Increased Abdominal Perimeter Differently Affects Respiratory Function in Men and Women.

Obesity is a worldwide epidemic being the main cause of cardiovascular, metabolic disturbances and chronic pulmonary diseases. The increase in body weight may affect the respiratory system due to fat deposition and systemic inflammation. Herein, we evaluated the sex differences in the impact of obesity and high abdominal circumference on basal ventilation. Thirty-five subjects, 23 women and 12 men with a median age of 61 and 67, respectively, were studied and classified as overweight and obese according to body mass index (BMI) and were also divided by the abdominal circumference. Basal ventilation, namely, respiratory frequency, tidal volume, and minute ventilation, was evaluated. In normal and overweight women, basal ventilation did not change, but obese women exhibited a decrease in tidal volume. In men, overweight and obese subjects did not exhibit altered basal ventilation. In contrast, when subjects were subdivided based on the abdominal perimeter, a higher circumference did not change the respiratory frequency but induced a decrease in tidal volume and minute ventilation in women, while in men these two parameters increased. In conclusion, higher abdominal circumference rather than BMI is associated with alterations in basal ventilation in women and men.

Exploring the Mediators that Promote Carotid Body Dysfunction in Type 2 Diabetes and Obesity Related Syndromes.

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O2, CO2, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders.

Contribution of adenosine and ATP to the carotid body chemosensory activity in ageing.

KEY POINTS: Adenosine and ATP are excitatory neurotransmitters involved in the carotid body (CB) response to hypoxia. During ageing the CB exhibits a decline in its functionality, demonstrated by decreased hypoxic responses. In aged rats (20-24 months old) there is a decrease in: basal and hypoxic release of adenosine and ATP from the CB; expression of adenosine and ATP receptors in the petrosal ganglion; carotid sinus nerve (CSN) activity in response to hypoxia; and ventilatory responses to ischaemic hypoxia. There is also an increase in SNAP25, ENT1 and CD73 expression. It is concluded that, although CSN activity and ventilatory responses to hypoxia decrease with age, adjustments in purinergic metabolism in the CB in aged animals are present aiming to maintain the contribution of adenosine and ATP. The possible significance of the findings in the context of ageing and in CB-associated pathologies is considered. ABSTRACT: During ageing the carotid body (CB) exhibits a decline in its functionality. Here we investigated the effect of ageing on functional CB characteristics as well as the contribution of adenosine and ATP to CB chemosensory activity. Experiments were performed in 3-month-old and 20- to 24-month-old male Wistar rats. Ageing decreased: the number of tyrosine hydroxylase immune-positive cells, but not type II cells or nestin-positive cells in the CB; the expression of P2X2 and A2A receptors in the petrosal ganglion; and the basal and hypoxic release of adenosine and ATP from the CB. Ageing increased ecto-nucleotidase (CD73) immune-positive cells and the expression of synaptosome associated protein 25 (SNAP25) and equilibrative nucleoside transporter 1 (ENT1) in the CB. Additionally, ageing did not modify basal carotid sinus nerve (CSN) activity or the activity in response to hypercapnia, but decreased CSN activity in hypoxia. The contribution of adenosine and ATP to stimuli-evoked CSN chemosensory activity in aged animals followed the same pattern of 3-month-old animals. Bilateral common carotid occlusions during 5, 10 and 15 s increased ventilation proportionally to the duration of ischaemia, an effect decreased by ageing. ATP contributed around 50% to ischaemic-ventilatory responses in young and aged rats; the contribution of adenosine was dependent on the intensity of ischaemia, being maximal in ischaemias of 5 s (50%) and much smaller in 15 s ischaemias. Our results demonstrate that both ATP and adenosine contribute to CB chemosensory activity in ageing. Though CB responses to hypoxia, but not to hypercapnia, decrease with age, the relative contribution of both ATP and adenosine for CB activity is maintained.

Neural correlates of anticipatory cardiac deceleration and its association with the speed of perceptual decision-making, in young and older adults.

