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- Obstructive sleep apnea: the effects of apnea-hypopnea index, oxygen desaturation and daytime sleepiness on cognitive functionPublication . Duarte, Laura Nedel; Silva, Dina; Coutinho, MiguelBackground: Obstructive sleep apnea (OSA), a sleep-disordered breathing, is recognized for having deleterious effects on cognition, however, the mechanisms mediating this effect as well as the specific cognitive functions affected remain unknown. The most reported deficits are in executive functions, attention and memory. An aetiological model suggests that sleep fragmentation and intermittent hypoxemia account for the development of cognitive impairment in OSA and may produce different patterns of cognitive decline (Beebe & Gozal, 2002). Additionally, research shows that excessive daytime sleepiness (EDS), a common symptom of OSA, plays an important role in neurocognitive dysfunction. Whether EDS is a result of sleep disruption, hypoxemia or it is an independent risk factor for neurocognitive dysfunction in OSA remains unclear. Research questions: This study investigated whether neuropsychological performance of OSA patients varies across group of patients with different OSA severity as well as from normative data and a comparative group. Moreover, this study explored whether the mean number of apneic events per hour (Apnea-Hypopnea Index/AHI), the length of time patients remain hypoxemic during sleep or EDS could predict particular neuropsychological deficits, while taking into account common OSA-related comorbidities. Finally, the relationship between AHI, desaturation indexes and EDS were analysed. Methods: Fifty-three participants were included (30 men, 23 women) aged 57.7 ± 10.9 years (range: 39–78 years); 38 were newly diagnosed, untreated OSA patients and 15 were controls. Participants were recruited from a group of patients referred for an evaluation of clinically suspected OSA. All participants underwent ambulatory PSG and neuropsychological evaluation. Degree of hypoxemia was operationalised by the average number of desaturations per hour (ODI) and time spent with saturation below 90% (SpO2<90%). Degree of disease severity/sleep fragmentation was represented by the AHI and EDS was characterized by Epworth Sleepiness Scale (ESS) scores. Findings: Compared to normative data, severely affected OSA patients presented mild impairment in a global cognitive measure (MoCA; z= -1.2). An analysis of the entire OSA cohort revealed moderate to severe deficits in attention, immediate verbal recall and delayed recall in 18.9%, 15.8% and 39.5% of the patients, respectively; mild to moderate deficits in visual memory in 18.4% of the patients as well as deficits in cognitive flexibility performance in 31.6% of the total OSA sample. Significant difference in the Digit Span Backward performance was detected between mild and moderate OSA patients (p=.017). However, this difference disappeared after the impact of slowed information processing was controlled (p>.05). Higher levels of EDS were associated with lower performance in the Stroop Test, regardless of disease severity (.20 ± .52 vs. -.33 ± .63 vs. -.35± .35, mild vs. moderate vs. severe EDS, p= .016). AHI and ODI were highly correlated (r=.90), AHI and ODI were moderately correlated with SpO2<90% (r=.45, r=.55, respectively). EDS did not significantly correlate with AHI or ODI, yet it was weakly, negatively correlated with SpO2<90% (r=-.40). Conclusion: The relationship between cognition and apnea severity is not completely linear. Severely affected patients presented deficits in general cognitive performance, yet no such deficits were observed in mild and moderate OSA patients. Although no further evidence of profound cognitive impairment was found in OSA patients when analysed according to disease severity, an analysis of the whole OSA sample revealed sustained attention, memory and cognitive flexibility deficits. Disease severity, desaturation indexes and EDS were not significant contributors to the prediction of these deficits, suggesting that perhaps another unexplored factor may account for cognitive impairment in OSA. Results revealed that increased subjective EDS was associated with poorer inhibitory control performance in apneic patients, substantiating the well-known detrimental effects of poor sleep on the prefrontal cortex circuitry. EDS was not associated with apnea or desaturation index, however, longer desaturations were associated with less sleep complains. Overall, this study emphasizes the impact of OSA on cognition as well as the importance of the psychological aspects of the disorder. The lack of access to full polysomnographic data and the modest sample size may have limited the investigation of the OSA-cognitive dysfunction association.
- Lauroylated histidine-enriched S4(13)-PV peptide as an efficient gene silencing mediator in cancer cellsPublication . Morais, Catarina M.; Cardoso, Ana M.; Aguiar, Luisa; Vale, Nuno; Nóbrega, Clévio; Zuzarte, Monica; Gomes, Paula; Pedroso de Lima, Maria C.; Jurado, Amalia S.PurposeThis study aimed to endow the cell-penetrating peptide (CPP) S4(13)-PV with adequate features towards a safe and effective application in cancer gene therapy.MethodsPeptide/siRNA complexes were prepared with two new derivatives of the CPP S4(13)-PV, which combine a lauroyl group attached to the N- or C-terminus with a histidine-enrichment in the N-terminus of the S4(13)-PV peptide, being named C12-H-5-S4(13)-PV and H-5-S4(13)-PV-C12, respectively. Physicochemical characterization of siRNA complexes was performed and their cytotoxicity and efficiency to mediate siRNA delivery and gene silencing in cancer cells were assessed in the absence and presence of serum.ResultsPeptide/siRNA complexes prepared with the C12-H-5-S4(13)-PV derivative showed a nanoscale (ca. 100 nm) particle size, as revealed by TEM, and efficiently mediated gene silencing (37%) in human U87 glioblastoma cells in the presence of 30% serum. In addition, the new C12-H-5-S4(13)-PV-based siRNA delivery system efficiently downregulated stearoyl-CoA desaturase-1, a key-enzyme of lipid metabolism overexpressed in cancer, which resulted in a significant decrease in the viability of U87 cells. Importantly, these complexes were able to spare healthy human astrocytes.ConclusionsThese encouraging results pave the way for a potential application of the C12-H-5-S4(13)-PV peptide as a promising tool in cancer gene therapy.