Endothelial dysfunction and C-reactive protein in relation with the severity of obstructive sleep apnea syndrome

STUDY OBJECTIVES: To investigate flow-mediated dilatation (FMD) and C-reactive protein (CRP) levels in patients with obstructive sleep apnea syndrome (OSAS) in relation with the severity of respiratory disturbances and hypoxemia. DESIGN: After subjects had completed nocturnal polysomnography, FMD was measured in the brachial artery, and blood samples were obtained to determine serum CRP levels. SETTING: Sleep laboratory in Seoul National University Bundang Hospital. PATIENTS: Ninety men: 22 normal controls, 28 subjects with mild to moderate OSAS, and 40 with severe OSAS. MEASUREMENTS AND RESULTS: FMD was found to be correlated with oxygen desaturation index (ODI), percentage of time below 90% O2 saturation, average O2 saturation, lowest O2 saturation, systolic blood pressure, apnea hypopnea index (AHI), and body mass index. In addition, CRP was correlated with body mass index, waist-to-hip ratio, neck circumference, diastolic pressure, average O2 saturation and percentage of time below 90% O2 saturation but not with AHI. Stepwise multiple regression showed that the ODI was a significant determinant of FMD (adjusted R2 = 10%, beta = -0.33, P < 0.01). In addition, body mass index (beta = 0.25, P < 0.05) and waist-to-hip ratio (beta = 0.21, P < 0.05) were found to be significantly correlated with CRP (adjusted R2 = 12%, P < 0.05), independently of other factors. There was no correlation between FMD and CRP. CONCLUSION: As a marker of nocturnal hypoxemia, ODI rather than AHI might better explain the relationship between OSAS and FMD. Because body mass index and waist-to-hip ratio were identified as risk factors of high serum CRP in OSAS, obesity should be considered when predicting cardiovascular complications in OSAS.     

Nocturnal oximetry parameters as predictors of sleep apnea severity in resource-limited settings

Nocturnal oximetry is an alternative modality for evaluating obstructive sleep apnea syndrome (OSAS) severity when polysomnography is not available. The Oxygen Desaturation (≥3%) Index (ODI3) and McGill Oximetry Score (MOS) are used as predictors of moderate-to-severe OSAS (apnea-hypopnea index-AHI >5 episodes/h), an indication for adenotonsillectomy. We hypothesised that ODI3 is a better predictive parameter for AHI >5 episodes/h than the MOS. All polysomnograms performed in otherwise healthy, snoring children with tonsillar hypertrophy in a tertiary hospital (November 2014 to May 2019) were analysed. The ODI3 and MOS were derived from the oximetry channel of each polysomnogram. Logistic regression was applied to assess associations of ODI3 or MOS (predictors) with an AHI >5 episodes/h (primary outcome). Receiver operating characteristic (ROC) curves and areas under ROC curves were used to compare the ODI3 and MOS as predictors of moderate-to-severe OSAS. The optimal cut-off value for each oximetry parameter was determined using Youden's index. Polysomnograms of 112 children (median [interquartile range] age 6.1 [3.9–9.1] years; 35.7% overweight) were analysed. Moderate-to-severe OSAS prevalence was 49.1%. The ODI3 and MOS were significant predictors of moderate-to-severe OSAS after adjustment for overweight, sex, and age (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.19–1.51); and OR 4.10, 95% CI 2.06–8.15, respectively; p < 0.001 for both). Area under the ROC curve was higher for the ODI3 than for MOS (0.903 [95% CI 0.842–0.964] versus 0.745 [95% CI 0.668–0.821]; p < 0.001). Optimal cut-off values for the ODI3 and MOS were ≥4.3 episodes/h and ≥2, respectively. The ODI3 emerges as preferable or at least a complementary oximetry parameter to MOS for detecting moderate-to-severe OSAS in snoring children when polysomnography is not available.     

Social inequalities in sleep‐disordered breathing: Evidence from the CoLaus|HypnoLaus study

Sleep‐disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep‐disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle‐related behaviours such as smoking and alcohol use, may also be risk factors for sleep‐disordered breathing. Here, we investigate the associations between socioeconomic status and sleep‐disordered breathing, as measured by sleep apnea–hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle‐related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population‐based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep‐disordered breathing was assessed through polysomnography and measured using the apnea–hypopnea index (AHI: number of apnea/hypopnea events/hr: ≥15/≥30 events), and the ≥3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: ≥15/≥30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population‐based study, we found that low socioeconomic status is a risk factor for sleep‐disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep‐disordered breathing and may help implement policies for identifying high‐risk profiles for this disorder.     