Warning stimuli in sensorimotor tasks induce a state of preparedness characterized by increased alertness, focused attention and immobility. This state of attentive anticipation is associated with heart rate deceleration. Ageing affects the amplitude of the anticipatory cardiac deceleration responses; yet, the impact of this physiological change on cognitive performance is still to be elucidated. In fact, how cardiac deceleration relates to brain function and cognitive performance in the context of perceptual decision-making and different levels of decision complexity remains unknown. Here, we aimed to investigate the relationship between cardiac deceleration, brain function, and performance in perceptual decision tasks and how these associate with age-related changes. We measured simultaneously the electrocardiogram, the pupilogram, and the electroencephalogram in 36 young and 39 older adults, while they were engaged in two auditory cued reaction time tasks: a detection task and a go/no-go task requiring inhibitory control. We observed robust cardiac deceleration responses that increased with increasing task complexity. Notably, stronger modulation of the cardiac response across tasks was associated with the ability to maintain response speed as decision complexity increased suggesting a link between cardiac deceleration and facilitation of perceptual decisions. Additionally, cardiac deceleration appears to have a cortical origin as it correlated with frontocentral event-related potentials. In contrast, beta oscillations at baseline and task-related beta suppression were not predictive of cardiac deceleration suggesting a dissociation between sensorimotor oscillatory activity and this cardiac response. Importantly, we found age-related changes in anticipatory cardiac deceleration associated with deficits in perceptual decision-making.

High fat diet blunts the effects of leptin on ventilation and on carotid body activity.

KEY POINTS: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models. ABSTRACT: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation.

Fate and Effect of Nano Tungsten Carbide Cobalt (WCCo) in the Soil Environment: Observing a Nanoparticle Specific Toxicity in Enchytraeus crypticus.

Tungsten carbide cobalt (WCCo) nanoparticles (NPs) are widely used in hard metal industries. Pulmonary diseases and risk of cancer are associated with occupational exposure, but knowledge about the environmental fate and effects is virtually absent. In this study, the fate and effects of crystalline WCCo NPs, WC, and Co2+ were assessed in the soil model Enchytraeus crypticus, following the standard Enchytraeid Reproduction Test (ERT). An additional 28 day exposure period compared to the ERT (i.e., a total of 56 days) was performed to assess longer-term effects. WCCo NPs affected reproduction at a concentration higher than the corresponding Co based (EC50 = 1500 mg WCCo/kg, equivalent to 128 mg Co/kg). WC showed no negative effect up to 1000 mg W/kg. Maximum uptake of Co was 10-fold higher for CoCl2 compared to WCCo exposed organisms. Overall toxicity seems to be due to a combined effect between WC and Co. This is supported by the soil bioavailable fraction and biological tissue measurements. Last, results highlight the need to consider longer exposure period of NPs for comparable methods standardized for conventional chemicals.

Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver.

AIMS/HYPOTHESIS: We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by high-energy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver. METHODS: Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used. RESULTS: CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue. CONCLUSIONS/INTERPRETATION: We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver.

Insulin resistance: a new consequence of altered carotid body chemoreflex?

Metabolic diseases affect millions of individuals across the world and represent a group of chronic diseases of very high prevalence and relatively low therapeutic success, making them suitable candidates for pathophysiological studies. The sympathetic nervous system (SNS) contributes to the regulation of energy balance and energy expenditure both in physiological and pathological states. For instance, drugs that stimulate sympathetic activity decrease food intake, increase resting metabolic rate and increase the thermogenic response to food, while pharmacological blockade of the SNS has opposite effects. Likewise, dysmetabolic features such as insulin resistance, dyslipidaemia and obesity are characterized by a basal overactivation of the SNS. Recently, a new line of research linking the SNS to metabolic diseases has emerged with the report that the carotid bodies (CBs) are involved in the development of insulin resistance. The CBs are arterial chemoreceptors that classically sense changes in arterial blood O2 , CO2 and pH levels and whose activity is known to be increased in rodent models of insulin resistance. We have shown that selective bilateral resection of the nerve of the CB, the carotid sinus nerve (CSN), totally prevents diet-induced insulin resistance, hyperglycaemia, dyslipidaemia, hypertension and sympathoadrenal overactivity. These results imply that the beneficial effects of CSN resection on insulin action and glucoregulation are modulated by target-related efferent sympathetic nerves through a reflex that is initiated in the CBs. It also highlights modulation of CB activity as a putative future therapeutic intervention for metabolic diseases.

