Sleep fragmentation disrupts Lyme arthritis resolution in mice.

STUDY OBJECTIVES: Lyme arthritis is a common late-stage complication of infection by Borrelia burgdorferi, the agent of Lyme disease. Patients with Lyme arthritis report increased levels of sleep disturbance associated with pain. Using a mouse model of experimental Lyme arthritis, we investigated the effect of disrupted sleep on the development and resolution of joint inflammation. METHODS: Lyme arthritis-susceptible C3H/HeJ mice (n = 10/group) were infected with B. burgdorferi and were left either alone (control) or subjected to sleep fragmentation (SF). Arthritis development or resolution were monitored. The impact of SF on immune and inflammatory parameters such as arthritis severity scores, anti-borrelia antibody production, and bacterial clearance was measured. We also determined the effect of SF on arthritis resolution in C3H mice deficient in leukotriene (LT) B4 signaling (BLT1/2-/-) who display delayed Lyme arthritis resolution. RESULTS: SF had no significant impact on Lyme arthritis development or inflammatory parameters regardless of whether SF treatment began 1 week prior to or congruent with infection. However, initiation of SF at the peak of arthritis resulted in a significant delay in arthritis resolution as measured by joint edema, arthritis severity scores, and decreased bacterial clearance from the joint. This was accompanied by significant changes in joint cytokine transcription levels (e.g., increased TNFα and decreased IL-4). SF has no significant impact on Lyme arthritis resolution in the BLT1/2-/- mice. CONCLUSIONS: Poor sleep, especially near the peak of arthritis inflammation, may delay initiation of resolution programs possibly through altering cytokine production and host immune responses, leading to defects in spirochete clearance and prolonged disease.

Senolytic-facilitated Reversal of End-Organ Dysfunction in a Murine Model of Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with accelerated biological aging and multiple end-organ morbidities. Current treatments, such as continuous positive airway pressure (CPAP), have shown limited cognitive, metabolic, and cardiovascular beneficial outcomes despite adherence. Thus, adjunct therapies aiming to reduce OSA burden, such as senolytics, could improve OSA outcomes.Objectives: To assess if targeting senescence in addition to partial normoxia mimicking "good" CPAP adherence can improve physiological outcomes in mice exposed to chronic intermittent hypoxia.Methods: We compared the effects of 6 weeks of therapy with either partial normoxic recovery alone or combined with the senolytic navitoclax after 16 weeks of intermittent hypoxia exposures, a hallmark of OSA, on multiphenotypic cardiometabolic and neurocognitive parameters.Measurements and Main Results: Our findings indicate that only when combined with navitoclax, partial normoxic recovery significantly improved sleepiness (sleep in the dark phase: 34% ± 4% vs. 26% ± 3%; P < 0.01), cognition (preference score: 51% ± 19% vs. 70% ± 11%; P = 0.048), coronary artery function (response to acetylcholine [vasodilation]: 56% ± 13% vs. 72% ± 10%; P < 0.001), glucose, and lipid metabolism and reduced intestinal permeability and senescence in multiple organs.Conclusions: These findings indicate that the reversibility of end-organ morbidities induced by OSA is not only contingent on restoration of normal oxygenation patterns but can be further enhanced by targeting other OSA-mediated detrimental cellular processes, such as accelerated senescence.

Recovery Mimicking “Ideal” CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents

Introduction: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. Methods: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic “ideal” continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. Results: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. Conclusion: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition. (AU)

Recovery Mimicking "Ideal" CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. RESULTS: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. CONCLUSION: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.

