REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal.

BACKGROUND: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. METHODS: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. RESULTS: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. CONCLUSIONS: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.

Emerging responses to the COVID-19 crisis from family farming and the agroecology movement in Latin America - A rediscovery of food, farmers and collective action.

CONTEXT: In Latin America, the so-called informal sector associated with family farming and the agroecology movements were instrumental at coping with and adapting to the COVID-19 challenges. OBJECTIVE: To assess the nature and extent of the early initiatives (first three months) deployed by this informal sector to cope with and adapt to the impacts of the COVID-19 pandemic on food production and consumption in several countries of the region. METHODS: We used key used informant consultation (n = 168), an online survey (n = 125) and the detailed characterisation of regional case studies (n = 4). Textual data was analysed and categorised using Reinert's method, combined with similarity analysis. RESULTS AND CONCLUSIONS: 65% of the initiatives were 'local' in terms of geographic reach, 30% of them started within the first month after the pandemic and most of them were urban or urban-rural, whereas only 29% of them were exclusively rural. The analysis of the textual information captured through the survey revealed four major types of initiatives that were deployed or adapted in response to COVID-19:1.Direct producer-to-consumer food sales, generally existing before the COVID-19 crisis but adapted/strengthened to cope with it;2.Short value chains that linked rural and urban organisations and individuals supported by national or local governments, readapted through new health and safety protocols;3.Newly developed support and training programs on sustainable food production for self-consumption or local commerce, in rural, urban or peri-urban settings;4.Food assistance and aid initiatives focusing on vulnerable populations, relying on solidarity networks associated with the agroecological movement. SIGNIFICANCE: The pandemic highlighted the key role played by local food systems and value chains and the need to strengthening them through public policies, as a way to build food resilience in times of crisis.

Small for gestational age-cognitive performance from infancy to adulthood: an observational study.

OBJECTIVE: To determine whether cognitive performance from infancy to adulthood is affected by being born small for gestational age (SGA), and if this depends on the SGA reference used. Furthermore, to determine SGA's effect while considering the effects of very preterm/very low birthweight (VP/VLBW), socio-economic status (SES) and parent-infant relationship. DESIGN, SETTING AND POPULATION: A total of 414 participants (197 term-born, 217 VP/VLBW) of the Bavarian Longitudinal Study. METHODS: Small for gestational age was classified using neonatal or fetal growth references. SES and the parent-infant relationship were assessed before the infant was 5 months old. MAIN OUTCOME MEASURES: Developmental (DQ) and intelligence (IQ) tests assessed cognitive performance on six occasions, from 5 months to 26 years of age. RESULTS: The fetal reference classified more infants as SGA (<10th centile) than the neonatal reference (n = 138, 33% versus n = 75, 18%). Using linear mixed models, SGA was associated with IQ -8 points lower than appropriate for gestational age, regardless of reference used (95% CI -13.66 to -0.64 and 95% CI -13.75 to -1.98). This difference narrowed minimally into adulthood. Being VP/VLBW was associated with IQ -16 (95% CI -21.01 to -10.04) points lower than term-born participants. Low SES was associated with IQ -14 (95% CI -18.55 to -9.06) points lower than high SES. A poor parent-infant relationship was associated with IQ -10 points lower than those with a good relationship (95% CI -13.91 to -6.47). CONCLUSIONS: Small for gestational age is associated with lower IQ throughout development, independent of VP/VLBW birth, low SES or poor parent-child relationship. Social factors effects on IQ comparable to those of SGA and should be considered for interventions. TWEETABLE ABSTRACT: Small for gestational age is associated with lower cognitive performance from infancy to adulthood.

New species of the genus Spectracanthicus (Loricariidae, Hypostominae, Ancistrini) from the Rio Javaés (Rio Araguaia basin), with a description of gross brain morphology.

A new species of Spectracanthicus is described from the Rio Javaés, Rio Araguaia basin. The new species is distinguished from its congeners (except Spectracanthicus immaculatus) by colour pattern: body dark grey to dark brown without dots or blotches (v. body colour with yellowish small dots in Spectracanthicus murinus, Spectracanthicus punctatissimus and Spectracanthicus tocantinensis and large white dots in Spectracanthicus zuanoni). It can be further distinguished from S. immaculatus by having thicker and less numerous teeth, with up to eight premaxillary and 20 dentary teeth (v. teeth thinner and more numerous with up to 22 premaxillary and 30 dentary teeth); dorsal and caudal fins without curved spines (v. dorsal and caudal fins with curved spines). Other osteological characters can also diagnose the new species from its congeners. In addition, a gross brain description and brief comments on the new species' ecological habitat are given.