Interleukin 6 as a marker of depression in women with sleep apnea

Depression is common in women with obstructive sleep apnea (OSA), but objective markers of depression have not yet been explored in such patients. We hypothesized that inflammation and antioxidant biomarkers may be associated with depression in a cohort of OSA women. We conducted a multicentre, cross‐sectional study in 247 women diagnosed with moderate‐to‐severe OSA. Depression was assessed by the depression subscale of the Hospital Anxiety and Depression Questionnaire (HAD‐D) and defined as a score ≥11. Associations between tumour necrosis factor α (TNFα), interleukin 6 (IL‐6), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), catalase (CAT), superoxide dismutase (SOD) and brain‐derived neurotrophic factor (BDNF) plasma levels and depression were assessed. The women had a median (25th‐75th percentiles) age of 58 (51–65) years, body mass index (BMI) of 33.5 (29.0–38.3) Kg/m², Epworth Sleepiness Scale (ESS) score of 10 (6–13) and apnea–hypopnea index (AHI) of 33.3 (22.8–49.3). Logistic regression analyses revealed that only IL6 levels were associated with the presence of depression (adjusted odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08–1.34), whereas linear regression further confirmed that IL6 levels were significantly associated with HAD‐D scores (β = .154; 95% CI, 0.03–0.30). Multivariate regression analysis showed that IL6 (OR, 1.22; 95% CI, 1.09–1.36), ESS (OR, 1.10; 95% CI 1.02–1.19) and physical activity <30 min/day (OR, 2.51; 95% CI, 1.25–5.05) were independent predictors of depression. Thus, we conclude that in a cohort of women with moderate‐to‐severe OSA, IL6 levels are independently associated with the presence of depression and correlate with depression scores. Low physical activity and higher ESS scores are also independent indicators of risk of depression in this population.     

The relationship between sleep-disordered breathing and high-sensitivity C-reactive protein in Japanese men

STUDY OBJECTIVES: Elevated C-reactive protein (CRP), an inflammatory marker and emerging risk factor for atherosclerosis and coronary heart disease, has been reported in overweight patients with sleep-disordered breathing (SDB). However, the contribution of C-reactive protein to this disease among non-overweight individuals is uncertain. We thus examined the relationship between serum C-reactive protein levels and nocturnal arterial oxygen desaturation, stratified by category of body mass index (BMI). DESIGN: Cross-sectional study. PARTICIPANTS: Subjects were 316 men with a mean BMI of 25.4 kg/m2, aged 20-79 years, who attended a sleep clinic at Osaka, Japan. MEASUREMENTS AND RESULTS: SDB was assessed by oxygen desaturation index (ODI) measured by pulse oximetry during sleep. We used 3% oxygen desaturations per hour (3% ODI), as the indicator of SDB. We also measured serum levels of C-reactive protein (CRP). After adjustment for age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking status, alcohol consumption, and daily sleep duration, mean high-sensitivity CRP levels were 0.63, 0.65, and 0.96 mg/L for SDB severity levels of 3%ODI<5, 5 to 19.9, and >=20, respectively (p for trend=0.015). This association with SDB tended to be stronger in non-overweight men (BMI<25 kg/m2) (0.47, 0.48 and 1.02 mg/L, p for trend=0.017) than in overweight men (BMI > or = 25 kg/m2) (0.92, 0.87 and 1.21 mg/L, p for trend=0.11). CONCLUSION: SDB is associated with increased levels of CRP, especially in non-overweight men. Our results suggest the importance of follow-up and control of SDB in the prevention of cardiovascular disease even in non-overweight SDB patients.     

Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness

Centrally active agents have a variable impact in patients with obstructive sleep apnoea (OSA) that is unexplained. How to phenotype the individual OSA response is clinically important, as it may help to identify who will be at risk of respiratory depression and who will benefit from a centrally active agent. Based on loop gain theory, we hypothesized that OSA patients with higher central chemosensitivity have higher breathing instability following the use of a hypnosedative, temazepam. In 20 men with OSA in a double‐blind, placebo‐controlled cross‐over trial we tested the polysomnographically (PSG) measured effects of temazepam 10 mg versus placebo on sleep apnoea. Treatment nights were at least 1 week apart. Ventilatory chemoreflexes were also measured during wakefulness in each subject. The patients (mean ± standard deviation; 44 ± 12 years) had predominantly mild‐to‐moderate OSA [baseline apnoea–hypopnoea index (AHI) = 16.8 ± 14.1]. Patients’ baseline awake central chemosensitivity correlated significantly with both the change of SpO₂ nadir between temazepam and placebo (r = ?0.468, P = 0.038) and oxygen desaturation index (ODI; r = 0.485, P = 0.03), but not with the change of AHI (r = 0.18, P = 0.44). Peripheral chemosensitivity and ventilatory recruitment threshold were not correlated with the change of SpO₂ nadir, ODI or AHI (all P > 0.05). Mild–moderate OSA patients with higher awake central chemosensitivity had greater respiratory impairment during sleep with temazepam. Relatively simple daytime tests of respiratory control may provide a method of determining the effect of sedative–hypnotic medication on breathing during sleep in OSA patients.     

Selective blockade of endothelial NF‐κB pathway differentially affects systemic inflammation and multiple organ dysfunction and injury in septic mice

Endothelium has long been considered both a source and a target of systemic inflammation. However, to what extent endothelial activation contributes to systemic inflammation remains unclear. This study addresses the relative contribution of endothelial activation to systemic inflammation and multiple organ dysfunction and injury (MOD/I) in an E. coli peritonitis model of sepsis. We prevented endothelial activation using transgenic (TG) mice that conditionally overexpress a mutant I‐κBα, a NF‐κB inhibitor, selectively on endothelium. TG mice and their transgene negative littermates (WT) were injected with saline or E. coli (10⁸ CFU per mouse). At 7 h after E. coli infection, markers of systemic inflammation, endothelial activation, and MOD/I were assessed. WT‐E. coli mice showed significantly increased serum levels of TNF‐α, IL‐1β, IFN‐γ, IL‐6, KC, and MCP‐1; tissue levels of TNF‐α, IL‐6, KC, MCP‐1, ICAM‐1, and VCAM‐1; endothelial leakage index in heart, lungs, liver, and kidney; significantly increased serum levels of AST, ALT, BUN, and creatinine; and increased mortality. Blockade of NF‐κB‐mediated endothelial activation in TG mice had no effects on serum levels of TNF‐α, IL‐1β, IFN‐γ, IL‐6, KC, and MCP‐1 (markers of systemic inflammation), and tissue levels of TNF‐α, IL‐6, KC, and MCP‐1, but significantly reduced tissue levels of ICAM‐1 and VCAM‐1 (markers of endothelial inflammation and activation) in those four organs. TG‐E. coli mice displayed reversed endothelial leakage index; reduced serum levels of AST, ALT, BUN, and creatinine; and improved survival. Our data demonstrate that endothelial NF‐κB‐driven inflammatory response contributes minimally to systemic inflammation, but plays a pivotal role in septic MOD/I, suggesting that endothelium is mainly a target rather than a source of systemic inflammation. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Synergistic effect of interleukin‐17 and tumour necrosis factor‐α on inflammatory response in hepatocytes through interleukin‐6‐dependent and independent pathways

The proinflammatory cytokines interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α are targets for treatment in many chronic inflammatory diseases. Here, we examined their role in liver inflammatory response compared to that of IL‐6. Human hepatoma cells (HepaRG, Huh7.5 and HepG2 cells) and primary human hepatocytes (PHH) were cultured with IL‐6, IL‐17 and/or TNF‐α. To determine the contribution of the IL‐6 pathway in the IL‐17/TNF‐α‐mediated effect, an anti‐IL‐6 receptor antibody was used. IL‐17 and TNF‐α increased in synergy IL‐6 secretion by HepaRG cells and PHH but not by Huh7.5 and HepG2 cells. This IL‐17/TNF‐α synergistic cooperation enhanced the levels of C‐reactive protein (CRP) and aspartate aminotransferase (ASAT) in HepaRG cell and PHH cultures through the induction of IL‐6. IL‐17/TNF‐α also up‐regulated IL‐8, monocyte chemoattractant protein (MCP)‐1 and chemokine (C‐C motif) ligand 20 (CCL20) chemokines in synergy through an IL‐6‐independent pathway. Interestingly, first exposure to IL‐17, but not to TNF‐α, was crucial for the initiation of the IL‐17/TNF‐α synergistic effect on IL‐6 and IL‐8 production. In HepaRG cells, IL‐17 enhanced IL‐6 mRNA stability resulting in increased IL‐6 protein levels. The IL‐17A/TNF‐α synergistic effect on IL‐6 and IL‐8 induction was mediated through the activation of extracellular signal‐regulated kinase (ERK)‐mitogen‐activated protein kinase, nuclear factor‐κB and/or protein kinase B (Akt)–phosphatidylinositol 3‐kinase signalling pathways. Therefore, the IL‐17/TNF‐α synergistic interaction mediates systemic inflammation and cell damage in hepatocytes mainly through IL‐6 for CRP and ASAT induction. Independently of IL‐6, the IL‐17A/TNF‐α combination may also induce immune cell recruitment by chemokine up‐regulation. IL‐17 and/or TNF‐α neutralization can be a promising therapeutic strategy to control both systemic inflammation and liver cell attraction.     