Cognitive Impairments, Neuroinflammation and Blood-Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation during the Daylight Period.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-brain barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks and in a subset 2 or 6 weeks of normal sleep recovery. The presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation, as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p < 0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patients with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Solriamfetol enhances wakefulness and improves cognition and anxiety in a murine model of OSA.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH). Excessive daytime sleepiness (EDS) is a common consequence of OSA and is associated with cognitive deficits and anxiety. Modafinil (MOD) and Solriamfetol (SOL) are potent wake-promoting agents clinically used to improve wakefulness in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to either IH or room air (RA) controls during the light phase for 16 weeks. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg) or vehicle (VEH) for 9 days while continuing IH exposures. Sleep/wake activity was assessed during the dark (active) phase. Novel object recognition (NOR), elevated-plus maze test (EPMT), and forced swim test (FST) were performed before and after drug treatment. RESULTS: IH exposure increased dark phase sleep percentage and reduced wake bouts lengths and induced cognitive deficits and anxiogenic effects. Both SOL and MOD treatments decreased sleep propensity under IH conditions, but only SOL promoted improvements in NOR performance (explicit memory) and reduced anxiety-like behaviors. CONCLUSION: Chronic IH, a hallmark feature of OSA, induces EDS in young adult mice that is ameliorated by both SOL and MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits and promotes anxiolytic effects. Thus, SOL could potentially benefit OSA patients beyond EDS management.

Solriamfetol improves chronic sleep fragmentation-induced increases in sleep propensity and ameliorates explicit memory in male mice.

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted.

Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition that is associated with oxidative stress, inflammation, and fibrosis, leading to endothelial dysfunction, arterial stiffness, and vascular insulin resistance, resulting in increased cardiovascular disease and overall mortality rates. To date, OSA remains vastly underdiagnosed and undertreated, with conventional treatments yielding relatively discouraging results for improving cardiovascular outcomes in OSA patients. As such, a better mechanistic understanding of OSA-associated cardiovascular disease (CVD) and the development of novel adjuvant therapeutic targets are critically needed. It is well-established that inappropriate mineralocorticoid receptor (MR) activation in cardiovascular tissues plays a causal role in a multitude of CVD states. Clinical studies and experimental models of OSA lead to increased secretion of the MR ligand aldosterone and excessive MR activation. Furthermore, MR activation has been associated with worsened OSA prognosis. Despite these documented relationships, there have been no studies exploring the causal involvement of MR signaling in OSA-associated CVD. Further, scarce clinical studies have exclusively assessed the beneficial role of MR antagonists for the treatment of systemic hypertension commonly associated with OSA. Here, we provide a comprehensive overview of overlapping mechanistic pathways recruited in the context of MR activation- and OSA-induced CVD and propose MR-targeted therapy as a potential avenue to abrogate the deleterious cardiovascular consequences of OSA.

Gut microbiota mediate vascular dysfunction in a murine model of sleep apnoea: effect of probiotics.

BACKGROUND: Obstructive sleep apnoea (OSA) is a chronic prevalent condition characterised by intermittent hypoxia (IH), and is associated with endothelial dysfunction and coronary artery disease (CAD). OSA can induce major changes in gut microbiome diversity and composition, which in turn may induce the emergence of OSA-associated morbidities. However, the causal effects of IH-induced gut microbiome changes on the vasculature remain unexplored. Our objective was to assess if vascular dysfunction induced by IH is mediated through gut microbiome changes. METHODS: Faecal microbiota transplantation (FMT) was conducted on C57BL/6J naïve mice for 6 weeks to receive either IH or room air (RA) faecal slurry with or without probiotics (VSL#3). In addition to 16S rRNA amplicon sequencing of their gut microbiome, FMT recipients underwent arterial blood pressure and coronary artery and aorta function testing, and their trimethylamine N-oxide (TMAO) and plasma acetate levels were determined. Finally, C57BL/6J mice were exposed to IH, IH treated with VSL#3 or RA for 6 weeks, and arterial blood pressure and coronary artery function assessed. RESULTS: Gut microbiome taxonomic profiles correctly segregated IH from RA in FMT mice and the normalising effect of probiotics emerged. Furthermore, IH-FMT mice exhibited increased arterial blood pressure and TMAO levels, and impairments in aortic and coronary artery function (p<0.05) that were abrogated by probiotic administration. Lastly, treatment with VSL#3 under IH conditions did not attenuate elevations in arterial blood pressure or CAD. CONCLUSIONS: Gut microbiome alterations induced by chronic IH underlie, at least partially, the typical cardiovascular disturbances of sleep apnoea and can be mitigated by concurrent administration of probiotics.

Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period.

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), and can lead to a vast array of end-organ morbidities, particularly affecting cardiovascular, metabolic and neurobehavioral functioning. OSA can induce cognitive and behavioral and mood deficits. Male C57Bl/6J 8-week-old mice were housed in custom-designed cages with a silent motorized mechanical sweeper traversing the cage floor at 2-min intervals (SF) during daylight for four weeks. Sleep control (SC) consisted of keeping sweeper immobile. IH consisted of cycling FiO2 21% 90 seconds-6.3% 90s or room air (RA; FiO2 21%) for sixteen weeks and combined SF-IH was conducted for nine weeks. Open field novel object recognition (NOR) testing, elevated-plus maze test (EPMT), and forced swimming test (FST) were performed. SF induced cognitive NOR performance impairments in mice along with reduced anxiety behaviors while IH induced deficits in NOR performance, but increased anxiety behaviors. SF-IH induced impaired performance in NOR test of similar magnitude to IH or SF alone. Combined SF-IH exposures did not affect anxiety behaviors. Thus, both SF an IH altered cognitive function while imposing opposite effects on anxiety behaviors. SF-IH did not magnify the detrimental effects of isolated SF or IH and canceled out the effects on anxiety. Based on these findings, the underlying pathophysiologic processes underlying IH and SF adverse effects on cognitive function appear to differ, while those affecting anxiety counteract each other.

Temporal changes in coronary artery function and flow velocity reserve in mice exposed to chronic intermittent hypoxia.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) that is implicated in an increased risk of cardiovascular disease (i.e., coronary heart disease, CHD) and associated with increased overall and cardiac-specific mortality. Accordingly, we tested the hypothesis that experimental IH progressively impairs coronary vascular function and in vivo coronary flow reserve. METHODS: Male C57BL/6J mice (8-week-old) were exposed to IH (FiO2 21% 90 s-6% 90 s) or room air (RA; 21%) 12 h/day during the light cycle for 2, 6, 16, and 28 weeks. Coronary artery flow velocity reserve (CFVR) was measured at each time point using a Doppler system. After euthanasia, coronary arteries were micro-dissected and mounted on wire myograph to assess reactivity to acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: Endothelium-dependent coronary relaxation to ACh was preserved after 2 weeks of IH (80.6 ± 7.8%) compared to RA (87.8 ± 7.8%, p = 0.23), but was significantly impaired after 6 weeks of IH (58.7 ± 16.2%, p = 0.02). Compared to ACh responses at 6 weeks, endothelial dysfunction was more pronounced in mice exposed to 16 weeks (48.2 ± 5.3%) but did not worsen following 28 weeks of IH (44.8 ± 11.6%). A 2-week normoxic recovery after a 6-week IH exposure reversed the ACh abnormalities. CFVR was significantly reduced after 6 (p = 0.0006) and 28 weeks (p < 0.0001) of IH when compared to controls. CONCLUSION: Chronic IH emulating the hypoxia-re-oxygenation cycles of moderate-to-severe OSA promotes coronary artery endothelial dysfunction and CFVR reductions in mice, which progressively worsen until reaching asymptote between 16 and 28 weeks. Normoxic recovery after 6 weeks exposure reverses the vascular abnormalities.

MicroRNA-219 loaded chitosan nanoparticles for treatment of glioblastoma.

