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We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.

The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A 2 -adenosine receptors stimulation and attenuated by D 2 -dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3′,5′-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced AGE (2011) 33:337-350 DOI 10.1007 Scientific knowledge on the subject The functional ventilatory consequences of the morphological and molecular changes in the carotid body observed in aged animals, as well as the ventilatory effects of dopamine and adenosine in old animals, are still unknown.What this study adds to the field The carotid body's peripheral control of ventilation is not impaired by aging. The preservation of the inhibitory and excitatory effects on ventilation caused by exogenous dopamine and adenosine, respectively, should be taken into account in the therapeutic use of these amines and their agonists and antagonists in elderly people. by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A 2A -adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.

Purpose The pharmacology and clinical pharmacology and therapeutics (CPT) education during the undergraduate medical curriculum of NOVA Medical School, Lisbon, Portugal, was changed from a traditional programme (i.e. discipline-based, lectures) to a problem-based learning (PBL) programme (i.e. integrated, case-based discussions) without an increase in teaching hours. The aim of this study was to investigate whether this change improved the prescribing competencies of final-year medical students. Methods Final-year students from both programmes (2015 and 2019) were invited to complete a validated prescribing assessment and questionnaire. The assessment comprised 24 multiple-choice questions in three subdomains (working mechanism, side-effects and interactions/contraindications), and five clinical case scenarios of common diseases. The questionnaire focused on self-reported prescribing confidence, preparedness for future prescribing task and education received. Results In total, 36 (22%) final-year medical students from the traditional programme and 54 (23%) from the PBL programme participated. Overall, students in the PBL programme had significantly higher knowledge scores than students in the traditional programme (76% (SD 9) vs 67% (SD 15); p = 0.002). Additionally, students in the PBL programme made significantly fewer inappropriate therapy choices (p = 0.023) and fewer erroneous prescriptions than did students in the traditional programme (p = 0.27). Students in the PBL programme felt more confident in prescribing, felt better prepared for prescribing as junior doctor and completed more drug prescriptions during their medical training. Conclusion Changing from a traditional programme to an integrated PBL programme in pharmacology and CPT during the undergraduate medical curriculum may improve the prescribing competencies of final-year students.

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.

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