α-Synuclein Overexpression and the Microbiome Shape the Gut and Brain Metabolome in Mice.

Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.

A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.

Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.

Convergent pathways of the gut microbiota-brain axis and neurodegenerative disorders.

Recent research has been uncovering the role of the gut microbiota for brain health and disease. These studies highlight the role of gut microbiota on regulating brain function and behavior through immune, metabolic, and neuronal pathways. In this review we provide an overview of the gut microbiota axis pathways to lay the groundwork for upcoming sessions on the links between the gut microbiota and neurogenerative disorders. We also discuss how the gut microbiota may act as an intermediate factor between the host and the environment to mediate disease onset and neuropathology. Based on the current literature, we further examine the potential for different microbiota-based therapeutic strategies to prevent, to modify, or to halt the progress of neurodegeneration.

Altered stress responses in adults born by Caesarean section.

Birth by Caesarean-section (C-section), which increases the risk for metabolic and immune disorders, disrupts the normal initial microbial colonisation of the gut, in addition to preventing early priming of the stress and immune-systems.. Animal studies have shown there are enduring psychological processes in C-section born mice. However, the long-term impact of microbiota-gut-brain axis disruptions due to birth by C-section on psychological processes in humans is unknown. Forty age matched healthy young male university students born vaginally and 36 C-section delivered male students were recruited. Participants underwent an acute stressor, the Trier social stress test (TSST), during a term-time study visit. A subset of participants also completed a study visit during the university exam period, representing a naturalistic stressor. Participants completed a battery of cognitive tests and self-report measures assessing mood, anxiety, and perceived stress. Saliva, blood, and stool samples were collected for analysis of cortisol, peripheral immune profile, and the gut microbiota. Young adults born by C-section exhibit increased psychological vulnerability to acute stress and a prolonged period of exam-related stress. They did not exhibit an altered salivary cortisol awakening response to the TSST, but their measures of positive affect were significantly lower than controls throughout the procedure. Both C-section and vaginally-delivered participants performed equally well on cognitive assessments. Most of the initial effects of delivery mode on the gut microbiome did not persist into adulthood as the gut microbiota profile showed modest changes in composition in adult vaginally-delivered and C-sectioned delivered subjects. From an immune perspective, concentrations of IL-1ß and 1L-10 were higher in C-section participants. These data confirm that there is a potential enduring effect of delivery mode on the psychological responses to acute stress during early adulthood. The mental health implications of these observations require further study regarding policies on C-section use.

Outcomes of acute basilar artery occlusion-real-world experience in a middle-income country.

OBJECTIVES: Our goal was to describe outcomes in a single-center, real-world series of patients with acute basilar artery occlusion in a middle-income country. In addition, we assessed potential outcome predictors. MATERIAL AND METHODS: Data from 28 patients were retrospectively reviewed. The primary outcome was death until last follow-up. Other outcomes were rates of favorable outcome until last follow-up and rates of intracranial hemorrhage. Outcomes were compared in subgroups according to several variables, including reperfusion (REP group) or no reperfusion (NOREP group) interventions, with chi-squared, Fisher's exact test, or Mann-Whitney tests. RESULTS: The rate of overall intrahospital death was 46%. Death until last follow-up occurred in 8/17 (47%) in the REP and in 7/11 (63%) of the NOREP group. Favorable outcomes were observed in 35.7% of the patients: 8/17 (47%) in REP and in 2/11 (18.1%) in NOREP. NIH stroke scale scores were significantly lower in patients with favorable outcomes. Intracranial hemorrhage was observed in 6/28 (21.4%) of the patients (all in REP group). Twenty patients were treated with anticoagulants within the first 24 h. No hemorrhage was observed in those treated with enoxaparin, while three occurred in subjects treated with unfractionated heparin. CONCLUSION: Together with other series, our results underscore the relevance of NIH stroke scale at admission as a prognostic marker, the importance of reperfusion to improve outcomes, and the need of clinical trials to compare the impact of treatment with anticoagulants within first 24 h in basilar artery occlusion.

Early-life oxytocin attenuates the social deficits induced by caesarean-section delivery in the mouse.

