Showing papers by "Peretz Lavie published in 2012"

Age- and gender-related characteristics of obstructive sleep apnea.

Abstract: The present study attempted to characterize the phenotype of men and women of different ages with a laboratory diagnosis of obstructive sleep apnea (OSA) using demographic, subjective complaints and medical history and to determine the best fitting apnea–hypopnea index (AHI) cutoff point for OSA diagnosis in each group. Data collected from 23,806 patients examined by a whole-night polysomnography were retrospectively analyzed. First, descriptive analysis was used to determine the gender-specific relationship between AHI and age, then binary logistic regression was used to determine the best fitting gender- and age-specific AHIs and the predictors of OSA in each age and gender group. Of the total number of patients, 70.7% had AHI >10, and men had consistently higher AHI than women. OSA severity rose linearly with age in normal-weight and obese women and in normal-weight men. The best fitting AHI cutoff point increased with age in both genders. Obesity and snoring were significant predictors of OSA in all age by gender groups, while hypertension and excessive daytime sleepiness were common to all men and the two older women groups. Insomnia-related complaints were negative predictors of obstructive sleep apnea syndrome (OSAS) in some of the groups. OSAS severity varies with age in both genders, while women have less severe syndrome in all ages. Obesity, snoring, hypertension, and excessive daytime sleepiness are OSAS predictors in both genders, while insomnia-related complaints are negative predictors.

Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling

Abstract: Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA) characterized by nightly intermittent hypoxia (IH). This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH) using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated the IH-induced Mcl-1 increase. In SH, only p38MAPK inhibition decreased Mcl-1 expression. Similar to neutrophils of healthy subjects exposed to IH (0.97± 0.2), in OSA neutrophils, Bax/Mcl-1 ratio was significantly lower compared to normoxic controls (1.0±0.5 vs.1.99±0.3, p=0.015), and Bax did not co-localize with mitochondria. These findings suggest that decreased Bax/Mcl-1 balance promotes neutrophil survival in IH in-vitro as well as in OSA patients. Moreover, Bax/Mcl-1 protein function in IH and SH might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.

CrossTalk opposing view: Most cardiovascular diseases in sleep apnoea are not caused by sympathetic activation

Abstract: graduatedfromtheDepartmentofBiologyattheTechnion–IsraelInstituteofTechnologyandobtainedpostdoctoraltrainingatHarvardMedicalSchool.CurrentlysheisanAssociateProfessorandtheHeadoftheLloydRiglerSleepApneaResearchLaboratoryintheRuthandBruceRappaportFaculty of Medicine, Technion. She specialized in biochemistry, cellular biology and inflammation.Her current research is aimed at understanding the pathophysiological mechanisms which lead tocardiovascular morbidity in sleep apnoea syndrome.

Screening for sleep disordered breathing among applicants for a professional driver's license

Abstract: Objectives:Individuals with sleep disordered breathing (SDB) are at high risk for falling asleep while driving. The aim of this study was to identify variables that would predict SDB among healthy young applicants for a professional driver's license.Method:A total of 301 applicants for a driver's li

Rebuttal from Lena Lavie and Peretz Lavie

Abstract: By arguing that only sympathetic activity is responsible for cardiovascular morbidities in OSAS, Kohler & Stradling (2012) conveniently ignore a vast literature linking SA with oxidative stress. A PubMed search using the terms ‘sympathetic’ and ‘oxidative stress’ in the title/abstract revealed 366 publications. The evidence that ROS initiate SA and regulate sympathetic outflow from autonomic ganglia is overwhelming. Although Kohler and Stradling cited Prabhakar et al. (2009) to support their argument that IH augments chemoreflex-stimulated sympathetic outflow by modulating oxygen sensing in the carotid body, they ignored the fact that the IH-mediated carotid body plasticity requires redox signalling, a fundamental finding indicated in the title. The mechanisms by which IH elevates ROS include activation of various NADPH oxidases, mitochondrial dysfunction, down-regulation of antioxidant enzymes, and AngII-dependent ROS formation resulting in hypertension (Lee & Griendling, 2008). Accordingly, in a double-blind placebo-controlled, randomized, crossover design, subjecting healthy humans to experimental IH increased blood pressure (BP) through activation of type I AngII (AT1) receptors and oxidative stress, and decreased nitric oxide (NO) metabolites. Moreover, treatment with losartan, an AT1 receptor blocker, abolished oxidative stress, improved NO bioavailability and prevented the IH-dependent increase in BP (Foster et al. 2010; Pialoux et al. 2011). Earlier, Mohan et al. (2001) demonstrated that decreased NO bioavailability was responsible for the increased sympathetic activation after 21 days of IH. These findings unequivocally support the involvement of ROS in elevating BP and augmenting sympathetic outflow under IH conditions. Although Kohler and Stradling accepted that ‘laboratory studies may support plausible hypothesis’ they doubted their ‘relevance to clinical medicine’. To support their position they cite failure of some studies to lessen cardiovascular risks by antioxidant treatments, while accepting the success of randomized controlled studies to treat hypertension in OSAS. We disagree with this position. First, although successful CPAP therapy attenuates BP and SA in OSAS, CPAP also attenuates ROS production and oxidative stress. Second, failure of clinical trials with antioxidants treatment to prevent cardiovascular events emphasizes the importance of laboratory studies to understand the complexity of various ROS sources, their intra/extracellular sites of action and their interactions with other ROS to promote cardiovascular diseases. Intakes of non-specific antioxidants, such as vitamin E, do not neutralize all ROS and cannot reverse oxidative stress in vivo. Furthermore, because of the heterogeneity of ROS sources and the polymorphism of the enzymes producing them, decreased concentrations in a particular ROS by an antioxidant do not imply that all other types of ROS will be abolished. Therefore, inhibiting the systems producing ROS, rather than scavenging ROS after being formed, is the appropriate approach to prevent cardiovascular sequelae. Targeting NADPH oxidases in vascular disease is an ongoing promising therapeutic methodology, which only laboratory research can provide (Drummond et al. 2011). Thus, it should be recognized that although SA contributes to hypertension and cardiovascular sequelae in OSAS, the dominant role of oxidative stress in activating SA is essential (Lavie & Lavie).