Recent evidence has implicated microRNA-219 (miR-219) in regulation of gene contributed in glioblastoma (GBM) pathogenesis. This study aimed to prepare miR-219 in chitosan (CS) nanoparticles (NPs), characterize and investigate their efficacy on human GBM cell line (U87 MG). NPs were prepared using ionic gelation method. The influence of process parameters on physicochemical characteristics of NPs was investigated. Apoptotic effect of miR-219 was examined on U87 MG cells. Formulated NPs showed particle size of 109 ± 2.18 nm, with poly dispersity index equal to 0.2 ± 0.05, and zeta potential of +20.5 ± 0.7 mV. Entrapment efficiency of miR-219 in loaded NP has reached 95%. The in vitro release study demonstrated sustained release pattern of miR-219 from CS-NPs. Gel retardation assay has confirmed the integrity of miR-219 after production process. The fabricated NPs reduced the survival of U87 MG cells to 78% after 24 h of post-transfection, and into 67.5% after 48 h. However, fibroblasts were not affected by the NPs, revealing their specificity for GBM cells. Given the tumour suppressing function of miR-219, and advantage of CS-NPs for gene delivery to the central nervous system, the presented NPs have a great potential for treatment of GBM.

PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea?

Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.

Snowballing Technique for High Flow Arteriovenous Fistula: A Technical Note.

A novel endovascular technique to occlude high flow direct arteriovenous fistulae is presented, where the distal tip of the microcatheter acts as a nucleus that the operator can grow a plug from a liquid embolic agent. Its advantages (such as cost-saving and distal reachability), disadvantages (such as embolic material instability), and technique are discussed.

Splanchnic venous thrombosis in a nephrotic patient following COVID-19 infection: a case report.

BACKGROUND: As the COVID-19 pandemic spread worldwide, case reports and small series identified its association with an increasing number of medical conditions including a propensity for thrombotic complications. And since the nephrotic syndrome is also a thrombophilic state, its co-occurrence with the SARS-CoV-2 infection is likely to be associated with an even higher risk of thrombosis, particularly in the presence of known or unknown additional risk factors. Lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of COVID-19-associated hypercoagulable state with other venous or arterial sites being much less frequently involved. Although splanchnic vein thrombosis (SVT) has been reported to be 25 times less common than usual site venous thromboembolism (VTE) and rarely occurs in nephrotic patients, it can have catastrophic consequences. A small number of SVT cases have been reported in COVID-19 infected patients in spite of their number exceeding 180 million worldwide. CASE PRESENTATION: An unvaccinated young adult male with steroid-dependent nephrotic syndrome (SDNS) who was in a complete nephrotic remission relapsed following contracting SARS-CoV-2 infection and developed abdominal pain and diarrhea. Abdominal US revealed portal vein thrombosis. The patient was anticoagulated, yet the SVT rapidly propagated to involve the spleno-mesenteric, intrahepatic and the right hepatic veins. In spite of mechanical thrombectomy, thrombolytics and anticoagulation, he developed mesenteric ischemia which progressed to gangrene leading to bowel resection and a complicated hospital course. CONCLUSION: Our case highlights the potential for a catastrophic outcome when COVID-19 infection occurs in those with a concomitant hypercoagulable state and reminds us of the need for a careful assessment of abdominal symptoms in SARS-CoV-2 infected patients.

Improved delivery of miR-1296 loaded cationic nanoliposomes for effective suppression of triple negative breast cancer.