The oxytocin (OXT) system has been strongly implicated in the regulation of social behaviour and anxiety, potentially contributing to the aetiology of a wide range of neuropathologies. Birth by Caesarean-section (C-section) results in alterations in microbiota diversity in early-life, alterations in brain development and has recently been associated with long-term social and anxiety-like behaviour deficits. In this study, we assessed whether OXT intervention in the early postnatal period could reverse C-section-mediated effects on behaviour, and physiology in early life and adulthood. Following C-section or per vaginum birth, pups were administered with OXT (0.2 or 2 µg/20 µl; s.c.) or saline daily from postnatal days 1-5. We demonstrate that early postnatal OXT treatment has long-lasting effects reversing many of the effects of C-section on mouse behaviour and physiology. In early-life, high-dose OXT administration attenuated C-section-mediated maternal attachment impairments. In adulthood, low-dose OXT restored social memory deficits, some aspects of anxiety-like behaviour, and improved gastrointestinal transit. Furthermore, as a consequence of OXT intervention in early life, OXT plasma levels were increased in adulthood, and dysregulation of the immune response in C-section animals was attenuated by both doses of OXT treatment. These findings indicate that there is an early developmental window sensitive to manipulations of the OXT system that can prevent lifelong behavioural and physiological impairments associated with mode of birth.

The gut microbiota-brain axis in behaviour and brain disorders.

In a striking display of trans-kingdom symbiosis, gut bacteria cooperate with their animal hosts to regulate the development and function of the immune, metabolic and nervous systems through dynamic bidirectional communication along the 'gut-brain axis'. These processes may affect human health, as certain animal behaviours appear to correlate with the composition of gut bacteria, and disruptions in microbial communities have been implicated in several neurological disorders. Most insights about host-microbiota interactions come from animal models, which represent crucial tools for studying the various pathways linking the gut and the brain. However, there are complexities and manifest limitations inherent in translating complex human disease to reductionist animal models. In this Review, we discuss emerging and exciting evidence of intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to neurological disorders. Continued advances from this frontier of biomedicine may lead to tangible impacts on human health.

Targeting the Gut Microbiota in Chagas Disease: What Do We Know so Far?

Chagas disease (CD) is a tropical and still neglected disease caused by Trypanosoma cruzi that affects >8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. T. cruzi infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to T. cruzi have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.

Enduring Behavioral Effects Induced by Birth by Caesarean Section in the Mouse.

Birth by Caesarean (C)-section impacts early gut microbiota colonization and is associated with an increased risk of developing immune and metabolic disorders. Moreover, alterations of the microbiome have been shown to affect neurodevelopmental trajectories. However, the long-term effects of C-section on neurobehavioral processes remain unknown. Here, we demonstrated that birth by C-section results in marked but transient changes in microbiome composition in the mouse, in particular, the abundance of Bifidobacterium spp. was depleted in early life. Mice born by C-section had enduring social, cognitive, and anxiety deficits in early life and adulthood. Interestingly, we found that these specific behavioral alterations induced by the mode of birth were also partially corrected by co-housing with vaginally born mice. Finally, we showed that supplementation from birth with a Bifidobacterium breve strain, or with a dietary prebiotic mixture that stimulates the growth of bifidobacteria, reverses selective behavioral alterations in C-section mice. Taken together, our data link the gut microbiota to behavioral alterations in C-section-born mice and suggest the possibility of developing adjunctive microbiota-targeted therapies that may help to avert long-term negative consequences on behavior associated with C-section birth mode.

Processo de esterilização sob a ótica dos profissionais do centro de material e esterilização / Sterilization process from the perspective of the professionals of the material and sterilization center / Procedimiento de esterilización bajo la óptica de los profesionales del centro de material y esterilización

Objetivo: Analisar o processo de trabalho dos profissionais de enfermagem atuantes no centro de material e esterilização (CME) acerca da esterilização de material cirúrgico. Método: Estudo descritivo, ancorado pela abordagem qualitativa e realizado com 11 profissionais de enfermagem do CME por meio de entrevista semiestruturada. Para avaliação dos dados, optou-se pela análise de conteúdo, modalidade temática transversal. Resultados: Os depoimentos apresentaram a descrição das etapas envolvidas no processo de esterilização, a relação com a segurança do paciente, as dificuldades no processo de trabalho e a educação permanente em saúde como meio possível de superar as dificuldades. Conclusão: Os trabalhadores têm conhecimento incipiente das etapas do processo de esterilização, com influência direta na segurança do paciente. Ações de gestão e de educação permanente em saúde são necessárias para garantir a qualidade do trabalho e possibilitar a redução de falhas nesse processo. Foram citadas, ainda, as dificuldades diárias encontradas pelo pessoal de enfermagem do CME.

