Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.

Efeitos de um programa de exercício multimodal em pessoas idosas institucionalizadas

Objetivo: Investigar os efeitos de um programa de exercício multimodal sobre o funcionamento cognitivo e aptidão física funcional em pessoas idosas institucionalizadas. Método: Os participantes foram selecionados por conveniência entre os utentes de duas instituições de apoio a pessoas idosas. O grupo inicial foi constituído por um total de 21 pessoas de ambos os sexos (77-92 anos). Inicialmente, foi garantido um “período de controlo” de 4 semanas, em que os participantes mantiveram as suas atividades de vida quotidianas normais. Posteriormente, todos os idosos integraram um programa de exercício multimodal durante 8 semanas. Para estudar os efeitos da intervenção foram recolhidos dados em 3 momentos distintos: previamente ao período de controlo, após o período de controlo e no final do programa de intervenção. Foram efetuados testes físicos/motores, cognitivos e de dupla-tarefa (motor-cognitivo). Durante as sessões de exercício, alternaram-se períodos constituídos por tarefas motoras com períodos em que as tarefas motoras implicavam uma mobilização simultânea de recursos cognitivos. Resultados: A análise estatística dos dados recolhidos nos três momentos de avaliação, revelou efeitos positivos da intervenção ao nível da atenção, tempo de reação, força muscular, agilidade e capacidade cardiorrespiratória. Nos testes realizados em dupla-tarefa, foram encontradas melhorias no teste timed up and go, mas não se verificaram melhorias no teste de tempo de reação. A análise estatística dos dados recolhidos nos três momentos de avaliação, revelou efeitos positivos (p<0.05). da intervenção ao nível da atenção, tempo de reação, força muscular, agilidade e capacidade cardiorrespiratória. Nos testes realizados em dupla-tarefa, foram encontradas melhorias no teste timed up and go (p<0.05), mas não se verificaram melhorias no teste de tempo de reação. Conclusões: Um programa de exercícios multimodal induz melhorias no funcionamento cognitivo e motor de pessoas idosas institucionalizadas. É aconselhada a divulgação deste tipo de intervenção para pessoas idosas institucionalizadas; Effects of a Multimodal Exercise Program for Elderly Institutionalized Abstract: Objective: To investigate wthe effects of a multimodal exercise program on cognitive functioning and physical fitness of institutionalized elderly. Method: Participants were selected by convenience among two nursing home residents. Twenty-one people (77-92 years old) of both genders participated. During the first 4 weeks (control period), participants were not engaged in the exercise program and continue with their normal daily life activities. After the control period, the group was engaged in a multimodal exercise program for 8 weeks (2 times per week). To study the effects of a multimodal exercise program, data were collected at three different times: prior to the control period, after the control period, and at the end of the intervention. Several motor tests (physical fitness), cognitive tests and dual-tasks (motor-cognitive) were performed. The exercise sessions alternated between periods of motor taks and periods with motor plus cognitive tasks performed simultaneously. Results: The analysis of the data collected in the three moments of evaluation, show positive effects of the exercise program in cognitive dimensions (information processing speed and attention) and functional physical fitness components (muscle resistance, cardiorespiratory fitness and dynamic balance). In tests carried out in dual-task conditions, the exercise program promoted improvements in the timed up and go test (with mental calculations). Statistical analysis of the data collected at the three evaluation moments revealed positive effects (p <0.05). Of attention intervention, reaction time, muscle strength, agility and cardiorespiratory capacity. In the double-task tests, improvements were found in the timed up and go test (p <0.05), but there were no improvements in the reaction time test. Conclusions: The results of this study indicate that a multimodal exercise program can improve cognitive functioning and physical fitness in institutionalized older people. Thus, this type of intervention should be promoted among nursing home residents.

