The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

Linking centennial scale anthropogenic changes and sedimentary records as lessons for urban coastal management.

Coastal eutrophication and urban flooding are increasingly important components of global change. Although increased seawater renewal by barrier openings and channelizing are common mitigation measures in coastal lagoons worldwide, their effects on these ecosystems are not fully understood. Here, we evaluated the relationships between human interventions in the watershed, artificial connections to the sea, and the sediment burial rates in an urban coastal lagoon (Maricá lagoon, Southeastern Brazil). Sediment accretion along with nutrient and carbon burial rates were determined in two sediment cores representing the past ∼120 years (210Pb dating) and associated with anthropogenic changes as indicated by historical records and geoinformation analyses. Lagoon infilling and eutrophication, expressed by the average sediment accretion, TP, TN, and OC burial rates, respectively, increased ∼9-18, 13-15, 11-14 and 11-12-fold from the earliest (<1950) to the most recent (2000-2017) period. These multi-proxy records confirm mechanistic links between deforestation, urbanization, and untreated sewage discharges. In addition, our findings reveal artificial connections to the sea may contribute to lagoonal eutrophication and infilling, particularly when not integrated with sewage treatment and forest conservation or reforestation in the watershed. Therefore, increased seawater renewal by physical interventions commonly considered as mitigation measures may in contrast cause severe degradation in coastal lagoons, causing harmful consequences that should be not neglected when implementing management practices.

Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: A systematic review.

INTRODUCTION: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. METHODS: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. RESULTS: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. DISCUSSION: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. HIGHLIGHTS: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias.

Psychometric properties of the Infant Motor Profile (IMP): A scoping review protocol.

INTRODUCTION: The IMP is a novel video-based instrument to assess motor behavior of infants. It evaluates gross and fine motor behavior in five domains: variation, adaptability, symmetry, fluency, and performance. The latter assesses motor milestones, the other four domains assess qualitative aspects of movements. Literature suggests that it is a promising tool for pediatric health care, as its assists early detection of neurodevelopmental disorders and facilitates the design and monitoring of early intervention. This, this scoping review (ScR) aims to evaluate the psychometric properties of the Infant Motor Profile (IMP). MATERIAL AND METHODS: A systematic search will be conducted to identify relevant studies up to October 15, 2022. All papers published in English that evaluated or used the IMP in children under two years of age will be included. The search will be performed in Pubmed, Lilacs, PEDro, Scielo, CINAHL, Embase, Web of Science, Ovid PsycINFO, Cochrane Database of Systematic Reviews, as well as in gray literature sources following the University of Toronto library guidelines. Standardized data extraction forms (Excel Tables) will be used to collect information. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for the Scoping Reviews (PRISMA-ScR) Checklist and JBI guidelines will be taken into consideration for results analysis and reporting. DISCUSSION: This Scoping Review will summarize available knowledge on the psychometric properties of the IMP. By proving that IMP is a reliable tool, a valid predictor of neurodevelopmental outcomes and a responsive instrument to measure change induced by early intervention, this will facilitate the implementation of the IMP in pediatric health care. It will assist the detection of infants at high risk of neurodevelopmental disorders, and it will facilitate the design of the tailor-made early intervention. SCOPING REVIEW PROTOCOL REGISTRATION: This scoping review protocol has been registered at Open Science Framework (OSF) (https://doi.org/10.17605/OSF.IO/4HYKZ).

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Neonatal bed status in Brazilian maternity hospitals: an exploratory analysis. / Situação dos leitos neonatais em maternidades brasileiras: uma análise exploratória.

Neonatal units should be organized as a progressive care line, with intermediate and intensive care beds (conventional and kangaroo). The aim of this study was to evaluate the status and adequacy of neonatal beds in maternity hospitals linked to the 'Stork Network' ("Rede Cegonha"). A descriptive study was conducted in 606 maternity hospitals in all regions of Brazil. The databases used belonged to the Stork Network Evaluation Survey and the National Live Birth System. To assess the distribution of neonatal beds by typology, the parameters proposed in Ordinance N. 930/2012 of the Ministry of Health were used. Most neonatal units are not organized as a progressive care line with the three types of bed planned. Kangaroo intermediate care beds comprise the minority of implanted beds. There is a concentration of intensive and intermediate beds in the Southeast and South regions, which show a kangaroo intermediate care bed deficit. Analyzing the adequacy of beds by the number of live births, one can observe an inadequacy of Kangaroo care beds in all regions of Brazil, as well as intensive bed deficit in the North and Northeast regions, and adequacy of conventional intermediate care beds in all regions.