Objective: To analyze the work process of nursing professionals working in the material and sterilization center (MSC) on the sterilization of surgical material. Method: A descriptive study, anchored by qualitative approach and carried out with 11 nursing professionals from MSC, through a semi-structured interview. In order to evaluate the data, content analysis was chosen, with transversal thematic modality. Results: The interviews presented the description of the steps involved in the sterilization process, the relationship with patient safety, difficulties in the work process, and permanent health education as a possible mean of overcoming difficulties. Conclusion: Workers have incipient knowledge of the steps of the sterilization process with a direct influence on patient safety. Management actions and permanent education in health are necessary to guarantee the quality of work and to enable the reduction of failures in the work process. The daily difficulties encountered by MSC nursing staff were also related.

Objetivo: Analizar el proceso de trabajo de los profesionales de enfermería actuantes en el CME sobre la esterilización de material quirúrgico. Método: Estudio descriptivo, anclado por el abordaje cualitativo y realizado con 11 profesionales de enfermería del CME, por medio de entrevista semiestructurada. Para la evaluación de los datos, se optó por el análisis de contenido, modalidad temática transversal. Resultados: Los testimonios presentaron la descripción de las etapas involucradas en el proceso de esterilización, la relación con la seguridad del paciente, las dificultades en el proceso de trabajo y la educación permanente en salud como medio posible de superar las dificultades. Conclusión: Los trabajadores tienen conocimiento incipiente de las etapas del proceso de esterilización con influencia directa en la seguridad del paciente. Las acciones de gestión y de educación permanente en salud son necesarias para garantizar la calidad del mismo y posibilitar la reducción de fallas en el proceso de trabajo. Aún se relacionó las dificultades diarias encontradas por el personal de enfermería del CME.

Early signs of colonic inflammation, intestinal dysfunction, and olfactory impairments in the rotenone-induced mouse model of Parkinson's disease.

The factors that trigger the pathophysiology of Parkinson's disease (PD) are unknown. However, it is suggested that environmental factors, such as exposure to pesticides, play an important role, in addition to genetic predisposition and aging. Early signs of PD can appear in the gastrointestinal (GI) tract and in the olfactory system, preceding the onset of motor impairments by many years. The present study assessed the effects of oral rotenone administration (30 mg/kg) in inducing GI and olfactory dysfunctions associated with PD in mice. Here we show that rotenone transiently increased myeloperoxidase activity within 24 h of administration. Leucocyte infiltration in the colon, associated with histological damage and disrupted GI motility, were observed following treatment with rotenone for 7 days. Moreover, 7 days of treatment with rotenone disrupted olfactory discrimination in mice without affecting social recognition ability. The presence of specific deficits in olfactory function occurred with a concomitant decrease in tyrosine hydroxylase-positive neurons and an increase in serotonin (5-hydroxytryptamine) turnover in the olfactory bulb. These findings suggest that in Swiss mice, exposure to rotenone induces GI and olfactory dysfunction involving immunological and neurotransmitter alterations, similar to early signs of PD. This provides further evidence for the involvement of the gut-brain axis in PD.

Strain differences in the susceptibility to the gut-brain axis and neurobehavioural alterations induced by maternal immune activation in mice.

There is a growing realization that the severity of the core symptoms of autism spectrum disorders and schizophrenia is associated with gastrointestinal dysfunction. Nonetheless, the mechanisms underlying such comorbidities remain unknown. Several genetic and environmental factors have been linked to a higher susceptibility to neurodevelopmental abnormalities. The maternal immune activation (MIA) rodent model is a valuable tool for elucidating the basis of this interaction. We induced MIA with polyinosinic-polycytidylic acid (poly I:C) at gestational day 12.5 and assessed behavioural, physiological and molecular aspects relevant to the gut-brain axis in the offspring of an outbred (NIH Swiss) and an inbred (C57BL6/J) mouse strain. Our results showed that the specific MIA protocol employed induces social deficits in both strains. However, alterations in anxiety and depression-like behaviours were more pronounced in NIH Swiss mice. These strain-specific behavioural effects in the NIH Swiss mice were associated with marked changes in important components of gut-brain axis communication: the endocrine response to stress and gut permeability. In addition, MIA-induced changes in vasopressin receptor 1a mRNA expression in the hypothalamus were observed in NIH Swiss mice only. Taken together, these data suggest that genetic background is a critical factor in susceptibility to the gut-brain axis effects induced by MIA.