Sex influences endothelial function in sleep-disordered breathing

BACKGROUND: The bases for the association between sleep-disordered breathing (SDB) and cardiovascular disease are poorly understood. Endothelial dysfunction, assessed with brachial artery ultrasonography, may predict cardiovascular risk and represent preclinical vascular disease. We determined whether flow-mediated dilation (FMD) and peak blood flow (PBF) increase after cuff occlusion is altered with SDB. METHODS: 193 participants (58% women) in a cohort study were studied with overnight polysomnography and subsequent brachial artery ultrasonography. SDB was quantified using the apnea-hypopnea index (AHI) and indexes of overnight desaturation and arousal frequency. Two-dimensional and Doppler-velocity measurements of the brachial artery were obtained at baseline and after 5 minutes of upper-arm cuff occlusion. FMD and PBF were defined as the percentage changes from baseline in brachial artery diameter and flow, respectively. RESULTS: In the entire sample, the AHI was inversely associated with both FMD (r = -0.30, P < .001) and PBF (r = -0.20, P < .001). However, sex-stratified univariate analyses showed that these relationships were exclusive to women. Specifically, FMD was significantly lower in women with an AHI > or = 15 than in women with lower AHI scores (P < .005), with no relationship between AHI and FMD in men. Additionally, PBF decreased significantly with increasing AHI (r = -0.29, P = .010) in women alone. Statistical modeling, adjusting for body mass index, age, and other covariates, similarly showed that SDB severity significantly influenced FMD and PBF, with significant interactions between sex and AHI, reinforcing that the associations between SDB severity and endothelial function were stronger in women than in men. CONCLUSIONS: Moderate levels of SBD are associated with impaired conduit and resistance endothelial function in women. Women with SDB may be more vulnerable to early SDB-related cardiovascular disease than are men.     

Screening for subclinical sleep-disordered breathing

We evaluated self-administered questionnaires and short sleep studies in screening for sleep-disordered breathing (SDB) in 40 hypertensive men ages 36-66 unselected for symptoms. Each subject completed a questionnaire including questions on sleep-related symptoms and underwent overnight polysomnography in which we evaluated the apnea-hypopnea index (AHI) and the percentage of time during which arterial O2 saturation was less than 90% (T90). The first 90 min of overnight study was evaluated separately, and 10 subjects with an AHI greater than or equal to 10 also underwent late afternoon nap study. By overnight polysomnography, 48% of the cohort had an AHI greater than or equal to 10, and 35% had a T90 greater than or equal to 10%. Using linear regression, we found no features of the symptom questionnaire that strongly predicted AHI. Only self-reported snoring and baseline arterial Po2 significantly predicted T90. The AHI and T90 were not significantly correlated. Considering an AHI greater than or equal to 10 in the overnight study as "abnormal" and an AHI greater than or equal to 10 on the short study as a "positive" test, the specificity of the AHI in the first 90 min was 100% (21/21), and the sensitivity was 42% (8/19). The sensitivity of the nap study was 60% (6/10). We conclude that in a cohort unselected for symptoms, the ability of self-administered questionnaires to predict SDB was low; short studies were only moderately sensitive for detecting an AHI greater than or equal to 10, and the AHI was not a major determinant of nocturnal desaturation.     