As unidades neonatais devem ser organizadas como uma linha de cuidados progressivos com leitos de cuidado intensivo e intermediário (convencional e canguru). O objetivo deste estudo foi avaliar a situação e a adequação dos leitos neonatais em maternidades da Rede Cegonha. Estudo descritivo, realizado em 606 maternidades em todas as regiões do Brasil. Os bancos de dados utilizados foram os da Avaliação da Atenção ao Parto e Nascimento em Maternidades da Rede Cegonha e do Sistema Nacional de Nascidos Vivos. Para avaliar a distribuição de leitos neonatais por tipologia, foram utilizados os parâmetros propostos na Portaria GM/MS nº 930/2012. A minoria das unidades se organiza como uma linha de cuidados progressiva com as três tipologias de leito previstas (24,42%). Os leitos de cuidado intermediário Canguru são a minoria dos leitos implantados (11,27%). Há uma concentração de leitos intensivos e intermediários nas regiões Sudeste e Sul, que apresentam déficit de leitos de cuidado intermediário Canguru. Ao analisar a adequação dos leitos pelo número de nascidos vivos, verifica-se inadequação dos leitos de cuidado Canguru em todas as regiões do Brasil, déficit de leitos intensivos nas regiões Norte e Nordeste e adequação de leitos de cuidado intermediário convencional em todas as regiões.

Situação dos leitos neonatais em maternidades brasileiras: uma análise exploratória / Neonatal bed status in Brazilian maternity hospitals: an exploratory analysis

Resumo As unidades neonatais devem ser organizadas como uma linha de cuidados progressivos com leitos de cuidado intensivo e intermediário (convencional e canguru). O objetivo deste estudo foi avaliar a situação e a adequação dos leitos neonatais em maternidades da Rede Cegonha. Estudo descritivo, realizado em 606 maternidades em todas as regiões do Brasil. Os bancos de dados utilizados foram os da Avaliação da Atenção ao Parto e Nascimento em Maternidades da Rede Cegonha e do Sistema Nacional de Nascidos Vivos. Para avaliar a distribuição de leitos neonatais por tipologia, foram utilizados os parâmetros propostos na Portaria GM/MS nº 930/2012. A minoria das unidades se organiza como uma linha de cuidados progressiva com as três tipologias de leito previstas (24,42%). Os leitos de cuidado intermediário Canguru são a minoria dos leitos implantados (11,27%). Há uma concentração de leitos intensivos e intermediários nas regiões Sudeste e Sul, que apresentam déficit de leitos de cuidado intermediário Canguru. Ao analisar a adequação dos leitos pelo número de nascidos vivos, verifica-se inadequação dos leitos de cuidado Canguru em todas as regiões do Brasil, déficit de leitos intensivos nas regiões Norte e Nordeste e adequação de leitos de cuidado intermediário convencional em todas as regiões.

Abstract Neonatal units should be organized as a progressive care line, with intermediate and intensive care beds (conventional and kangaroo). The aim of this study was to evaluate the status and adequacy of neonatal beds in maternity hospitals linked to the 'Stork Network' ("Rede Cegonha"). A descriptive study was conducted in 606 maternity hospitals in all regions of Brazil. The databases used belonged to the Stork Network Evaluation Survey and the National Live Birth System. To assess the distribution of neonatal beds by typology, the parameters proposed in Ordinance N. 930/2012 of the Ministry of Health were used. Most neonatal units are not organized as a progressive care line with the three types of bed planned. Kangaroo intermediate care beds comprise the minority of implanted beds. There is a concentration of intensive and intermediate beds in the Southeast and South regions, which show a kangaroo intermediate care bed deficit. Analyzing the adequacy of beds by the number of live births, one can observe an inadequacy of Kangaroo care beds in all regions of Brazil, as well as intensive bed deficit in the North and Northeast regions, and adequacy of conventional intermediate care beds in all regions.

