The evolving concept of multimorbidity and migraine.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

Ca2+ pushes and pulls energetics to maintain ATP balance in atrial cells: computational insights.

To maintain atrial function, ATP supply-to-demand matching must be tightly controlled. Ca2+ can modulate both energy consumption and production. In light of evidence suggesting that Ca2+ affects energetics through "push" (activating metabolite flux and enzymes in the Krebs cycle to push the redox flux) and "pull" (acting directly on ATP synthase and driving the redox flux through the electron transport chain and increasing ATP production) pathways, we investigated whether both pathways are necessary to maintain atrial ATP supply-to-demand matching. Rabbit right atrial cells were electrically stimulated at different rates, and oxygen consumption and flavoprotein fluorescence were measured. To gain mechanistic insight into the regulators of ATP supply-to-demand matching in atrial cells, models of atrial electrophysiology, Ca2+ cycling and force were integrated with a model of mitochondrial Ca2+ and a modified model of mitochondrial energy metabolism. The experimental results showed that oxygen consumption increased in response to increases in the electrical stimulation rate. The model reproduced these findings and predicted that the increase in oxygen consumption is associated with metabolic homeostasis. The model predicted that Ca2+ must act both in "push" and "pull" pathways to increase oxygen consumption. In contrast to ventricular trabeculae, no rapid time-dependent changes in mitochondrial flavoprotein fluorescence were measured upon an abrupt change in workload. The model reproduced these findings and predicted that the maintenance of metabolic homeostasis is due to the effects of Ca2+ on ATP production. Taken together, this work provides evidence of Ca2+ "push" and "pull" activity to maintain metabolic homeostasis in atrial cells.

Effects of Moderate-Intensity Physical Training on Skeletal Muscle Substrate Transporters and Metabolic Parameters of Ovariectomized Rats.

A deficit of estrogen is associated with energy substrate imbalance, raising the risk of metabolic diseases. Physical training (PT) is a potent metabolic regulator through oxidation and storage of substrates transported by GLUT4 and FAT CD36 in skeletal muscle. However, little is known about the effects of PT on these carriers in an estrogen-deficit scenario. Thus, the aim of this study was to determine the influence of 12 weeks of PT on metabolic variables and GLUT4 and FAT CD36 expression in the skeletal muscle of animals energetically impaired by ovariectomy (OVX). The trained animals swam 30 min/day, 5 days/week, at 80% of the critical load intensity. Spontaneous physical activity was measured biweekly. After training, FAT CD36 and GLUT4 expressions were quantified by immunofluorescence in the soleus, as well as muscular glycogen and triglyceride of the soleus, gluteus maximus and gastrocnemius. OVX significantly reduced FAT CD36, GLUT4 and spontaneous physical activity (p < 0.01), while PT significantly increased FAT CD36, GLUT4 and spontaneous physical activity (p < 0.01). PT increased soleus glycogen, and OVX decreased muscular triglyceride of gluteus maximus. Therefore, OVX can cause energy disarray through reduction in GLUT4 and FAT CD36 and their muscle substrates and PT prevented these metabolic consequences, masking ovarian estrogen's absence.

Pathophysiological Bases of Comorbidity in Migraine.

Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors.

Intense nocturnal warming alters growth strategies, colouration and parasite load in a diurnal lizard.

In the past decades, nocturnal temperatures have been playing a disproportionate role in the global warming of the planet. Yet, they remain a neglected factor in studies assessing the impact of global warming on natural populations. Here, we question whether an intense augmentation of nocturnal temperatures is beneficial or deleterious to ectotherms. Physiological performance is influenced by thermal conditions in ectotherms and an increase in temperature by only 2°C is sufficient to induce a disproportionate increase in metabolic expenditure. Warmer nights may expand ectotherms' species thermal niche and open new opportunities for prolonged activities and improve foraging efficiency. However, increased activity may also have deleterious effects on energy balance if exposure to warmer nights reduces resting periods and elevates resting metabolic rate. We assessed whether warmer nights affected an individual's growth, dorsal skin colouration, thermoregulation behaviour, oxidative stress status and parasite load by exposing yearling common lizards (Zootoca vivipara) from four populations to either ambient or high nocturnal temperatures for approximately 5 weeks. Warmer nocturnal temperatures increased the prevalence of ectoparasitic infestation and altered allocation of resources towards structural growth rather than storage. We found no change in markers for oxidative stress. The thermal treatment did not influence thermal preferences, but influenced dorsal skin brightness and luminance, in line with a predicted acclimation response in colder environments to enhance heat gain from solar radiation. Altogether, our results highlight the importance of considering nocturnal warming as an independent factor affecting ectotherms' life history in the context of global climate change. ​.