Social support moderates the relationship between sleep and inflammation in a population at high risk for developing cardiovascular disease

Poor sleep and low social support have each been associated with mortality and morbidity from chronic illness, and a small body of research suggests that the two interact to influence systemic inflammation whereby good social relationships may buffer the relationship between poor sleep and increased inflammation. The current study investigated interactions between sleep and social support in the prediction of inflammation in a clinical population (prehypertensive and hypertensive individuals) at high risk for the development of cardiovascular disease. Using a standardized subjective measure of sleep quality, we found that social support moderated the association between sleep and circulating levels of both IL‐6 and CRP, such that poor sleep appeared to confer a risk of increased inflammation only in those participants who also reported low social support. In women, the same relationship was observed for TNF‐α. These results extend previous findings into a clinical population and also demonstrate that sleep quality and social support interact in the prediction of two previously uninvestigated clinically relevant inflammatory markers (CRP and TNF‐α). High levels of perceived social support may compensate for the negative health impact of poor sleep quality and vice versa.     

Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation

Background Probiotics are widely studied both in the treatment and prevention of allergic diseases, but their mode of action is poorly known. Objective Our aim was to examine the effect of probiotic bacteria on in vivo cytokine, antibody, and inflammatory responses in allergy‐prone infants. Methods In a randomized double‐blind study, probiotic bacteria or placebo were given for 1 month before delivery to mothers and for 6 months to infants with a family history of allergy. Plasma samples were analysed for C‐reactive protein (CRP), total IgA and IgE, food‐specific IgA, IgG, and IgE, IL‐2, IL‐4, IL‐6, IL‐10, TNF‐α, and IFN‐γ. We analysed the associations of immunological and inflammatory parameters at age 6 months with probiotic treatment and allergic phenotype at 2 years. Results Infants receiving probiotic bacteria had higher plasma levels of CRP (P=0.008), total IgA (P=0.016), total IgE (P=0.047), and IL‐10 (P=0.002) than infants in the placebo group. Increased plasma CRP level at age 6 months was associated with a decreased risk of eczema [odds ratio (OR) 0.41 [95% confidence interval (CI) 0.17–0.99], P=0.046], and with a decreased risk of allergic disease [OR 0.38 (95% CI 0.16–0.87), P=0.023] at age 2 years, when adjusted with probiotic use. Conclusion The association of CRP with a decreased risk of eczema at 2 years of age in allergy‐prone children supports the view that chronic, low‐grade inflammation protects from eczema. Probiotic‐induced low‐grade inflammation was characterized by elevation of IgE, IgA, and IL‐10, the changes typically observed in helminth infection‐associated induction of regulatory mechanisms. The findings emphasize the role of chronic microbial exposure as an immune modulator protecting from allergy.     

CPAP治疗阻塞型睡眠呼吸暂停综合征前后患者血清IL-6和TNF-α的动态变化

目的：通过研究阻塞型睡眠呼吸暂停综合征（OSAS）患者血浆白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的水平及经持续气道正压通气（CPAP）治疗前后的变化,探讨IL-6和TNF-α在OSAS患者发病机制及病理生理中的作用。方法：①选择我院OSAS患者60例及正常人30例,详细询问病史,对所有观察对象于晨起采集静脉血标本,采用放射免疫分析集中检测血浆IL-6、TNF-α水平。比较OSAS组与对照组间血浆IL-6、TNF-α水平的差异;分析OSAS患者血浆IL-6、TNF-α水平与睡眠呼吸暂停低通气指数（AHI）和最低血氧饱和度的相关性。②OSAS组患者进行CPAP治疗并随访,3个月后复查上述各项指标,比较OSAS患者经CPAP治疗前后血浆IL-6、TNF-α水平等指标变化。结果：OSAS组患者血浆IL-6和TNF-α水平分别为（25.92±4.48）pg/ml,（11.27±2.60）pg/ml。较对照组升高（13.21±1.97）pg/ml,（5.83±0.99）pg/ml差异有统计学意义。②OSAS患者血浆IL-6和TNF-α水平与其AHI均呈正相关,相关系数分别为0.456（P〈0.05）,0.464（P〈0.05）。OSAS患者血浆IL-6和TNF-α水平与其最低血氧饱和度均呈负相关,相关系数分别为-0.495（P〈0.05）,-0.483（P〈0.05）。③OSAS患者进行CPAP治疗并随访,3个月后回访20例,再次测定血浆IL-6、TNF-α水平,分别为（15.37±1.78）pg/ml,（6.79±0.87）pg/ml较治疗前减低,差异有统计学意义。结论：CPAP治疗能有效地降低OSAS患者的血浆IL-6及TNF-α水平。     

Inflammatory markers and bariatric surgery: a meta-analysis

Objective

Obesity is a state of chronic low grade inflammation with increased levels of inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF) α. The changes of some of the above markers after bariatric surgery are not consistent across studies. The objective of this study is to confirm the changes in blood levels of CRP, IL-6 and TNFα after bariatric surgery.