Emerging plant-based proteins: comparison from extraction to functional properties and food application

The increasing demand for alternatives to meat food products, which is linked to ethical and environmental reasons, highlights the necessity of using different protein sources. Plant proteins provide a valid option, thanks to the relative low costs, high availability and wide supply sources. The current process used to produce plant concentrates and isolates is the alkaline extraction followed by isoelectric precipitation. However, despite the high purity of the proteins, it presents some drawbacks. Innovative protein extraction processes are emerging, with the aim of reducing the environmental impact and the costs, as well as improving the functional properties. In this study, the traditional wet protein extraction and another simplified wet process were used to obtain protein-rich extracts out of different plants. The sources considered in the project were de-oiled sunflower and canola, chickpea, lentils, and the camelina meal, an emerging oleaginous seed interesting for its high content of omega 3. The extracts obtained from the two processes were then analysed for their capacities to hold water and fat, to form gel and a stable foam. Results highlighted strong differences concerning the protein content, yield and functionalities. The extracts obtained with the alkaline process confirmed the literature data about the four plant sources (sunflower, canola, chickpea and lentils) and allow to obtain a camelina concentrate with a protein content of 63 % and a protein recovery of 41 %. The second easiest process was not effective to obtain a protein enrichment in oleaginous sources, whereas an enrichment of 10 and 15 % was obtained in chickpea and lentils, respectively. The functional properties were also completely different: the easiest process produced protein ingredients completely water-soluble at pH 7, with a discrete foaming capacity compared to the extracts obtained with alkaline process. These characteristics could make these extracts suitable for the plant milk-analogue products.

Triple combination therapy in pulmonary arterial hypertension

Pulmonary arterial hypertension is a severe disease characterized by increasing in pulmonary vascular resistance leading to right ventricular failure and death. Currently available drugs for treatment of PAH act on three different pathways responsible of the pathogenesis of this disease: the endothelin pathway, the nitric oxide pathway and the prostacyclin pathway. The purpose of our study was to reassess our experience on the use of drugs that interact on the pathobiological line of prostacyclin so we retrospectively included all patients, referred to our center from February 1995 to December 2021, who received therapy with i.v. Epoprostenol, s.c. Treprostinil or oral Selexipag. Firstly, we observed that patients treated with Epoprostenol were significantly more compromised at baseline when compared to the two other groups and evaluating the effects of the three different drugs, it emerged that patients treated with Epoprostenol had significantly greater improvements in respect to those treated with Treprostinil and Selexipag. In the second part of our analysis we assessed the effects of these drugs when used as third line strategy in order to limit many confounding factors that could influence demographic, clinical and hemodynamic characteristics of patient populations. The differences emerged in exercise capacity and baseline hemodynamics reflect the fact that in our clinical practice, we add Epoprostenol as third line therapy in more compromised patients, Treprostinil in intermediate situations and Selexipag in less impaired conditions. Comparing the effects of treatments between baseline and first follow-up we noticed smaller benefits with Selexipag when compared with intravenous and subcutaneous strategies but it’s important to weight baseline patient’s differences. Our analysis confirmed clinical and functional benefits for the use of both prostacyclin analogues and prostacyclin receptor agonists in terms of improved functional class, six-minute walking distance and cardiopulmonary hemodynamics.

Confronto delle differenti strategie terapeutiche nei pazienti con cuore polmonare cronico tromboembolico