5-ALA-mediated photodynamic therapy reduces the parasite load in mice infected with Leishmania braziliensis.

Photodynamic therapy (PDT) has proven to be an effective alternative for the treatment of cutaneous leishmaniasis. Skin lesions consist of ulcers with well-defined raised edges, and granular floor. Th1 immune response is the protective profile in patients infected with Leishmania. In this study, the photodynamic therapy with 5-aminolevulinic acid, the parasitic load, and the modulation of the immune response was evaluated in mice infected with Leishmania braziliensis. Balb/c mice were infected with L. braziliensis and subsequently treated with three sections of PDT. The parasite load and mRNA expression of cytokines (IFN-γ, IL-4, IL-17, IL-22, IL-27, IL-10) and transcription factors (GATA-3, Foxp3 and T-bet) were analysed by quantitative PCR. The parasite load in the treated group was significantly lower than in the untreated group (P<.0001); in PDT treated animals, we observed an increase in IFN-γ and T-bet mRNA (P=.012 and P=.0071). There was a significant reduction in mRNA expression of IL-22 associated with an increased expression of IL-27 mRNA in the animals treated with light only (P=.0001). 5-ALA associated with photodynamic therapy promotes a reduction in parasite load and an increased expression of IFN-γ and T-bet mRNA.

Interference of single walled carbon nanotubes (SWCNT) in the measurement of lipid peroxidation in aquatic organisms through TBARS assay.

Nanomaterials (NM) exhibit unique properties due their size and relative area, but the mechanisms and effects in the living organisms are yet to be unfold in their totality. Potential toxicity mechanisms concerning NM as carbon nanotubes include oxidative stress generation. Several fluorimetric and colorimetric methods have been systematically used to measure NM toxicity, and controversial results have been reported. One of the problems can be related to the interference effects induced by NM, leading to artifacts that can lead to misleading conclusions. In present study, it was performed in vitro assays with two aquatic species: the zebrafish Danio rerio and the polychaete Laeonereis acuta to evaluate the potential interference capacity of single-wall carbon nanotubes (SWCNT) in a fluorometric method (TBARS assay) to measure lipid peroxidation. Obtained results indicated that gills and brain of zebrafish presented a lowered fluorescence only at extremely high concentrations (50 and 500mg/L). Determinations in anterior, middle, and posterior body regions of L. acuta showed a quite different pattern: high fluorescence at low SWCNT concentrations (0.5mg/L) and lowering at the highest (500mg/L). To eliminate matrix effect of biological samples, tests employing the standard for TBARS assay, 1,3,3-tetramethoxipropane, were run and the results showed again higher fluorescence values at low concentrations (0.5-5mg SWCNT/L), a technique artifact that could lead to misleading conclusions since higher fluorescence values implicate higher TBARS concentration, implying oxidative stress. Using the colorimetric FOX assay with cumene hydroperoxide as standard presented remarkable better results since no artifacts were observed in the same SWCNT concentration range that employed with the TBARS technique.

Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease.

Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.

Listeria monocytogenes isolates from food and food environment harbouring tetM and ermB resistance genes.