Acometimento visceral e ocular simultâneo em infecção por toxocara canis acompanhado de farmacodermia / Concurrent visceral and ocular involvementin toxocara canis infection and pharmacodermia

A toxocaríase humana é uma infecção parasitária de distribuição mundial causada pelos nematelmintos das espécies Toxocara canis e Toxocara cati, presentes no intestino do cão e do gato, respectivamente. Clinicamente, na maioria das vezes, é assintomática, porém pode apresentar-se de duas formas: visceral ou ocular. Visceralmente, gera uma síndrome hipereosinofílica crônica, acompanhada por leucocitose e hepatomegalia, podendo ocorrer algum grau de infiltrado pulmonar e febre. Na toxocaríase ocular, ocorre uveite intermediária ou posterior, podendo haver formação de granuloma, geralmente unilateral. O acometimento misto é raro, o que motivou este relato. Trata-se de paciente de 19 anos, sexo masculino, que apresentou como sintoma inicial perda da acuidade visual em olho esquerdo. Recebeu tratamento, sem melhora, com sulfametoxazol + trimetoprima e corticoide, fazendo farmacodermia. Evoluiu com diarreia, febre, dor abdominal e hepatoesplenomegalia. Descartadas infecções agudas por toxoplasmose, sífilis, vírus da imunodeficiência humana (HIV), citomegalovirose e dengue; apresentou leucocitose com hipereosinofilia. Foi solicitada sorologia para toxocaríase, confirmando esta infecção. Após o tratamento, apresentou completa remissão dos sintomas. O objetivo aqui foi debater os fatores confundidores, diagnósticos diferenciais, necessidade de exames complementares específicos e conduta terapêutica, de acordo com o quadro clínico.(AU)

Human toxocariasis is a worldwide parasitic infection caused by ascarid nematodes species: Toxocara canis and Toxocara cati, that are present in the intestines of dogs and cats, respectively. Although clinically, most human infections are asymptomatic, two syndromes of human toxocariasis are recognized: visceral and ocular. The visceral form is a hypereosinophilic syndrome accompanied by leukocytosis, hepatomegaly, some degree of pulmonary infiltrate and fever. In ocular toxacariasis there is intermediate or posterior uveitis, and there may be granuloma formation, usually unilateral. The simultaneous involvement of the two forms is rare, which is what, motivated this report. It is a 19-year-old male patient who initially presented loss of visual acuity in the left eye. He received treatment, without improvement, with sulfamethoxazole-trimethoprim and corticoid, causing a pharmacodermia. He developed diarrhea, fever, abdominal pain and hepatosplenomegaly. It was discarded acute infections by toxoplasmosis, syphilis, human immunodeficiency virus (HIV), cytomegalovirus and dengue. The patient also manifested leukocytosis with hypereosinophilia. Serological testing for toxacariasis was requested, diagnosing the infection. After treatment, he progressed with full symptoms remission. The aim of this study was to discuss confounding factors, differential diagnoses, the need for specific complementary exams and therapeutic management, according to the clinical aspects.(AU)

New amphiphilic neamine derivatives active against resistant Pseudomonas aeruginosa and their interactions with lipopolysaccharides.

The development of novel antimicrobial agents is urgently required to curb the widespread emergence of multidrug-resistant bacteria like colistin-resistant Pseudomonas aeruginosa. We previously synthesized a series of amphiphilic neamine derivatives active against bacterial membranes, among which 3',6-di-O-[(2"-naphthyl)propyl]neamine (3',6-di2NP), 3',6-di-O-[(2"-naphthyl)butyl]neamine (3',6-di2NB), and 3',6-di-O-nonylneamine (3',6-diNn) showed high levels of activity and low levels of cytotoxicity (L. Zimmermann et al., J. Med. Chem. 56:7691-7705, 2013). We have now further characterized the activity of these derivatives against colistin-resistant P. aeruginosa and studied their mode of action; specifically, we characterized their ability to interact with lipopolysaccharide (LPS) and to alter the bacterial outer membrane (OM). The three amphiphilic neamine derivatives were active against clinical colistin-resistant strains (MICs, about 2 to 8 µg/ml), The most active one (3',6-diNn) was bactericidal at its MIC and inhibited biofilm formation at 2-fold its MIC. They cooperatively bound to LPSs, increasing the outer membrane permeability. Grafting long and linear alkyl chains (nonyl) optimized binding to LPS and outer membrane permeabilization. The effects of amphiphilic neamine derivatives on LPS micelles suggest changes in the cross-bridging of lipopolysaccharides and disordering in the hydrophobic core of the micelles. The molecular shape of the 3',6-dialkyl neamine derivatives induced by the nature of the grafted hydrophobic moieties (naphthylalkyl instead of alkyl) and the flexibility of the hydrophobic moiety are critical for their fluidifying effect and their ability to displace cations bridging LPS. Results from this work could be exploited for the development of new amphiphilic neamine derivatives active against colistin-resistant P. aeruginosa.