L'endoarteriectomia polmonare (PEA) rappresenta la terapia più efficace per il cuore polmonare cronico tromboembolico (CTEPH). Tuttavia, una quota sostanziale di pazienti sono non operabili ma hanno altre possibili strategie di trattamento: terapia medica e angioplastica polmonare(BPA). In questo studio abbiamo confrontato l'efficacia delle diverse strategie di trattamento del CTEPH nel mondo reale. Metodi: Sono stati inclusi tutti i pazienti con CTEPH riferiti al nostro centro. Abbiamo valutato l'efficacia della terapia medica a breve termine sui dati clinici, funzionali, capacità di esercizio e profilo emodinamico (indipendentemente dalle strategie di trattamento successive), l'efficacia di PEA e BPA (indipendentemente dalle strategie di trattamento precedenti/successive); Abbiamo inoltre riportato l'efficacia a lungo termine dei diversi trattamenti. Risultati: Sono stati inclusi in totale 467 pazienti (il 39% trattato solo con terapia medica, il 43% sottoposto a PEA, il 13% sottoposto a BPA e il 5% non ha ricevuto alcuna terapia). I pazienti trattati solo con terapia medica sono stati il gruppo più vecchio in termini di età, e confrontati rispetto ai pazienti sottoposti a PEA, mostravano minore capacità di esercizio, un profilo di rischio più elevato e minor miglioramento del profilo emodinamico, funzionale e della sopravvivenza. I pazienti sottoposti a BPA hanno avuto un miglioramento emodinamico inferiore rispetto ai pazienti sottoposti PEA, ma un miglioramento funzionale, dell'esercizio fisico e del profilo di rischio, e di sopravvivenza sovrapponibile ai pazienti sottoposti a PEA; la sopravvivenza è risultata migliore rispetto ai pazienti tsottoposti a sola terapia medica. Il gruppo di controllo storico di pazienti non trattati con alcuna terapia ha avuto la peggiore sopravvivenza. Conclusioni: Abbiamo confermato la superiorità della PEA rispetto a qualsiasi trattamento nei pazienti affetti da CTEPH, nei pazienti non operabili o con PH persistente/ricorrente dopo PEA, la BPA determina una prognosi migliore rispetto alla sola terapia medica.

The Effect Of Celastrol, A Triterpene With Antitumorigenic Activity, On Conformational And Functional Aspects Of The Human 90kda Heat Shock Protein Hsp90α, A Chaperone Implicated In The Stabilization Of The Tumor Phenotype.

Hsp90 is a molecular chaperone essential for cell viability in eukaryotes that is associated with the maturation of proteins involved in important cell functions and implicated in the stabilization of the tumor phenotype of various cancers, making this chaperone a notably interesting therapeutic target. Celastrol is a plant-derived pentacyclic triterpenoid compound with potent antioxidant, anti-inflammatory and anticancer activities; however, celastrol's action mode is still elusive. In this work, we investigated the effect of celastrol on the conformational and functional aspects of Hsp90α. Interestingly, celastrol appeared to target Hsp90α directly as the compound induced the oligomerization of the chaperone via the C-terminal domain as demonstrated by experiments using a deletion mutant. The nature of the oligomers was investigated by biophysical tools demonstrating that a two-fold excess of celastrol induced the formation of a decameric Hsp90α bound throughout the C-terminal domain. When bound, celastrol destabilized the C-terminal domain. Surprisingly, standard chaperone functional investigations demonstrated that neither the in vitro chaperone activity of protecting against aggregation nor the ability to bind a TPR co-chaperone, which binds to the C-terminus of Hsp90α, were affected by celastrol. Celastrol interferes with specific biological functions of Hsp90α. Our results suggest a model in which celastrol binds directly to the C-terminal domain of Hsp90α causing oligomerization. However, the ability to protect against protein aggregation (supported by our results) and to bind to TPR co-chaperones are not affected by celastrol. Therefore celastrol may act primarily by inducing specific oligomerization that affects some, but not all, of the functions of Hsp90α. To the best of our knowledge, this study is the first work to use multiple probes to investigate the effect that celastrol has on the stability and oligomerization of Hsp90α and on the binding of this chaperone to Tom70. This work provides a novel mechanism by which celastrol binds Hsp90α.

Relationship Between Lower-limb Muscle Strength And Functional Independence Among Elderly People According To Frailty Criteria: A Cross-sectional Study.

