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Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

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.

Little is known about undergraduate education on antibiotic prescribing in Europe and even less about the antibiotic prescribing skills of nearly-graduated medical students. This study aimed to evaluate the antibiotic prescribing skills of final-year medical students across Europe and the education they received during medical training. In a cross-sectional study, final-year medical students from 17 medical schools in 15 European countries were asked to prescribe for two written case reports of infectious diseases (acute bronchitis and community-acquired pneumonia). The appropriateness of antimicrobial therapy was determined using a scoring form based on local guidelines. Teachers from each medical school were asked to complete a standardised questionnaire about the teaching and assessment of undergraduate education on antibiotic use. In total, 856 final-year medical students (95.6%) completed the assessment and 16 teachers (94.1%) completed the questionnaire. Overall, 52.7% (range 26-83%) of the 1.683 therapies prescribed were considered appropriate. The mean number of contact hours for undergraduate education on antimicrobials was 25.6 (range 2-90). Differences in education styles were found to have a significant impact on students performance, with a problem-based learning style being associated with more appropriate antimicrobial prescribing than a traditional learning style (46.0% vs. 22.9%; P amp;lt; 0.01). Although there are differences between medical schools, final-year medical students in Europe lack prescribing skills for two common infectious diseases, possibly because of inadequate undergraduate education on antibiotic use and general prescribing. To improve students skills, interactive teaching methods such as prescribing for simulated and real patients should be used. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved., Funding Agencies|European Association of Clinical Pharmacology and Therapeutics (EACPT)

Background: The goal of the study was to analyze the factors associated with quality of life (QoL) in institutionalized older adults with dementia, based on self and proxy ratings, and if these characteristics differ by dementia severity. Methods: Cross-sectional study of 525 people with dementia (PwD) and their caregivers (professional or family caregivers). Two different QoL questionnaires, leading to three measures, were used: QoL in Alzheimer's disease scale (QOL-AD), self and proxy-rated, and QoL in late-stage dementia scale (QUALID), proxy-rated. Multivariate linear regression models were tested for each QoL measure and for mild/moderate and severe stages of dementia. Results: Multiple regression analyses showed a significant association between the three QoL measures and depression. Functional ability was significantly associated with QoL when assessed by proxy. Other factors such as education level, leisure activities and frequency of visits were significantly related with QOL-AD by proxy. The associated factors that differed by dementia severity were education level for moderate dementia, and frequency of visits and who answered the questionnaire (professional vs. family member) for severe dementia. Conclusions: QoL was consistently associated with depressive symptoms independently of the measures as well as functional ability and social leisure activities when the QoL questionnaire was rated by proxy. Treating depressive symptoms, increasing social activities and maintaining the functional ability may decrease the deterioration of QoL in institutionalized older adults with dementia.

The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2 and pH levels. Hypoxia, hypercapnia and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnoea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future.

Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O(2)) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O(2)) and in response to hypoxias of different intensities (10, 5, and 2% O(2)) to study the release pathways. We found that ZM241385, an A(2) antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 30.8 and 72.5%, respectively. Suramin, a P(2)X antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O(2) levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.

[Objectives]: Carotid body (CB) chemoreceptor cells are PO2, PCO2/pH sensors-efectors which upon a decrease in PO2 or a PCO2/[H+] increase, release neurotransmitters that regulate the firing rate in the sensory fibres of the carotid sinus nerve (CSN). CSN terminate in the brainstem, where the information it coveys is integrated to generate compensatory ventilatory responses aimed to normalize blood gases. The chemoreceptor cells possess a wide array of neurotransmitters, whose relative significance in the genesis of conducted activity in the CSN is unknown. Present study, carried out in young adult rats, aimed to define the significance of adenosine and ATP to generate conducted action potentials in the CSN at different intensities of hypoxia. [Materials]: To ascertain their significance we have measured: a) adenosine and ATP receptors in the somas of the CSN sensory neurons; b) metabolic profile of adenosine and ATP in chemoreceptor cells and their rate of release at several PO2 levels, c) effect of selective adenosine and ATP antagonists on the firing frequencies recorded in the CSN; d) effect of adenosine and ATP antagonists on ventilation at different ischemic hypoxic intensities; e) some additional data on aged animals and in animals exposed to chronic sustained hypoxia (CSH) would also be presented. [Results]: Findings indicate that adenosine and ATP are the main players of the hypoxic chemotransmission in the CB sensory synapse. Adenosine is more relevant during mild hypoxia while ATP is prime during intense hypoxia. This relative contribution is maintained in aging, although overall CB drive lessens. In CSH the role of adenosine in fixing CSN responses and ventilation to acute hypoxic tests seems maintained, but ATP function seems to decrease. [Conclusions]: In the presentation of our data we shall also provide some information on the functional significance of adenosine and ATP on the central control of breathing.

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 (A2B) was down-regulated and that in petrosal ganglion (A2A) 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.