Methods

A Pubmed and EMBASE search was performed for studies measuring the above cytokines in blood before and after bariatric surgery. A meta-analysis was performed for the changes in CRP, TNFα and IL-6 for the maximum follow-up time in each study as well as for discrete follow-up times.

Results

Only observational studies could be retrieved. Bariatric surgery produces about 66 and 27?% reduction in CRP and IL-6 levels, respectively. The change in TNFα after bariatric surgery did not approach statistical significance.

Conclusion

Bariatric surgery decreases the low grade inflammation associated with obesity as measured by CRP and IL-6 levels. The change of TNFα after bariatric surgery should be further investigated with randomized trials.     

Correlation between the severity of obstructive sleep apnea and heart rate variability indices

The risk of cardiovascular disease is known to be increased in obstructive sleep apnea syndrome (OSAS). Its mechanism can be explained by the observation that the sympathetic tone increases due to repetitive apneas accompanied by hypoxias and arousals during sleep. Heart rate variability (HRV) representing cardiac autonomic function is mediated by respiratory sinus arrhythmia, baroreflex-related fluctuation, and thermoregulation-related fluctuation. We evaluated the heart rate variability of OSAS patients during night to assess their relationship with the severity of the symptoms. We studied overnight polysomnographies of 59 male untreated OSAS patients with moderate to severe symptoms (mean age 45.4+/- 11.7 yr, apnea-hypopnea index [AHI]=43.2+/-23.4 events per hour, and AHI >15). Moderate (mean age 47.1+/-9.4 yr, AHI=15-30, n=22) and severe (mean age 44.5 +/-12.9 yr, AHI >30, n=37) OSAS patients were compared for the indices derived from time and frequency domain analysis of HRV, AHI, oxygen desaturation event index (ODI), arousal index (ArI), and sleep parameters. As a result, the severe OSAS group showed higher mean powers of total frequency (TF) (p=0.012), very low frequency (VLF) (p= 0.038), and low frequency (LF) (p=0.002) than the moderate OSAS group. The LF/HF ratio (p=0.005) was higher in the severe group compared to that of the moderate group. On the time domain analysis, the HRV triangular index (p=0.026) of severe OSAS group was significantly higher. AHI was correlated best with the LF/HF ratio (r(p))=0.610, p<0.001) of all the HRV indices. According to the results, the frequency domain indices tended to reveal the difference between the groups better than time domain indices. Especially the LF/HF ratio was thought to be the most useful parameter to estimate the degree of AHI in OSAS patients.     

Plasma IL‐6 concentration correlates with clinical disease activity and serum C‐reactive protein concentration in chronic urticaria patients

Background Our previous study was the first to demonstrate enhanced plasma IL‐6 concentrations in chronic urticaria (CU). It is known that C‐reactive protein (CRP) is a sensitive marker of an underlying systemic inflammation, triggered mainly as a response to IL‐6. Objective To evaluate plasma IL‐6 concentration in CU patients relating to the clinical disease activity and serum CRP concentration. Methods Serum CRP and plasma IL‐6 concentrations were measured in 58 CU patients and 30 healthy subjects. Ten CU patients were evaluated twice, during the active period as well as upon the spontaneous clinical remission of the disease. CU activity was assessed with the use of the symptom scores recommended by EAACI/GALEN/EDF guidelines. Results IL‐6 and CRP concentrations were significantly increased in CU patients as compared with the healthy subjects, whereas they decreased remarkably upon the spontaneous remission. IL‐6 concentration was associated with weekly urticaria activity scores and also significant differences were found between patients showing different degrees of urticarial activity. Significant correlation was observed between IL‐6 and CRP concentrations. Conclusions and Clinical Relevance This study reinforces evidence that, apart from a local cutaneous inflammation, CU is associated with a systemic inflammatory response. Such acute‐phase response is manifested by increased circulating IL‐6, which varies along with CRP changes and may be related to the urticarial activity. Cite this as: A. Kasperska‐Zajac, J. Sztylc, E. Machura and G. Jop, Clinical & Experimental Allergy, 2011 (41) 1386–1391.     