Sub-lethal doses of polybrominated diphenyl ethers affect some biomarkers involved in energy balance and cell cycle, via oxidative stress in the marine fish cell line SAF-1.

Polybrominated diphenyl ethers (PBDEs) are a class of persistent contaminants which are found all over the world in the marine environment. Sparus aurata fibroblast cell line (SAF-1) was exposed to increasing concentrations of PBDEs 47 and 99, until 72 h to evaluate the cytotoxicity, reactive oxygen species (ROS) production and the expression of some selected molecular markers related to cell cycle, cell signaling, energetic balance and oxidative stress (p53, erk-1, hif-1α and nrf-2), by real-time PCR. Furthermore, SAF-1 cells were exposed for 7 and 15 days to sub-lethal concentrations, in order to evaluate the response of some biomarkers by immunoblotting (p53, ERK-1, AMPK, HIF-1α and NRF-2). After 48 and 72 h, the cells showed a significant decrease of cell vitality as well as an increase of intracellular ROS production. Gene expression analysis showed that sub-lethal concentrations of BDE-99 and 47, after 72 h, up-regulated cell cycle and oxidative stress biomarkers, although exposure to 100 µmol L-1 down-regulated the selected markers related to cell cycle, cell signaling, energetic balance. After 7 and 15 days of sub-lethal doses exposure, all the analyzed markers resulted affected by the contaminants. Our results suggest that PBDEs influence the cells homeostasis first of all via oxidative stress, reducing the cell response and defense capacity and affecting its energetic levels. This situation of stress and energy imbalance could represents a condition that, modifying some of the analyzed biochemical pathways, would predispose to cellular transformation.

Ecotoxicological evaluation of gilthead seabream (Sparus aurata) exposed to the antibiotic oxytetracycline using a multibiomarker approach.

Oxytetracycline (OTC) is an antibiotic widely used in human and veterinary medicines. Since the primary toxicity occurs mainly at molecular/biochemical levels, the study of different biological responses corresponds to a sensitive and crucial approach. The aim of the present study was to assess the toxic effects of OTC in gilthead seabream (Sparus aurata) through the use of multibiomarkers and elucidate about the possible toxicological mechanisms involved. S. aurata were acutely (96 h: 0.04-400 µg/L) and chronically (28 days: 0.0004-4 µg/L) exposed to OTC. Detoxification, antioxidant defense, lipid peroxidation, genotoxicity, neurotransmission and energy metabolism biomarkers were evaluated. OTC impaired the detoxification pathways and caused peroxidative damage and genotoxicity. The relevance of the here-obtained data is high, since significant effects were recorded for levels already reported to occur in the wild, meaning that environmentally-exposed marine organisms (including those cultured at fish farms) are not completely exempt of risks posed by OTC.

Salinity stress from the perspective of the energy-redox axis: Lessons from a marine intertidal flatworm.

In the context of global change, there is an urgent need for researchers in conservation physiology to understand the physiological mechanisms leading to the acquisition of stress acclimation phenotypes. Intertidal organisms continuously cope with drastic changes in their environmental conditions, making them outstanding models for the study of physiological acclimation. As the implementation of such processes usually comes at a high bioenergetic cost, a mitochondrial/oxidative stress approach emerges as the most relevant approach when seeking to analyze whole-animal responses. Here we use the intertidal flatworm Macrostomum lignano to analyze the bioenergetics of salinity acclimation and its consequences in terms of reactive oxygen/nitrogen species formation and physiological response to counteract redox imbalance. Measures of water fluxes and body volume suggest that M. lignano is a hyper-/iso-regulator. Higher salinities were revealed to be the most energetically expensive conditions, with an increase in mitochondrial density accompanied by increased respiration rates. Such modifications came at the price of enhanced superoxide anion production, likely associated with a high caspase 3 upregulation. These animals nevertheless managed to live at high levels of environmental salinity through the upregulation of several mitochondrial antioxidant enzymes such as superoxide dismutase. Contrarily, animals at low salinities decreased their respiration rates, reduced their activity and increased nitric oxide formation, suggesting a certain degree of metabolic arrest. A contradictory increase in dichlorofluorescein fluorescence and an upregulation of gluthathione-S-transferase pi 1 (GSTP1) expression were observed in these individuals. If animals at low salinity are indeed facing metabolic depression, the return to seawater may result in an oxidative burst. We hypothesize that this increase in GSTP1 could be a "preparation for oxidative stress", i.e. a mechanism to counteract the production of free radicals upon returning to seawater. The results of the present study shed new light on how tolerant organisms carry out subcellular adaptations to withstand environmental change.