Nowadays, microRNA is considered an attractive strategy for the effective treatment of cancer. A significant delivery of microRNA for cancer therapy remains a significant obstacle to target cancer cells. The restoring microRNA-1296 (miR-1296) has immense therapeutic efficacy in triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast tumors with the progression of malignant transformation. This study aimed to develop a cationic nanoliposome that can serve as a miR-1296 carrier and studied its efficiency in TNBC. The efficacy of miR-1296 liposomes was evaluated on its apoptotic effect, cellular uptake, and potential chemotherapy sensitization in the TNBC cell line (MDA-MB-231). For in vitro viability study, the apoptotic effect was performed to validate protein expression using Alamar blue kit and western blot. The transfection of miR-1296 into TNBC cells was also investigated using cisplatin as a TNBC resistance drug. The fluorescent miR-1296-cy3 liposome was used for cellular uptake study. The miR-liposome was successfully prepared with a particle size of 123.6 ± 1.3 nm and encapsulation efficiency of 94.33%. A dose of 0.5 uM has significantly reduced the viability of MDA-MB-231 to be 33.45%±5.29 (P < 0.001). This result was validated by down-expression of CCND1, and PARP1, the miR-1296 receptor, and apoptosis marker. The image of the miR-1296-cy3 liposome showed cytoplasmic intracellular localization. It was found high sensitization of TNBC cell line for miR-1296 liposome compared to cisplatin (P < 0.001). Future in vivo research may answer questions concerning safety and stability. This study demonstrates that miR-191 liposomes may have promising clinical applications for TNBC therapy.

Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). Patients with OSA have increased biomarkers of aging such as telomere shortening. We used PCR to report shortened telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH. Our data indicate that IH, a hallmark of OSA, accelerates vascular and renal aging that may contribute to OSA-induced CVD and CKD.

The gut microbiome as a target for adjuvant therapy in obstructive sleep apnea.

Introduction: Gut dysbiosis is assumed to play a role in obstructive sleep apnea (OSA)-associated morbidities. Pre- and probiotics, short chain fatty acids (SCFA) and fecal matter transplantation (FMT) may offer potential as novel therapeutic strategies that target this gut dysbiosis. As more mechanisms of OSA-induced dysbiosis are being elucidated, these novel approaches are being tested in preclinical and clinical development. Areas covered: We examined the evidence linking OSA to gut dysbiosis and discuss the effects of pre- and probiotics on associated cardiometabolic, neurobehavioral and gastrointestinal disorders. The therapeutic potential of SCFA and FMT are also discussed. We reviewed the National Center for Biotechnology Information database, including PubMed and PubMed Central between 2000 - 2020. Expert opinion: To date, there are no clinical trials and only limited evidence from animal studies describing the beneficial effects of pre- and probiotic supplementation on OSA-mediated dysbiosis. Thus, more work is necessary to assess whether prebiotics, probiotics and SCFA are promising future novel strategies for targeting OSA-mediated dysbiosis.

Fecal microbiota transplantation from mice exposed to chronic intermittent hypoxia elicits sleep disturbances in naïve mice.

Obstructive sleep apnea (OSA) is a chronic prevalent condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). Evidence suggests that OSA can alter the gut microbiome (GM) diversity and composition that may then promote the occurrence of some of the OSA-associated morbidities. However, it is unclear whether perturbations in the GM caused by IH can elicit sleep disturbances that underlie the increased sleep propensity that occurs in IH-exposed mice. To evaluate this issue, we exposed C57Bl/6 J mice to IH or room air (RA) for 6 weeks, and fecal matter was collected and frozen. C57Bl/6 J naïve mice were then randomly assigned to a fecal microbiota transfer (FMT) protocol for 3 weeks with either IH or RA fecal slur, and their GM was then analyzed using 16 s rRNA sequencing. In addition, FMT recipients underwent sleep recordings using piezoelectric approaches for 3 consecutive days. As anticipated, FMT-IH and FMT-RA mice showed different taxonomic profiles that corresponded to previous effects of IH on GM. Furthermore, FMT-IH mice exhibited increased sleep duration and the frequency of longer sleep bouts during the dark cycle, suggesting increased sleepiness (p < 0.0001 vs. FMT-RA mice). Thus, alterations of GM diversity induced by IH exposures can elicit sleep disturbances in the absence of concurrent IH, suggesting that sleep disturbances can be mediated, at least in part, by IH-induced alterations in GM.