In patients with suspected acute stroke, CT perfusion-based cerebral blood flow maps cannot substitute for DWI in measuring the ischemic core.

BACKGROUND: Neuroimaging may guide acute stroke treatment by measuring the volume of brain tissue in the irreversibly injured "ischemic core." The most widely accepted core volume measurement technique is diffusion-weighted MRI (DWI). However, some claim that measuring regional cerebral blood flow (CBF) with CT perfusion imaging (CTP), and labeling tissue below some threshold as the core, provides equivalent estimates. We tested whether any threshold allows reliable substitution of CBF for DWI. METHODS: 58 patients with suspected stroke underwent DWI and CTP within six hours of symptom onset. A neuroradiologist outlined DWI lesions. In CBF maps, core pixels were defined by thresholds ranging from 0%-100% of normal, in 1% increments. Replicating prior studies, we used receiver operating characteristic (ROC) curves to select thresholds that optimized sensitivity and specificity in predicting DWI-positive pixels, first using only pixels on the side of the brain where infarction was clinically suspected ("unilateral" method), then including both sides ("bilateral"). We quantified each method and threshold's accuracy in estimating DWI volumes, using sums of squared errors (SSE). For the 23 patients with follow-up studies, we assessed whether CBF-derived volumes inaccurately exceeded follow-up infarct volumes. RESULTS: The areas under the ROC curves were 0.89 (unilateral) and 0.90 (bilateral). Various metrics selected optimum CBF thresholds ranging from 29%-32%, with sensitivities of 0.79-0.81, and specificities of 0.83-0.85. However, for the unilateral and bilateral methods respectively, volume estimates derived from all CBF thresholds above 28% and 22% were less accurate than disregarding imaging and presuming every patient's core volume to be zero. The unilateral method with a 30% threshold, which recent clinical trials have employed, produced a mean core overestimation of 65 mL (range: -82-191), and exceeded follow-up volumes for 83% of patients, by up to 191 mL. CONCLUSION: CTP-derived CBF maps cannot substitute for DWI in measuring the ischemic core.

In Acute Stroke, Can CT Perfusion-Derived Cerebral Blood Volume Maps Substitute for Diffusion-Weighted Imaging in Identifying the Ischemic Core?

BACKGROUND AND PURPOSE: In the treatment of patients with suspected acute ischemic stroke, increasing evidence suggests the importance of measuring the volume of the irreversibly injured "ischemic core." The gold standard method for doing this in the clinical setting is diffusion-weighted magnetic resonance imaging (DWI), but many authors suggest that maps of regional cerebral blood volume (CBV) derived from computed tomography perfusion imaging (CTP) can substitute for DWI. We sought to determine whether DWI and CTP-derived CBV maps are equivalent in measuring core volume. METHODS: 58 patients with suspected stroke underwent CTP and DWI within 6 hours of symptom onset. We measured low-CBV lesion volumes using three methods: "objective absolute," i.e. the volume of tissue with CBV below each of six published absolute thresholds (0.9-2.5 mL/100 g), "objective relative," whose six thresholds (51%-60%) were fractions of mean contralateral CBV, and "subjective," in which two radiologists (R1, R2) outlined lesions subjectively. We assessed the sensitivity and specificity of each method, threshold, and radiologist in detecting infarction, and the degree to which each over- or underestimated the DWI core volume. Additionally, in the subset of 32 patients for whom follow-up CT or MRI was available, we measured the proportion of CBV- or DWI-defined core lesions that exceeded the follow-up infarct volume, and the maximum amount by which this occurred. RESULTS: DWI was positive in 72% (42/58) of patients. CBV maps' sensitivity/specificity in identifying DWI-positive patients were 100%/0% for both objective methods with all thresholds, 43%/94% for R1, and 83%/44% for R2. Mean core overestimation was 156-699 mL for objective absolute thresholds, and 127-200 mL for objective relative thresholds. For R1 and R2, respectively, mean±SD subjective overestimation were -11±26 mL and -11±23 mL, but subjective volumes differed from DWI volumes by up to 117 and 124 mL in individual patients. Inter-rater agreement regarding the presence of infarction on CBV maps was poor (kappa = 0.21). Core lesions defined by the six objective absolute CBV thresholds exceeded follow-up infarct volumes for 81%-100% of patients, by up to 430-1002 mL. Core estimates produced by objective relative thresholds exceeded follow-up volumes in 91% of patients, by up to 210-280 mL. Subjective lesions defined by R1 and R2 exceeded follow-up volumes in 18% and 26% of cases, by up to 71 and 15 mL, respectively. Only 1 of 23 DWI lesions (4%) exceeded final infarct volume, by 3 mL. CONCLUSION: CTP-derived CBV maps cannot reliably substitute for DWI in measuring core volume, or even establish which patients have DWI lesions.

