gaze-evoked nystagmus, caused by demyelination near or within areas classically involved in central positional vertigo. However, she also had positional vertigo from coincident BPPV (and not central positional vertigo). This was initially a treatment resistant-posterior semicircular canal cupulolithiasis but it later progressed to a posterior semicircular canal canalolithiasis, with symptoms promptly resolving after a repositioning manoeuvre.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

Background Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. Methods In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. Results We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1 H-spectroscopy primarily showed N -acetyl-aspartate reduction; 18 fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2 . Conclusions AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

•Observational, retrospective, multicenter study in 5 Hospital Centers in Portugal.•Inclusion criteria Wingerchuk 2006: 67 patients included (21 definite NMO; 46 NMOSD).•Demographic features were similar to other studies.•Concomitant autoimmune disease was significantly associated with AQP4-IgG positivity. Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the CNS. There have been few epidemiologic studies on NMO, none in Portugal. To analyze the clinical, biological and MRI characteristics from a cohort of Portuguese patients who fulfilled the Wingerchuk 2006 NMO/NMOSD criteria. To identify and characterize those who had concomitant autoimmune disease or circulating autoantibodies. We performed an observational, retrospective, multicenter study in 5 Hospital Centers in Portugal. Sixty-seven patients fulfilled the inclusion criteria. They were mainly Caucasian, 55 female. Median age at onset was 32.0 years and mean follow-up 7.4±6.0 years. Twenty-one patients were definite NMO and optic neuritis (ON) the most frequent initial presentation. Forty-six were classified as NMO spectrum disorders. The main subtypes were recurrent ON and single longitudinally extensive transverse myelitis. Twenty-four patients had positive AQP4-IgG. Twenty-three had other circulating autoantibodies. Fifteen out of 67 patients had concomitant autoimmune disease. There was a significant correlation between the presence of autoimmune disease and the positivity for AQP4-IgG. Five patients died, all definite NMO. This is the first study about this rare disease in Portugal. Demographic features were similar to other studies. The existence of concomitant autoimmune disease was significantly associated with seropositivity for AQP4-IgG.

Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD.

To investigate the relationship between social deprivation and the food environment. Furthermore, to evaluate if the food environment is associated with the prevalence of obesity among students in Brazilian public schools. Cross-sectional. For the classification of obesity, weight and height were measured, and the cut-off point of BMI-for-age Z-score >+2 was adopted. Social deprivation level was determined from the Health Vulnerability Index (HVI). To assess the food environment, the density of food establishments in urban residential areas was calculated. Associations between the food environment and the presence of obesity were estimated by binary logistic regression through a generalized estimating equations model. Juiz de Fora, Minas Gerais, Brazil. Children and adolescents (n 661) aged 7-14 years. The lowest social deprivation level showed a higher density of all types of establishments that sold predominantly unhealthy foods. An inverse association was found between the density of supermarkets and hypermarkets and the presence of obesity (OR=0·58; 95 % CI 0·36, 0·93). For the other categories of food retailers, no significant differences were found. The findings reinforce the need for public policies that promote equality in the food environments of the city. Also, further investigations into the influence of the presence of supermarkets on the nutritional status of children and adolescents are required.

To verify differences in the availability, variety, quality and price of unprocessed and ultra-processed foods in supermarkets and similar establishments in neighbourhoods with different social deprivation levels at Juiz de Fora, Minas Gerais, Brazil. Cross-sectional study. The Obesogenic Environment Study in São Paulo's Food Store Observation Tool (ESAO-S) was applied in thirty-three supermarket chains, wholesale and retail supermarkets. Fruits, vegetables and ultra-processed foods were available in almost all establishments, without differences according to Health Vulnerability Index (HVI; which varies from 0 to 1 point and the higher the worse; P > 0·05). Most establishments were concentrated in low vulnerability areas and offered healthy foods with greater variety and quality, despite higher prices. The Healthy Food Store Index (HFSI; which varies from 0 to 16 points and the higher the best) was calculated from the ESAO-S and the mean score was 8·91 (sd 1·51). The presence and variety of unprocessed foods count as positive points, as do the absence of ultra-processed products. When HFSI was stratified by HVI, low HVI neighbourhoods presented higher HFSI scores, compared with medium, high and very high HVI neighbourhoods (P = 0·001). Supermarkets and similar establishments are less dense in areas of greater social deprivation and have lower prices of healthy foods, but the variety and quality of those foods are worse, compared with areas of low vulnerability. We found worse HFSI for supermarkets located in areas with greater vulnerability. Those findings can guide specific public policies improving the urban food environment.