UNLABELLED: Listeria monocytogenes is a foodborne pathogen that has become an important cause of human and animal diseases worldwide. The purpose of this study was to evaluate the serotypes, virulence potential, antimicrobial resistance profile, and genetic relationships of 50 L. monocytogenes isolates from food and food environment in southern Brazil. In this study, the majority of L. monocytogenes isolates belonged to the serotypes 1/2b (42%) and 4b (26%), which are the main serotypes associated with human listeriosis. In addition, all isolates harboured internalin genes (inlA, inlC, inlJ), indicating a virulence potential. The isolates were sensitive to most of the antimicrobial compounds analysed, and five isolates (10%) were multi-resistant. Two isolates harboured antimicrobial resistance genes (tetM and ermB) and in one of them, the gene was present in the plasmid. Moreover, according to the pulsed field gel electrophoresis assay, two multi-resistant isolates were a single clone isolated from food and the processing plant. The isolates were susceptible to the most frequently used antibiotics for listeriosis treatment. However, the presence of multidrug-resistant isolates and antimicrobial resistance genes including in the plasmid could even be transferred between bacterial species, suggesting a potential health risk to consumers and a potential risk of spreading multi-resistance genes to other bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Listeria monocytogenes is an important agent of foodborne diseases. The results of this study suggest a potential capacity of L. monocytogenes isolates from food and food environment to cause human infections. Antimicrobial multi-resistance profiles were detected in 10%, and two isolates harboured tetM and ermB resistance genes. Moreover, the present research can help to build up a better knowledge about antimicrobial resistance of L. monocytogenes. Additionally, we found one isolate carrying tetM resistance gene in a plasmid, that suggests a possible transmission between commensal and/or other pathogenic bacteria of food environment, thereby raising up concerns regarding bacterial resistance.

Drosha, DGCR8, and Dicer mRNAs are down-regulated in human cells infected with dengue virus 4, and play a role in viral pathogenesis.

Dengue virus (DENV) and its four serotypes (DENV1-4) belong to the Flavivirus genus of the Flaviviridae family. DENV infection is a life-threatening disease, which results in up to 20,000 deaths each year. Viruses have been shown to encode trans-regulatory small RNAs, or microRNAs (miRNAs), which bind to messenger RNA and negatively regulate host or viral gene expression. During DENV infections, miRNAs interact with proteins in the RNAi pathway, and are processed by ribonucleases such as Dicer and Drosha. This study aims to investigate Drosha, DGCR8, and Dicer expression levels in human A-549 cells following DENV4 infection. DENV4 infected A-549 cells were collected daily for 5 days, and RNA was extracted to quantify viral load. Gene expression of Drosha, Dicer, and DGCR8 was determined using quantitative PCR (RT-qPCR). We found that DENV4 infection exhibited the highest viral load 3 days post-infection. Dicer, Drosha, and DGCR8 showed reduced expression following DENV4 infection as compared with negative controls. In addition, we hypothesize that reduced expression of DGCR8 may not only be related to miRNA biogenesis, but also other small RNAs. This study may change our understanding regarding the relationship between host cells and the dengue virus.

Injury of primary afferent neurons may contribute to osteoarthritis induced pain: an experimental study using the collagenase model in rats.

OBJECTIVE: Pain exacerbated by movement and loading on the joint is the major symptom of osteoarthritis (OA), but the mechanisms of chronic pain in this pathology are still poorly understood. Using the intra-articular (i.a.) injection of collagenase in the knee of rats as a model of OA, we aimed at evaluating whether injury of sensory neurons may contribute to the development of OA-associated nociception. DESIGN: OA was induced by i.a. injection of collagenase into the left knee joint of adult male Wistar rats. Histopathological changes and movement and loading-induced nociception were assessed for 6 weeks. A time-course analysis of the expression of the neuronal injury markers activating transcription factor-3 (ATF-3) and neuropeptide Y (NPY) and of the neuropeptide SP in the dorsal root ganglion (DRG) was performed. Gabapentin's effect on nociception was evaluated, as well as the expression of the α2δ-1 voltage-gated calcium channel subunit. RESULTS: Collagenase induced the development of OA-like histopathological changes and of movement-induced nociception. Altered expression of ATF-3, NPY and SP was observed in the DRG, correlating with the degree of articular degeneration after 6 weeks of disease progression. Repeated administration of gabapentin reversed the nociceptive responses 6 weeks after the induction of OA. α2δ-1 was upregulated in the DRG. CONCLUSION: By inducing nociceptive behaviours associated with relevant joint structural changes, the i.a. injection of collagenase presents itself as a pertinent model for the study of OA pain. The findings in this study support the hypothesis that injury of sensory neurons innervating OA joints may be a significant element in the mechanisms of OA-associated pain.

Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review.

Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed.

Comparison of moulting methods for layers: high-zinc diet versus fasting.