Sclerostin,TNF‐alpha and Interleukin‐18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients

Patients with chronic renal failure are known to have renal osteodystrophy (bone disease) and increased calcification of vessels. A new marker of bone disease, sclerostin, the two pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐alpha) and interleukin‐18 (IL‐18), and the fibroblast growth factor‐23 (FGF‐23) receptor‐associated marker Klotho were tested in 84 haemodialysis (HD) patients and in healthy controls. The patients had significantly higher levels of the three former markers than of the controls while Klotho was significantly higher in the controls. Low level, but significant, correlations were observed in the patient group when the levels of these four markers were compared to each other and to those of 5 cytokines and growth factors tested earlier; high‐sensitive CRP (hsCRP), interleukin‐6 (IL‐6), hepatocyte growth factor (HGF), fibroblast growth factor‐23 (FGF‐23) and soluble urokinase plasminogen activator (suPAR). Ln sclerostin correlated positively to Ln hsTNF‐alpha, Ln HGF and Ln suPAR. Ln hsTNF‐alpha correlated positively to Ln sclerostin, Ln hsCRP, Ln IL‐6, Ln FGF‐23, Ln suPAR and Ln IL‐18. Ln IL‐18 correlated positively to Ln suPAR and Ln TNF‐alpha. Ln Klotho correlated negatively to Ln hsCRP but did not correlate to Ln FGF‐23. The markers studied here may be involved in the calcification of vessels seen in HD patients due to a combination of inflammation and bone disease. The mechanisms are still not fully known but may be of importance for future therapeutic possibilities in this group of patients.     

ORIGINAL ARTICLE: Immune Status,Psychosocial Distress and Reduced Quality of Life in Infertile Patients with Endometriosis

Problem The aim of the study was to identify if (i) psychosocial factors differ in endometriosis; (ii) related psychosocial aspects alter immune markers of depression/sickness behaviour; and (iii) serum immune marker may be indicative for endometriosis. Method of study We enrolled 103 women in a case–control study. Psychosocial data were obtained, serum levels of interleukin (IL)‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12, IL‐13, interferon (IFN)‐γ, TNF‐α, IFN‐α and soluble intercellular adhesion molecule‐1 (sICAM‐1) were analysed. Results Among 69 eligible patients, endometriosis was diagnosed in 38 women. Patients with endometriosis reported reduced quality of life, increased stress perception/depressive symptoms; the Th1/Th2 ratio was in favour of Th1, accompanied by the increased levels of IFN‐α. sICAM‐1 levels were unaffected. No correlation could be confirmed between psychosocial and immune markers. Conclusion Women with endometriosis may benefit from strategies contributing to reduction of stress and development of coping mechanisms, thus helping to break the vicious circle of inflammation, sickness behaviour and depression.     

Association between obstructive sleep apnea severity and endothelial dysfunction in an increased background of cardiovascular burden

The objective of this study is to examine whether increasing obstructive sleep apnea (OSA) severity is associated with worsening endothelial function. The design is a cross‐sectional examination of the baseline assessment of a multi‐centre randomized controlled clinical trial examining the effects of oxygen, continuous positive airway pressure (CPAP) therapy or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an apnea–hypopnea index (AHI) of 15–50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included. OSA severity indices [oxygen desaturation index (ODI), AHI and percentage of sleep time below 90% oxygen saturation (total sleep time <90)] and a measure of endothelium‐mediated vasodilatation [Framingham reactive hyperaemia index (F‐RHI) derived from peripheral arterial tonometry (PAT)] were assessed. The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 SD and mean F‐RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F‐RHI differed above and below an ODI of 24.6 (P = 0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% [95% confidence interval (CI): 0%, 5%; P = 0.05], while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: 0%, 27%; P = 0.05) per 5‐unit increase in ODI. A similar pattern was observed between AHI and F‐RHI. No relation was noted with total sleep time <90 and F‐RHI. There was evidence of a graded decline in endothelial function in association with higher levels of intermittent hypoxaemia.     

Associations between sleep apnea and advanced brain aging in a large-scale population study

Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer’s dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea–hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.