Multivariate pattern analysis reveals subtle brain anomalies relevant to the cognitive phenotype in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common genetic condition associated with cognitive dysfunction. However, the pathophysiology of the NF1 cognitive deficits is not well understood. Abnormal brain structure, including increased total brain volume, white matter (WM) and grey matter (GM) abnormalities have been reported in the NF1 brain. These previous studies employed univariate model-driven methods preventing detection of subtle and spatially distributed differences in brain anatomy. Multivariate pattern analysis allows the combination of information from multiple spatial locations yielding a discriminative power beyond that of single voxels. Here we investigated for the first time subtle anomalies in the NF1 brain, using a multivariate data-driven classification approach. We used support vector machines (SVM) to classify whole-brain GM and WM segments of structural T1 -weighted MRI scans from 39 participants with NF1 and 60 non-affected individuals, divided in children/adolescents and adults groups. We also employed voxel-based morphometry (VBM) as a univariate gold standard to study brain structural differences. SVM classifiers correctly classified 94% of cases (sensitivity 92%; specificity 96%) revealing the existence of brain structural anomalies that discriminate NF1 individuals from controls. Accordingly, VBM analysis revealed structural differences in agreement with the SVM weight maps representing the most relevant brain regions for group discrimination. These included the hippocampus, basal ganglia, thalamus, and visual cortex. This multivariate data-driven analysis thus identified subtle anomalies in brain structure in the absence of visible pathology. Our results provide further insight into the neuroanatomical correlates of known features of the cognitive phenotype of NF1.

GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact.

Alterations in the balance between excitatory and inhibitory neurotransmission have been implicated in several neurodevelopmental disorders. Neurofibromatosis type 1 is one of the most common monogenic disorders causing cognitive deficits for which studies on a mouse model (Nfl(+/-)) proposed increased γ-aminobutyric acid-mediated inhibitory neurotransmission as the neural mechanism underlying these deficits. To test whether a similar mechanism translates to the human disorder, we used magnetic resonance spectroscopy to measure γ-aminobutyric acid levels in the visual cortex of children and adolescents with neurofibromatosis type 1 (n = 20) and matched control subjects (n = 26). We found that patients with neurofibromatosis type 1 have significantly lower γ-aminobutyric acid levels than control subjects, and that neurofibromatosis type 1 mutation type significantly predicted cortical γ-aminobutyric acid. Moreover, functional imaging of the visual cortex indicated that blood oxygen level-dependent signal was correlated with γ-aminobutyric acid levels both in patients and control subjects. Our results provide in vivo evidence of γ-aminobutyric acidergic dysfunction in neurofibromatosis type 1 by showing a reduction in γ-aminobutyric acid levels in human patients. This finding is relevant to understand the physiological profile of the disorder and has implications for the identification of targets for therapeutic strategies.

Validation of a Spanish version of the psychological inflexibility in pain scale (PIPS) and an evaluation of its relation with acceptance of pain and mindfulness in sample of persons with fibromyalgia.

BACKGROUND: Psychological flexibility has been suggested as a fundamental process in health. The Psychological Inflexibility in Pain Scale (PIPS) is one of the scales employed for assessing psychological inflexibility in pain patients. The aim of this study was to validate the Spanish version of the PIPS and secondly, to compare it to two other psychological constructs, the acceptance of pain and mindfulness scales. METHODS: The PIPS was translated into Spanish by two bilingual linguistic experts, and then, back-translated into English to assess for equivalence. The final Spanish version was administered along with the Pain Visual Analogue Scale, Fibromyalgia Impact Questionnaire, Hospital Anxiety Depression Scale, Pain Catastrophizing Scale, Chronic Pain Acceptance Questionnaire and the Mindful Attention Awareness Scale, to 250 Spanish patients with fibromyalgia. Face validity, construct validity, reliability (internal consistency and test-retest) and convergent validity were tested. Also a multiple regression analysis was carried out.The usual guidelines have been followed for cross-cultural adaptations. RESULTS: Data were very similar to the ones obtained in the original PIPS version. The construct validity confirmed the original two-components solution which explained 61.6% of the variance. The Spanish PIPS had good test-retest reliability (intraclass correlation coefficient 0.97) and internal consistency reliability (Cronbach's alpha: 0.90). The Spanish PIPS' score correlated significantly with worse global functioning (r = 0.55), anxiety (r = 0.54), depression (r = 0.66), pain catastrophizing (r = 0.62), pain acceptance (r = -0.72) and mindfulness (r = -0.47), as well as correlating modestly with pain intensity (r = 0.12). The multiple regression analyses showed that psychological inflexibility, acceptance and mindfulness are not overlapped. CONCLUSIONS: The Spanish PIPS scale appears to be a valid and reliable instrument for the evaluation of psychological inflexibility among a sample of fibromyalgia patients. These results ensure the use of this scale in research as well as in clinical practice. Psychological inflexibility measures processes different from other related components such as acceptance and mindfulness.

Assessing the impact of age on everyday cognitive function with a virtual environment task: The EcoKitchen.