The serum biochemical profiles, thyroid hormones, body weights and the production and quality of eggs subsequent to moulting, were compared in laying hens subjected to conventional forced moulting or forced moulting with a diet high in zinc. A total of 200 Dekalb White laying hens in their second production cycle were studied. Blood sampling was conducted in a factorial experimental design (2 × 3) with two methods of moulting (fasting or zinc) and three sampling periods (pre-moult, moult and subsequent peak). Total egg protein content, including globulins, was greater with the zinc diet, whereas egg weight and albumen percentage were greater after fasting. The zinc method resulted in an increased shell thickness and calcium percentage but lower percentage of phosphorus. During the moulting period, the hens in the zinc group had heavier mean body weights. It was concluded that moulting with a high-zinc diet could replace fasting, without negative effects on body weight, biochemical variables or subsequent egg quality and production. The zinc method was also better for the birds' welfare.

Knowledge, attitudes and practices of cervical cancer screening among female students enrolled in higher education institutions in Cabo Verde.

Cervical cancer (CC) is the fourth most common cancer among women in the world and the second in Africa. CC is the third most frequent cancer and the first cause of cancer-related death among women in Cabo Verde, with an estimated incidence of 17 cases per 100,000 women. The mortality rate is around 10.5% and represents one of the largest percentages of all types of cancer diagnosed in women in the country. The high mortality rate can be explained by the absence of a national screening programme and a lack of human and physical resources. This study aims to determine the level of knowledge, attitudes and practices on CC among undergraduate female students in Cabo Verde in 2020. Methods: A descriptive cross-sectional study, using a self-administered structured questionnaire, was conducted in six higher education institutions (HEI) in Cabo Verde between November and December 2020. A total of 618 female undergraduate students were recruited using a simple random sampling technique. Descriptive statistical data analysis was used to report the results. Results: The response rate was 96.6% (n = 618). Most of the participants, 90.6% (549), were single, with average age of 21.79 years (SD =±4). Although most of the participants had already heard about CC (94.6%), most students showed a low knowledge about this disease (86.2%). Moreover, only 9.1% reported having been screened for CC. Conclusion: Most undergraduate female students enrolled in HEI in Cabo Verde have poor knowledge and unfavourable attitudes toward CC. The level of knowledge is quite unsatisfactory. Within this context, the implementation of health policies focused on human papillomavirus education, prevention strategies, and CC screening is crucial.

Production of polysaccharide from Agaricus subrufescens Peck on solid-state fermentation.

The interest upon products obtained from fungi has increased during the recent years. Among the most noticeable, nutraceuticals, enzymes, and natural drugs occupy a privileged position. Fungal biomass for the obtainment of those products can be produced either by solid-state fermentation (SSF) or submersed fermentation. SSF has been employed for the production of spawn on pretreated wheat grains with the objective of increasing the fungal polysaccharide (glucomannans) contents. Among the important factors for the production of spawn, time of cooking, time of resting after grain cooking, consequently grain moisture, substrate pH, temperature of incubation, and initial inoculum amount are among the most significant. For wheat grains, cooking time of 21 min followed by a 24-min resting time has been shown as optimal for the production of glucomannans by the fungus Agaricus subrufescens (=Agaricus brasiliensis). Amendments of CaSO(4) (up to 3 %) and CaCO(3) (up to 1 %) had an important influence on the substrate pH. In general, better results for glucomannan production were obtained when no supplement was added or when up to 0.25 % CaCO(3) (pH 6.6) has been added to the mix. Our results demonstrate that the inoculum amount necessary for the best polysaccharide levels is around 10.3 %, while the best temperature is around 27.2 °C. Besides using the spawn for its main purpose, it could potentially and alternatively be used as nutraceutical due to the high levels of glucomannan observed (6.89 %), a compound technically proven to be a potent immunostimulatory and antitumoral agent.

Anaesthesia in a parturient with systemic mastocytosis.

Mastocytosis is characterized by clonal expansion of mast cells, with abnormal accumulation in different organs. Perioperatively, numerous stimuli may lead to the release of vasoactive substances by mast cells. Parturients with systemic mastocytosis pose a challenge to the anesthesiologist: on one hand, the pain and stress of labor may lead to greater mast cell activation and, on the other, the administration of drugs that may possibly trigger the release of mast cell mediators. The authors describe a case of a 34-year-old pregnant woman with systemic mastocytosis who requests labor analgesia. An epidural analgesia was performed after induction of labor, after considering anesthetic particularities. The epidural procedure, labor and delivery were uneventful. A review of systemic mastocytosis is provided and its anesthetic considerations are discussed.

