Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice.

Narcolepsy type-1 (NT1) is a lifelong sleep disease, characterised by impairment of the orexinergic system, with a typical onset during adolescence and young adulthood. Since the wake-sleep cycle physiologically changes with ageing, this study aims to compare sleep patterns between orexin-knockout (KO) and wild type (WT) control mice at different ages. Four groups of age-matched female KO and WT mice (16 weeks of age: 8 KO-YO and 9 WT-YO mice; 87 weeks of age: 13 KO-OLD and 12 WT-OLD mice) were implanted with electrodes for discriminating wakefulness, rapid-eye-movement sleep (REMS), and non-REMS (NREMS). Mice were recorded for 48 h in their home cages and for 7 more hours into a plethysmographic chamber to characterise their sleep-breathing pattern. Regardless of orexin deficiency, OLD mice spent less time awake and had fragmentation of this behavioural state showing more bouts of shorter length than YO mice. OLD mice also had more NREMS bouts and less frequent NREMS apneas than YO mice. Regardless of age, KO mice showed cataplexy-like episodes and shorter REMS latency than WT controls and had a faster breathing rate and an increased minute ventilation during REMS. KO mice also had more wakefulness, NREMS and REMS bouts, and a shorter mean length of wakefulness bouts than WT controls. Our experiment indicated that the lack of orexins as well as ageing importantly modulate the sleep and breathing phenotype in mice. The narcoleptic phenotype caused by orexin deficiency in female mice was substantially preserved with ageing.

Characterisation of sleep apneas and respiratory circuitry in mice lacking CDKL5.

CDKL5 deficiency disorder is a rare genetic disease caused by mutations in the CDKL5 gene. Central apneas during wakefulness have been reported in patients with CDKL5 deficiency disorder. Studies on CDKL5-knockout mice, a CDKL5 deficiency disorder model, reported sleep apneas, but it is still unclear whether these events are central (central sleep apnea) or obstructive (obstructive sleep apnea) and may be related to alterations of brain circuits that modulate breathing rhythm. This study aimed to discriminate central sleep apnea and obstructive sleep apnea in CDKL5-knockout mice, and explore changes in the somatostatin neurons expressing high levels of neurokinin-1 receptors within the preBötzinger complex. Ten adult male wild-type and 12 CDKL5-knockout mice underwent electrode implantation for sleep stage discrimination and diaphragmatic activity recording, and were studied using whole-body plethysmography for 7 hr during the light (resting) period. Sleep apneas were categorised as central sleep apnea or obstructive sleep apnea based on the recorded signals. The number of somatostatin neurons in the preBötzinger complex and their neurokinin-1 receptors expression were assessed through immunohistochemistry in a sub-group of animals. CDKL5-knockout mice exhibited a higher apnea occurrence rate and a greater prevalence of obstructive sleep apnea during rapid eye movement sleep, compared with wild-type, whereas no significant difference was observed for central sleep apnea. Moreover, CDKL5-knockout mice showed a reduced number of somatostatin neurons in the preBötzinger complex, and these neurons expressed a lower level of neurokinin-1 receptors compared with wild-type controls. These findings underscore the pivotal role of CDKL5 in regulating normal breathing, suggesting its potential involvement in shaping preBötzinger complex neural circuitry and controlling respiratory muscles during sleep.

Endovascular treatment of chronic ilio-femoral vein obstruction with extension below the inguinal ligament in patients with post-thrombotic syndrome.

OBJECTIVE: This study aimed to evaluate postoperative outcomes of patients with chronic iliofemoral venous outflow obstruction and post-thrombotic syndrome (PTS) who underwent endovascular recanalization and stenting across the inguinal ligament. METHODS: All consecutive patients with chronic iliofemoral venous outflow obstruction and PTS were included in the analysis, from January 2018 and February 2022. Preoperative, intraoperative, and postoperative outcomes were assessed. Primary endpoints analyzed were major adverse events (MAEs) at 30 days and primary patency rate at 2 years of follow-up. Secondary endpoints assessed were secondary patency rate, target vessel revascularization, and clinical improvement evaluated with the Venous Clinical Severity Score (VCSS) classification, Villalta scale, and visual analog scale (VAS), respectively. RESULTS: A total of 63 patients (mean age, 48.1 ± 15.5 years; female, 61.9%) were evaluated. No intraoperative and 30-day postoperative complications were documented. The technical success rate was achieved at 100%. Overall, one in-stent occlusion and five in-stent restenosis were detected during follow-up. The primary patency rate was 93.7% (95% confidence interval [CI], 87.8%-99.9%) and 92.1% (95% CI, 85.6%-99%), at 1- and 2-year follow-up, respectively (Kaplan-Meier analysis). Target vessel revascularization was conducted in two cases, resulting in a secondary patency of 98.4% (95% CI, 95.4%-100%) at 2 years of follow-up. Stent fracture and/or migration were not observed during follow-up. A significant clinical improvement in the patient's quality of life was documented. The median improvement of VCSS and Villalta scores were 4 (interquartile range, 2-7; P = .001), and 3 (interquartile range, 1.5-5; P = .001) vs baseline at the last follow-up. Overall, pain reduction of 17 mm on the VAS scale was documented at 2 years of follow-up. At multivariate analysis, presence of trabeculation into the femoral vein and deep femoral vein (odds ratio, 1.89; 95% CI, 0.15-6.11; P = .043), and Villalta scale >15 points at admission (odds ratio, 1.89; 95% CI, 0.15-6.11; P = .043) were predictive for in-stent occlusion during the follow-up. CONCLUSIONS: The use of a dedicated venous stent across the inguinal ligament was safe and effective for the treatment of symptomatic iliofemoral venous disease with acceptable primary and secondary patency rates at 2 years of follow-up.

How to study sleep apneas in mouse models of human pathology.

Sleep apnea, the most widespread sleep-related breathing disorder (SBD), consists of recurrent episodes of breathing cessation during sleep. This condition can be classified as either central (CSA) or obstructive (OSA) sleep apnea, with the latest being the most common and toxic. Due to the complexity of living organisms, animal models and, particularly, mice still represent an essential tool for the study of SBD. In the present review we first discuss the methodological pros and cons in the use of whole-body plethysmography to coupling respiratory and sleep measurements and to characterize CSA and OSA in mice; then, we draw an updated and objective picture of the methods used so far in the study of sleep apnea in mice. Most of the studies present in the literature used intermittent hypoxia to mimic OSA in mice and to investigate consequent pathological correlates. On the contrary, few studies using genetic manipulation or high-fat diets investigated the pathogenesis or potential treatments of sleep apnea. To date, mice lacking orexins, hemeoxygenase-2, monoamine oxidase A, Phox2b or Cdkl5 can be considered validated mouse models of sleep apnea. Moreover, genetically- or diet-induced obese mice, and mice recapitulating Down syndrome were proposed as OSA models. In conclusion, our review shows that despite the growing interest in the field and the need of new therapeutical approaches, technical complexity and inter-study variability strongly limit the availability of validated mouse of sleep apnea, which are essential in biomedical research.