Demanda energética de diferentes manejos de solo no cultivo de milho / Energy demand of different soil managments in corn crop

O balanço energético permite identificar as possíveis entradas e saídas de energia no processo de produção, resultando no saldo energético final do processo produtivo. O objetivo do presente trabalho foi avaliar os fluxos de energia de diferentes sistemas de cultivo para produção de milho na região de Lavras-MG. Foi realizado o estudo da eficiência energética e o balanço energético quantificando-se o coeficiente energético de cada componente envolvido no processo de produção e se determinaram as matrizes de consumo energético nas formas de insumos, mão-de-obra, equipamentos, produção de grãos e restos culturais. Foi utilizado o delineamento de blocos casualizados com quatro repetições, onde os tratamentos eram constituídos pelos sistemas de manejo de solo. Para os dados das entradas e saídas de energia, balanço energético e a eficiência, os mesmos quando significativos foram submetidos ao teste de comparação de média Scot-Knott a 5 % de probabilidade. Os resultados indicaram que a contribuição do dispêndio energético dos fertilizantes, herbicidas e combustíveis foi determinante para o elevado consumo energético dos sistemas de cultivo estudados, sendo o efeito contrario para as energias referentes às fontes de origem biológica. Para as condições do presente experimento, dentre os sistemas de condução avaliados, do ponto de vista energético os sistemas de plantio direto, cultivo mínimo e convencional apresentaram o mesmo desempenho.

The energetic balance permits to identify all the possible energy inputs and outputs in the production system, resulting in the final energetic balance of the productive process. The aim of this study was to evaluate the energy flows of different crop systems for maize production in Lavras-MG. A study of energy efficiency and energy balance was conducted, quantifying the energy ratio of each component involved in the production process and determined the matrices in the forms of energy inputs, labor, equipment, grain and debris cultural. A randomized block design was used with four replications, where treatments were made by the studied treatments. For data inputs and outputs of energy, energy balance and efficiency, they were significant when tested for comparison of average Scot-Knott at 5% probability. The results indicated the contribution of energy expenditure of fertilizers, herbicides and fuel was crucial to the energy intensive farming systems studied, the opposite effect to the energies related to sources of biological origin. For the conditions of this experiment, among the conducted systems evaluated from the point of view of energy systems of tillage, minimum tillage and conventional showed the same performance.

Autophagy in the control of food intake.

The cellular nutrient sensing apparatus detects nutritional depletion and transmits this information to downstream effectors that generate energy from alternate sources. Autophagy is a crucial catabolic pathway that turns over redundant cytoplasmic components in lysosomes to provide energy to the starved cell. Recent studies have described a role for hypothalamic autophagy in the control of food intake and energy balance. Activated autophagy in hypothalamic neurons during starvation mobilized neuron-intrinsic lipids to generate free fatty acids that increased AgRP levels. AgRP neuron-specific inhibition of autophagy decreased fasting-induced increases in AgRP levels and food intake. Deletion of autophagy in AgRP neurons led to constitutive increases in levels of proopiomelanocortin and its active processed product, α-melanocyte stimulating hormone that contributed to reduced adiposity in these rodents. The current manuscript discusses these new findings and raises additional questions that may help understand how hypothalamic autophagy controls food intake and energy balance. These studies may have implications for designing new therapies against obesity and insulin resistance.

Influencia del mérito genético para la producción de leche en un hato holstein sobre el balance energético, indicadores del metabolismo energético y la reactivación ovárica posparto / Influence of genetic merit for milk production of a holstein herd, on energy balance, metabolic profiles and the postpartum ovarian resumption

El propósito de este trabajo fue determinar la influencia del mérito genético para la producción de leche sobre el balance energético, los indicadores del metabolismo energético y la reactivación ovárica posparto. Para este estudio, se utilizaron 10 vacas Holstein puras de diferente mérito genético para la producción de leche, que se alimentan bajo un sistema de pastoreo rotacional con suplementación de concentrado. A estos animales se les realizó un seguimiento durante los 10.4 (± 2.5), 21.6 (± 4.3), 31.8(± 4.5), 42.3 (± 4.2), y 51.9 (± 3.9) días posparto, los cuales constituyeron los periodos de muestreo. En cada muestreo, los animales fueron pesados con cinta métrica, se les evaluó la con se estimó su balance de energía. Además, se tomaron muestras de suero sanguíneo para evaluar las concentraciones de glucosa y colesterol; y se efectuó un seguimiento de la reactivación ovárica por ultrasonografía. La mayoría de las vacas reiniciaron su actividad ovárica en la segunda semana posparto y más de la mitad presentaron su primera ovulación durante el periodo experimental. Se encontró una relación estadísticamente significativa (p<0.05) y con pendiente negativa entre el mérito genético para la producción de leche y la magnitud del nadir del BEN, sin embargo el mérito genético no tuvo influencia significativa sobre los días al nadir del BEN, dado que las vacas de mérito genético alto, como bajo incrementaron el consumo y la producción de leche siguiendo patrones similares, pero con magnitudes diferentes. De igual forma el merito genético no se relacionó significativamente con los días a la primera ovulación. Además, ninguna de las variables del balance de energía, ni los metabolitos sanguíneos afectaron los días a la primera ovulación o el número de folículos clasificados por tamaño.