More realistic assessment tools are imperative for a better understanding of the impact of age-related cognitive deficits on functional status. With this in mind, we probed the ability of the EcoKitchen, a non-immersive virtual environment task with increasing executively demanding kitchen chores, to detect the effects of aging on the simulated everyday functioning of healthy adults. Fifty-three adults (age between 23 and 77 years) were assessed with the EcoKitchen and a set of conventional paper-and-pencil neuropsychological tests. The associations between the baseline features of study participants and each of the two different assessment methods were examined. The associations between the EcoKitchen variables and an executive composite score were also explored. Our results showed that older individuals present deficits in the performance of both the EcoKitchen task and standard assessment methods. Notably, we found that, unlike conventional tests, accuracy in the EcoKitchen task was not related to the education level and IQ score of participants. Moreover, the EcoKitchen performance time was significantly correlated with executive tests. We have demonstrated that the EcoKitchen task, an ecologically relevant computerized neuropsychological assessment tool, might be more suitable than classic paper-and-pencil tests to capture the impact of aging on everyday cognitive function, as it proved to be less prone to the influence of confounding factors. Additionally, we have shown that executive function plays an important role in the timely performance of cognitively challenging virtual environment tasks.

Chronic caffeine intake in adult rat inhibits carotid body sensitization produced by chronic sustained hypoxia but maintains intact chemoreflex output.

Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A(2B)) was down-regulated and that in petrosal ganglion (A(2A)) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.

Cognition, function and awareness of disease impact in early Parkinson's and Huntington's disease.

PURPOSE: Patients with Parkinson's and Huntington's Disease (PD and HD) present impairments in cognitively challenging everyday activities. This study contrasts these two basal ganglia disorders on the ability to perform daily life- like tasks and their level of awareness regarding the disease impact on function. METHODS: 19 controls, 10 early-onset PD, 20 early stage PD, and 15 early manifest HD patients were compared in the "EcoKitchen," a virtual reality task with increasing executive load, the "Behavioural Assessment of Dysexecutive Syndrome battery - BADS," and "The Adults and Older Adults Functional Assessment Inventory - IAFAI," a self-report functional questionnaire. The EcoKitchen clinical correlates were investigated. RESULTS: All clinical groups presented slower EcoKitchen performance than controls, however, only HD patients showed decreased accuracy. HD and PD patients exhibited reduced BADS scores compared to the other study participants. Importantly, on the IAFAI, PD patients signalled more physically related incapacities and HD patients indicated more cognitively related incapacities. Accordingly, the EcoKitchen performance was significantly associated with PD motor symptom severity. CONCLUSIONS: Our findings suggest differential disease impact on cognition and function across PD and HD patients, with preserved awareness regarding disease- related functional sequelae. These observations have important implications for clinical management, research and rehabilitation.Implications for rehabilitationPatients with early stage Parkinson's and Huntington's disease have diagnosis-specific impairments in the performance of executively demanding everyday activities and, yet, show preserved awareness about the disease impact on their daily life.An active involvement of patients in the rehabilitation process should be encouraged, as their appraisal of the disease effects can help on practical decisions about meaningful targets for intervention, vocational choices, quality-of-life issues and/or specific everyday skills to boost.The EcoKitchen, a non-immersive virtual reality task, can detect and quantify early deficits in everyday-like tasks and is therefore a valuable tool for assessing the effects of rehabilitation strategies on the functional cognition of these patients.Rehabilitation efforts in the mild stages of Parkinson's and Huntington's disease should be aware of greater time needs from the patients in the performance of daily life tasks, target executive skills, and give a more prominent role to patients in symptoms report and management.

A 2 Adenosine Receptors Mediate Whole-Body Insulin Sensitivity in a Prediabetes Animal Model: Primary Effects on Skeletal Muscle.

Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A1 antagonist, 0.4 mg/kg), SCH58261 (A2A antagonist, 0.5 mg/kg), or MRS1754 (A2B antagonist, 9.5 µg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A1, A2A, A2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A1, A2A, and A2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A1, A2A expression was increased in HSu group, while A2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A1 and A2A block upregulated the expression of these receptors. A2 adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.

Carotid body chemosensitivity: early biomarker of dysmetabolism in humans.