[Growth of infants assisted in nursing appointments in childcare]. / Crescimento de lactentes atendidos na consulta de enfermagem em puericultura.

This study aimed to describe the growth during the introduction of complementary feeding to infants assisted in the nursing appointment in childcare. It is a descriptive, cross-sectional, quantitative study developed through research in 51 medical records of children aged 4-8 months, from September to October 2012 in a university hospital in the city of Recife, PE. Data were analyzed using Epi Info software, version 6.04 and described in simple and relative frequencies. It was found that for 33% of the children. complementary foods were introduced at six months. Of these, 88.2%, 69.2% and 57.1% showed ascending weight-for-age growth curves, and 88.2%, 66.7% and 71.4% ascending length-for-age growth curves at six, seven and eight months respectively. Children with appropriate and timely introduction of complementary feeding showed upward growth curves and adequate nutritional status.

Growth of infants assisted in nursing appointments in childcare / El crecimiento de los lactantes atendidos en consulta de enfermería en el cuidado de los niños / Crescimento de lactentes atendidos na consulta de enfermagem em puericultura

This study aimed to describe the growth during the introduction of complementary feeding to infants assisted in the nursing appointment in childcare. It is a descriptive, cross-sectional, quantitative study developed through research in 51 medical records of children aged 4-8 months, from September to October 2012 in a university hospital in the city of Recife, PE. Data were analyzed using Epi Info software, version 6.04 and described in simple and relative frequencies. It was found that for 33% of the children. complementary foods were introduced at six months. Of these, 88.2%, 69.2% and 57.1% showed ascending weight-for-age growth curves, and 88.2%, 66.7% and 71.4% ascending length-for-age growth curves at six, seven and eight months respectively. Children with appropriate and timely introduction of complementary feeding showed upward growth curves and adequate nutritional status.

Estudio tiene como objetivo describir el crecimiento durante la introducción de la alimentación complementaria en los niños tratados en la consulta de enfermería en el cuidado infantil. Estudio descriptivo, transversal, cuantitativo, desarrollado a través de la investigación de 51 casos de niños de cuatro a ocho meses, de septiembre a octubre de 2012, en un hospital universitario de la ciudad de Recife, PE. Los datos fueron analizados mediante Epi Info versión 6.04 y se describen en la frecuencia simple y relativa. Se encontró que 33% de los niños presentó alimentos complementarios a los seis meses. De estos, 88,2%, 69,2% y 57,1% fue la edad ascendente versus curvas de peso y 88,2%, 66,7% y 71,4% de largo versus edad ascendente en seis, siete y ocho meses respectivamente. Los niños que introducen correctamente la alimentación complementaria mostraron curvas de crecimiento al alza y un estado nutricional adecuado.

Estudo que objetivou descrever o crescimento durante a introdução da alimentação complementar em lactentes atendidos na consulta de Enfermagem em puericultura. Estudo descritivo, transversal, quantitativo, desenvolvido por meio de pesquisa em 51 prontuários de crianças de quatro a oito meses, no período de setembro a outubro de 2012, em um hospital universitário localizado na cidade de Recife, PE. Os dados foram analisados no Epi Info versão 6.04 e descritos em frequência simples e relativa. Verificou-se que 33% das crianças introduziram a alimentação complementar aos seis meses. Dessas, 88,2%, 69,2% e 57,1% apresentaram as curvas de peso por idade ascendentes, e 88,2%, 66,7% e 71,4% tiveram curvas de comprimento por idade ascendentes aos seis, sete e oito meses, respectivamente. Crianças com introdução correta da alimentação complementar apresentaram curvas de crescimento ascendentes e estado nutricional adequado.