The aim of this research was to establish the genetic merit for milk yield influence on energy balance, energy metabolic profiles and the postpartum ovarian resumption. In this research, 10 pure-Holstein Friesian dairy cows, varying in genetic merit values for milk yield and fed on a rotational-grazing system with a supplementary concentrate ration were used. A serial of examinations were performed on10.4 (± 2.5), 21.6 (± 4.3), 31.8 (± 4.5), 42.3 (± 4.2), and 51.9 (± 3.9) postpartum days. In every sampling day animals were weighed by tape measure, their body condition score were calculated and the energy balance was estimated for every cow. In addition, blood serum tests were performed to analyze glucose and cholesterol blood concentration and an ultrasonographic assessment was executed to determine ovarian resumption. Nearly all cows had an ovarian resumption on the second week postpartum and more than a half had shown their first postpartum ovulation on the trial period. The genetic merit values for milk yield were not related with production values, therefore, the dependent variables of milk yield did not fluctuated with genetic merit. There was a significant negative relationship (p<0.05) between genetic merit for milk production and the nadir extent of net energy balance (NEB). Although, the genetic merit did not have significant influence on the number of days between calving to the nadir-attaining day, because high genetic merit cows as low genetic merit cows increased the intake and milk yield following similar patterns, but with different extents. In the same way, the genetic merit did not have significant relationship with the interval of calving to first ovulation. Furthermore, no one of the energy balance variables or blood metabolites influenced the interval of calving to first ovulation or the amount of follicles classified by size.

Avaliação do estado nutricional e do balanço energético de um grupo de atletas de ginástica artística / Evaluation of nutritional status and energetic balance of artistic gymnasts

O presente estudo teve por objetivo avaliar o estado nutricional de um grupo de atletas de ginástica artística. Participaram do estudo 14 atletas, com idade entre 11 e 15 anos, classificadas, de acordo com os critérios estabelecidos pela OMS (1995), como pré-puberes. Foram avaliados: massa corporal, estatura, e calculado o IMC (índice de massa corporal). A composição corporal foi avaliada a partir de bioimpedância elétrica (Biodynamics, 450e). O gasto energético de repouso (GER) e o gasto energético diário foram analisados por calorimetria indireta (VO2000- Inbrasport) adicionada do fator atividade (diário de atividade física). A partir de três diários alimentares foi calculada a ingestão de: energia (Kcal), macronutrientes (g), fibras (g), ferro (mg), cálcio (mg) e vitamina C. Algumas variáveis foram correlacionadas a partir do coeficiente de Pearson (p<0,05). Principais resultados: IMC = 15,85 ± 1,39Kg/m2; gordura corporal= 11,64 ± 3,16 e massa magra corporal= 27,06 ± 5,14Kg. Os valores obtidos por calorimetria ndireta não apresentaram correlação significativa com as fórmulas preditivas. O balanço energético foi negativo para o grupo (-1143,08Kcal). As alterações no balanço energético e a baixa gordura corporal observadas no presente estudo apontam para a necessidade de trabalhos educativos junto às atletas e seus técnicos no que diz respeito à alimentação, ao controle da massa corporal e à saúde.

The nutritional status of artistic gymnasts (14 girls, 11 to 15 years old, without menarche and pubertal signals) was evaluated. Body mass, stature, and body mass index (BMI) have been measured together with body composition, evaluated by bioelectrical impedance. Daily energetic expenditure was calculated from resting metabolic rate (RMR) including the activity factor, obtained from daily physical activity. Three food diary were filled by the evaluated group, from which the ingested energy (Kcal), macronutrients (g), dietetic fiber (g), iron (mg), calcium (mg) and vitamin C (mg) were obtained. Correlations among variables were calculated from Pearson´s coefficient, adopting p<0,05. The main results were: BMI = 15,85 ± 1,39Kg/m2; body fat= 11,64 ± 3,16 and 3,59 ± 1,32Kg; lean mass= 27,06 ± 5,14Kg. Energetic balance presented negative values (-1143, 08Kcal). The energetic balance alterations and low body fat found in the present study pointed the need of education programs with the athletes and technical staff, regarding feeding schedule, body weight control and health.