Muscle strength and functional independence are considered to be determinants of frailty levels among elderly people. The aim here was to compare lower-limb muscle strength (LLMS) with functional independence in relation to sex, age and number of frailty criteria, and to ascertain the influence of these variables on elderly outpatients' independence. Quantitative cross-sectional study, in a tertiary hospital. The study was conducted on 150 elderly outpatients of both sexes who were in a cognitive condition allowing oral communication, between October 2005 and October 2007. The following instruments were used: five-times sit-to-stand test (FTSST), Functional Independence Measurement (FIM) and Lawton's Instrumental Activities of Daily Living Scale (IADL). Descriptive, comparative, multivariate, univariate and Cronbach alpha analyses were performed. The mean time taken in the FTSST was 21.7 seconds; the mean score for FIM was 82.2 and for IADL was 21.2; 44.7% of the subjects presented 1-2 frailty criteria and 55.3% > 3 criteria. There was a significant association between LLMS and functional independence in relation to the number of frailty criteria, without homogeneity regarding sex and age. Functional independence showed significant influence from sex and LLMS. Elderly individuals with 1 or 2 frailty criteria presented greater independence in all FTSST scores. The subjects with higher LLMS presented better functional independence.

Cluster Analysis To Identify Elderly People's Profiles: A Healthcare Strategy Based On Frailty Characteristics.

The new social panorama resulting from aging of the Brazilian population is leading to significant transformations within healthcare. Through the cluster analysis strategy, it was sought to describe the specific care demands of the elderly population, using frailty components. Cross-sectional study based on reviewing medical records, conducted in the geriatric outpatient clinic, Hospital de Clínicas, Universidade Estadual de Campinas (Unicamp). Ninety-eight elderly users of this clinic were evaluated using cluster analysis and instruments for assessing their overall geriatric status and frailty characteristics. The variables that most strongly influenced the formation of clusters were age, functional capacities, cognitive capacity, presence of comorbidities and number of medications used. Three main groups of elderly people could be identified: one with good cognitive and functional performance but with high prevalence of comorbidities (mean age 77.9 years, cognitive impairment in 28.6% and mean of 7.4 comorbidities); a second with more advanced age, greater cognitive impairment and greater dependence (mean age 88.5 years old, cognitive impairment in 84.6% and mean of 7.1 comorbidities); and a third younger group with poor cognitive performance and greater number of comorbidities but functionally independent (mean age 78.5 years old, cognitive impairment in 89.6% and mean of 7.4 comorbidities). These data characterize the profile of this population and can be used as the basis for developing efficient strategies aimed at diminishing functional dependence, poor self-rated health and impaired quality of life.

[recommendations For Physical Exercise Practice During Pregnancy: A Critical Review].

Physical exercise is recommended for all healthy pregnant women. Regular practice of exercises during pregnancy can provide many physical and psychological benefits, with no evidence of adverse outcomes for the fetus or the newborn when exercise is performed at mild to moderate intensity. However, few pregnant women engage in this practice and many still have fears and doubts about the safety of exercise. The objective of the present study was to inform the professionals who provide care for Brazilian pregnant women about the current recommendations regarding physical exercise during pregnancy based on the best scientific evidence available. In view of the perception that few systematic models are available about this topic and after performing several studies in this specific area, we assembled practical information of interest to both the professionals and the pregnant women. We also provide recommendations about the indications, contraindications, modalities (aerobics, resistance training, stretching and pelvic floor training), frequency, intensity and duration indicated for each gestational trimester. The review addresses physical exercise recommendation both for low risk pregnant women and for special populations, such as athletes and obese, hypertensive and diabetic subjects. The advantages of an active and healthy lifestyle should be always reinforced during and after gestation since pregnancy is an appropriate period to introduce new habits because pregnant women are usually more motivated to adhere to recommendations. Thus, routine exams, frequent returns and supervision are recommended in order to provide new guidelines that will have long-term beneficial effects for both mother and child.

Leaf-, Panel- And Latex-expressed Sequenced Tags From The Rubber Tree (hevea Brasiliensis) Under Cold-stressed And Suboptimal Growing Conditions: The Development Of Gene-targeted Functional Markers For Stress Response.