OBJECTIVE: The carotid bodies (CBs) are peripheral chemoreceptor organs classically described as being O2 sensors, which are increasingly emerging as core players in metabolic control. Herein we evaluated CB activity in prediabetes patients and determined its correlation with dysmetabolism clinical features. DESIGN AND METHODS: Prediabetes patients were recruited at the Cardiology Service, Hospital Santa Marta, Centro Hospitalar Lisboa Central, EPE (CHLC-EPE). The study was approved by CHLC-EPE and NOVA Medical School Ethics Committee. Thirty-three prediabetic and 14 age-matched, non-prediabetic, volunteers had their peripheral chemosensitivity evaluated by the Dejours test. Serum biomarkers of metabolic disease, insulin sensitivity (HOMA-IR), blood pressure, carotid intima-media thickness (cIMT) and glucose tolerance were assessed. RESULTS: CB chemosensitivity was significantly increased in prediabetic group (P < 0.01). Fasting blood, glucose intolerance, fasting insulin and HOMA-IR were significantly higher in prediabetes patients. Insulin resistance correlated both with peripheral chemosensitivity, assessed by the Dejours test (P < 0.05) and with abdominal circumference (P < 0.01). HbA1c correlated with HOMA-IR (P < 0.05) and left cIMT (P < 0.05) in prediabetes patients. CONCLUSIONS: We conclude that CB is overactive in prediabetes subjects and that peripheral chemosensitivity correlates with fasting insulin and insulin resistance representing a novel non-invasive functional biomarker to forecast early metabolic disease.

Age-related differences in event-related potentials and pupillary responses in cued reaction time tasks.

Deficits in the noradrenergic system are associated with age-related cognitive decline, yet how healthy aging influences the functional properties of this arousal system is still poorly understood. We addressed this question in humans using pupillometry, a well-established indicator of activity levels in the locus coeruleus (LC), the main noradrenergic center in the brain. We recorded the pupillogram and the electroencephalogram of 36 young and 39 older adults, while they were engaged in cued reaction time tasks known to elicit LC responses in monkeys. Event-related potentials (ERPs) revealed significant group differences. Older adults showed higher cortical activation during preparatory processes reflected in enhanced cue-evoked frontocentral ERPs and reduced parietal ERPs at the time of the motor response. In contrast, the amplitude of the task-related pupillary responses did not show a significant group effect. Our findings suggest that aging-related changes in cortical processing during motor preparation and execution, as documented by electroencephalogram, are not accompanied by changes in the amplitude of activation of the LC, as documented by pupillography.

Cell In Vitro Testing with Soil Invertebrates-Challenges and Opportunities toward Modeling the Effect of Nanomaterials: A Surface-Modified CuO Case Study.

Soil invertebrates have been widely used in ecotoxicology studies for decades, although their use as in vitro models, albeit promising, has not been pursued as much. The immune cells of earthworms (coelomocytes) and the coelomic fluid can be used, and are a highly relevant in vitro system. Although it has been tested before, to cover the testing of nanomaterials (NMs), several challenges should be considered. NMs characteristics (dispersibility, agglomeration, etc.) can interfere with the common in vitro methodologies, not only during exposure, but also during the measurements. Here, we have assessed the effect of a CuO NMs case study using surface-modified particles, functionalized for safe-by-design strategies with ascorbate, citrate, polyethylenimine, and polyvinylpyrrolidinone, plus the pristine CuO NMs and copper chloride (CuCl2) for comparison. Eisenia fetida's coelomocytes were exposed for 24 h via the coelomic fluid. Changes in cell viability were evaluated using flow cytometry. All materials affected the cells in a dose-related manner, where CuCl2 was the most toxic followed by the citrate-coated CuO NM. There was a strong correlation between NM characteristics, e.g., the hydrodynamic size, and the EC50 (50% Effect Concentrations) values. This screening further confirms the potential for the usage of the standard earthworm model as an in vitro standard. Further detailed in vitro studies are needed using other NMs aiming toward their implementation and standardization. Additional cell endpoints can also be assessed, making it a high content tool for mechanistic understanding.

Multigenerational exposure to cobalt (CoCl2) and WCCo nanoparticles in Enchytraeus crypticus.

Cobalt and cobalt nanoparticles have many applications, for example, in the hard metal industry and in tires. The assessment of long term effects is crucial, as these materials are persistent. For many organism groups, multigenerational (MG) exposure is a highly relevant scenario for persistent materials. In this study, the biological effect of CoCl2 (salt) and Tungsten Carbide Cobalt nanoparticles (WCCo NPs) exposure was assessed in an MG test (4 generations in spiked + 2 generations in clean soil) using the OECD/ISO standard soil test species Enchytraeus crypticus. To ensure transgenerational survival, sublethal concentrations were used to assess the MG impact. MG exposure did not increase toxicity (survival, reproduction). There was an increase in reproduction at low concentrations of Co. Materials were characterized in the exposure media and the organisms in terms of Co content. Uptake of Co-occurred from exposure to both CoCl2 and WCCo, although without toxicity for WCCo. Cobalt from CoCl2 exposure seemed to be stored, whereas for WCCo it was eliminated.