Anesthetic considerations in a laboring woman with systemic mastocytosis. / Consideraciones anestésicas en una parturienta con mastocitosis sistémica.

Mastocytosis is characterized by clonal expansion of mast cells, with abnormal accumulation in different organs. Perioperatively, numerous stimuli may lead to the release of vasoactive substances by mast cells. Parturients with systemic mastocytosis pose a challenge to the anesthesiologist: on one hand, the pain and stress of labor may lead to greater mast cell activation and, on the other, the administration of drugs that may possibly trigger the release of mast cell mediators. The authors describe a case of a 34-year-old pregnant woman with systemic mastocytosis who requests labor analgesia. An epidural analgesia was performed after induction of labor, after considering anesthetic particularities. The epidural procedure, labor and delivery were uneventful. A review of systemic mastocytosis is provided and its anesthetic considerations are discussed.

Detection of uncommon rotavirus A strains P[8]G8 and P[4]G8 in the city of Rio de Janeiro, 2002.

Group A rotaviruses (RV-A) are the major cause of gastroenteritis in infants and young children around the world. Each year RV-A causes approximately 11 million episodes of severe diarrhea, with an estimated of 611,000 deaths. Epidemiologic surveys have identified P[8]G1, P[4]G2, P[8]G3, P[8]G4, and P[8]G9 as the most common global genotypes associated with diarrhea in children up to 5-year old. Surveillance studies and documentation of RV-A G and P genotypes is necessary for a comprehensive evaluation of the evolution of new strains, and assessing the capability of vaccines to provide heterotypic protection. It is known that reassortments are the driving force for genetic diversity through sudden changes in RV-A genome. In this study, we identified two unusual P/G combinations, P[8]G8 and P[4]G8, occurring in Rio de Janeiro during 2002. Results obtained in this study suggest that P[8]G8 RV-A strain originated from a reassortment event that occurred between RV-A P[4]G8 and P[8]G9 strains circulating in Rio de Janeiro in the same year. G8 strains identified in this study, as well as G8 strains detected in Recife by Montenegro et al. [Montenegro et al. (2007) J Med Virol 79: 335-340], showed a close genetic relationship with strains from Africa, where this genotype have become prevalent.

Ventromedial medullary pathway mediating cardiac responses evoked from periaqueductal gray.

Periaqueductal gray (PAG) is a midbrain region that projects to areas controlling behavioral and autonomic outputs and is involved in the behavioral and physiological components of defense reactions. Since Raphe Pallidus (RPa) is a medial medullary region comprising sympathetic premotor neurons governing heart function, it is worth considering the PAG-RPa path. We assessed: i) whether PAG projects to RPa; ii) the amplitude of cardiac responses evoked from PAG; iii) whether cardiovascular responses evoked from PAG rely on RPa. Experiments conducted in Wistar rats (±300 g) were approved by Ethics Committee CEUA-UFG (092/18). Firstly, (n = 3), monosynaptic retrograde tracer Retrobeads was injected into RPa; PAG slices were analyzed. Other two groups (n = 6 each) were anesthetized with urethane (1.4 g/kg) and chloralose (120 mg/kg) and underwent craniotomy, tracheostomy, catheterization of femoral artery and vein and of cardiac left ventricle. In one group, we injected the GABAA receptor antagonist, bicuculline methiodide (BMI - 40 pmol/100 nL) into lateral/dorsolateral PAG. Another group was injected (100 nL) with the GABAA receptor agonist muscimol (20 mM) into RPa, 20 min before BMI into PAG. The results were: i) retrogradely labelled neurons were found in PAG; ii) PAG activation by BMI caused positive chronotropism and inotropism, which were accompanied by afterload increases; iii) RPa inhibition with Muscimol reduced heart rate, arterial and ventricular pressures; iv) the subsequent PAG activation still increased arterial pressure, cardiac chronotropy and inotropy, but these responses were significantly attenuated. In conclusion, PAG activation increases cardiac chronotropy and inotropy, and these responses seem to rely on a direct pathway reaching ventromedial medullary RPa neurons.