Hevea brasiliensis is a native species of the Amazon Basin of South America and the primary source of natural rubber worldwide. Due to the occurrence of South American Leaf Blight disease in this area, rubber plantations have been extended to suboptimal regions. Rubber tree breeding is time-consuming and expensive, but molecular markers can serve as a tool for early evaluation, thus reducing time and costs. In this work, we constructed six different cDNA libraries with the aim of developing gene-targeted molecular markers for the rubber tree. A total of 8,263 reads were assembled, generating 5,025 unigenes that were analyzed; 912 expressed sequence tags (ESTs) represented new transcripts, and two sequences were highly up-regulated by cold stress. These unigenes were scanned for microsatellite (SSR) regions and single nucleotide polymorphisms (SNPs). In total, 169 novel EST-SSR markers were developed; 138 loci were polymorphic in the rubber tree, and 98 % presented transferability to six other Hevea species. Locus duplication was observed in H. brasiliensis and other species. Additionally, 43 SNP markers in 13 sequences that showed similarity to proteins involved in stress response, latex biosynthesis and developmental processes were characterized. cDNA libraries are a rich source of SSR and SNP markers and enable the identification of new transcripts. The new markers developed here will be a valuable resource for linkage mapping, QTL identification and other studies in the rubber tree and can also be used to evaluate the genetic variability of other Hevea species, which are valuable assets in rubber tree breeding.

Whole Cortical And Default Mode Network Mean Functional Connectivity As Potential Biomarkers For Mild Alzheimer's Disease.

The search for an Alzheimer's disease (AD) biomarker is one of the most relevant contemporary research topics due to the high prevalence and social costs of the disease. Functional connectivity (FC) of the default mode network (DMN) is a plausible candidate for such a biomarker. We evaluated 22 patients with mild AD and 26 age- and gender-matched healthy controls. All subjects underwent resting functional magnetic resonance imaging (fMRI) in a 3.0 T scanner. To identify the DMN, seed-based FC of the posterior cingulate was calculated. We also measured the sensitivity/specificity of the method, and verified a correlation with cognitive performance. We found a significant difference between patients with mild AD and controls in average z-scores: DMN, whole cortical positive (WCP) and absolute values. DMN individual values showed a sensitivity of 77.3% and specificity of 70%. DMN and WCP values were correlated to global cognition and episodic memory performance. We showed that individual measures of DMN connectivity could be considered a promising method to differentiate AD, even at an early phase, from normal aging. Further studies with larger numbers of participants, as well as validation of normal values, are needed for more definitive conclusions.

Volumetric Capnography For The Evaluation Of Chronic Airways Diseases.

Obstructive lung diseases of different etiologies present with progressive peripheral airway involvement. The peripheral airways, known as the silent lung zone, are not adequately evaluated with conventional function tests. The principle of gas washout has been used to detect pulmonary ventilation inhomogeneity and to estimate the location of the underlying disease process. Volumetric capnography (VC) analyzes the pattern of CO2 elimination as a function of expired volume. To measure normalized phase 3 slopes with VC in patients with non-cystic fibrosis bronchiectasis (NCB) and in bronchitic patients with chronic obstructive pulmonary disease (COPD) in order to compare the slopes obtained for the groups. NCB and severe COPD were enrolled sequentially from an outpatient clinic (Hospital of the State University of Campinas). A control group was established for the NCB group, paired by sex and age. All subjects performed spirometry, VC, and the 6-Minute Walk Test (6MWT). Two comparisons were made: NCB group versus its control group, and NCB group versus COPD group. The project was approved by the ethical committee of the institution. Statistical tests used were Wilcoxon or Student's t-test; P<0.05 was considered to be a statistically significant difference. Concerning the NCB group (N=20) versus the control group (N=20), significant differences were found in body mass index and in several functional variables (spirometric, VC, 6MWT) with worse results observed in the NCB group. In the comparison between the COPD group (N=20) versus the NCB group, although patients with COPD had worse spirometric and 6MWT values, the capnographic variables mean phase 2 slope (Slp2), mean phase 3 slope normalized by the mean expiratory volume, or mean phase 3 slope normalized by the end-tidal CO2 concentration were similar. These findings may indicate that the gas elimination curves are not sensitive enough to monitor the severity of structural abnormalities. The role of normalized phase 3 slope may be worth exploring as a more sensitive index of small airway disease, even though it may not be equally sensitive in discriminating the severity of the alterations.

Selection And Validation Of Reference Genes For Functional Studies In The Calliphoridae Family.

The genera Cochliomyia and Chrysomya contain both obligate and saprophagous flies, which allows the comparison of different feeding habits between closely related species. Among the different strategies for comparing these habits is the use of qPCR to investigate the expression levels of candidate genes involved in feeding behavior. To ensure an accurate measure of the levels of gene expression, it is necessary to normalize the amount of the target gene with the amount of a reference gene having a stable expression across the compared species. Since there is no universal gene that can be used as a reference in functional studies, candidate genes for qPCR data normalization were selected and validated in three Calliphoridae (Diptera) species, Cochliomyia hominivorax Coquerel, Cochliomyia macellaria Fabricius, and Chrysomya albiceps Wiedemann . The expression stability of six genes ( Actin, Gapdh, Rp49, Rps17, α -tubulin, and GstD1) was evaluated among species within the same life stage and between life stages within each species. The expression levels of Actin, Gapdh, and Rp49 were the most stable among the selected genes. These genes can be used as reliable reference genes for functional studies in Calliphoridae using similar experimental settings.

Acute Exercise Decreases Trb3 Protein Levels In The Hypothalamus Of Obese Rats.

To evaluate the effects of acute exercise on the TRB3 protein levels and interaction between TRB3/Akt proteins in the hypothalamus of obese rats. In addition, we evaluated the relationship between TRB3 and endoplasmic reticulum stress (ER stress) and verified whether an acute exercise session is able to influence these processes. In the first part of the study, the rats were divided into three groups: control (lean) - fed with a standard rodent chow, DIO - fed with a high fat diet and DIO submitted to a swimming acute exercise protocol (DIO-EXE). In the second part of the study, we used other three groups: control (lean) receiving an intracerebroventricular (i.c.v.) infusion of vehicle, lean receiving an i.c.v. infusion of thapsigargin, and lean receiving an i.c.v infusion of thapsigargin and performing an acute exercise session. Four hours after the exercise session, the food intake was measured and the hypothalamus was dissected and separated for subsequent protein analysis by immunoblotting and Real Time PCR. The acute exercise session reduced the TRB3 protein levels, disrupted the interaction between TRB3/Akt proteins, increased the phosphorylation of Foxo1 and restored the anorexigenic effects of insulin in the hypothalamus of DIO rats. Interestingly, the suppressive effects of acute exercise on TRB3 protein levels may be related, at least in part, to the decrease of ER stress (evaluated though pancreatic ER kinase phosphorylation - pPERK and C/EBP homologous protein - CHOP protein levels) in the hypothalamus. In conclusion, the reduction of hypothalamic TRB3 protein levels mediated by exercise may be associated with the reduction of ER stress. These data provided a new mechanism by which an acute exercise session improves insulin sensitivity in hypothalamus and restores food intake control in obesity.

Synaptic Rearrangement Following Axonal Injury: Old And New Players.

Following axotomy, the contact between motoneurons and muscle fibers is disrupted, triggering a retrograde reaction at the neuron cell body within the spinal cord. Together with chromatolysis, a hallmark of such response to injury is the elimination of presynaptic terminals apposing to the soma and proximal dendrites of the injured neuron. Excitatory inputs are preferentially eliminated, leaving the cells under an inhibitory influence during the repair process. This is particularly important to avoid glutamate excitotoxicity. Such shift from transmission to a regeneration state is also reflected by deep metabolic changes, seen by the regulation of several genes related to cell survival and axonal growth. It is unclear, however, how exactly synaptic stripping occurs, but there is substantial evidence that glial cells play an active role in this process. In one hand, immune molecules, such as the major histocompatibility complex (MHC) class I, members of the complement family and Toll-like receptors are actively involved in the elimination/reapposition of presynaptic boutons. On the other hand, plastic changes that involve sprouting might be negatively regulated by extracellular matrix proteins such as Nogo-A, MAG and scar-related chondroitin sulfate proteoglycans. Also, neurotrophins, stem cells, physical exercise and several drugs seem to improve synaptic stability, leading to functional recovery after lesion.