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Summary: Breathing disorders in sleep are prevalent phenomena profoundly affecting the cardiovascular system. Mortality studies of sleep apnea patients revealed maximum risk of dying in younger patients and a pronounced age-decline in relative mortality reaching non significant levels in patients older than 50 years. We hypothesize that the age decline mortality risk in sleep apnea can be explained by cardiovascular and cerebrovascular protection conferred by ischemic preconditioning resulting from the nocturnal cycles of hypoxia-reoxygenation. The association of ischemic preconditioning with increase levels of vascular endothelial growth factor, increased production of oxygen reactive species, heat shock proteins, adenosine, and TNF-α, all demonstrated in sleep apnea, provide preliminary support to our hypothesis. [Copyright &y& Elsevier]

Obstructive sleep apnea (OSA), a breathing disorder in sleep characterized by intermittent hypoxia and sleep fragmentation, constitutes an independent risk factor for cardiovascular morbidity. Investigating how this breathing disorder modulates immune responses may facilitate understanding one of the risk factors for atherosclerosis. T cells play a significant role in atherogenesis and plaque development via cytokine production and by directly contributing to vascular injury. Using flow cytometry and chromium release assays, we found that CD4 and CD8 T cells of OSA patients undergo phenotypic and functional changes and acquire cytotoxic capabilities. Thus, a shift in CD4 and CD8 T cells toward type 2 cytokine dominance with increased IL-4 expression was noted. IL-10 expression in T cells was negatively correlated with the severity of OSA, as determined by the apnea-hypopnea index (AHI), whereas TNF-α was positively correlated. CD8 T cells of OSA patients expressed a fourfold increase in TNF-α and CD40 ligand (CD40L), and exhibited an increased OSA severity-dependent cytotoxicity against endothelial cells. The percentage of CD4+CD28null and cytotoxicity of CD4 T lymphocytes were also significantly higher in OSA patients than in controls. Nasal continuous positive airway pressure (nCPAP) treatment, which ameliorated the severity of OSA, significantly lowered TNF-α and CD40L expression, and decreased cytotoxicity in CD8 T cells. In conclusion, increased cytotoxicity and cytokine imbalance in CD4 and CD8 T cells may be involved in atherogenesis in OSA. Nasal CPAP treatment ameliorates some lymphocyte dysfunctions and thus may moderate some atherogenic pathways. [ABSTRACT FROM AUTHOR]

Background: There is accumulated evidence that plasma concentration of the sulfur-containing amino-acid homocysteine (Hcy) is a prognostic marker for cardiovascular morbidity and mortality. Both fasting levels of Hcy and post methionine loading levels are used as prognostic markers. The aim of the present study was to investigate the existence of a daily rhythm in plasma Hcy under strictly controlled nutritional and sleep-wake conditions. We also investigated if the time during which methionine loading is performed, i.e., morning or evening, had a different effect on the resultant plasma Hcy concentration. Methods: Six healthy men aged 23-26 years participated in 4 experiments. In the first and second experiments, the daily rhythm in Hcy as well as in other amino acids was investigated under a normal or an inverse sleep-wake cycle. In the third and fourth, Hcy concentrations were investigated after a morning and evening methionine loading. To standardize food consumption in the first two experiments, subjects received every 3 hours 150 ml of specially designed low-protein liquid food (Ensure® formula). Results: In both the first and second experiments there was a significant daily rhythm in Hcy concentrations with a mid-day nadir and a nocturnal peak. Strikingly different 24-h patterns were observed in methionine, leucine, isoleucine and tyrosine. In all, the 24-h curves revealed a strong influence of both the sleep-wake cycle and the feeding schedule. Methionine loading resulted in increased plasma Hcy levels during both morning and evening experiments, which were not significantly different from each other. Conclusions: There is a daily rhythm in plasma concentration of the amino acid Hcy, and this rhythm is independent of sleep-wake and food consumption. In view of the fact that increased Hcy concentrations may be associated with increased cardiovascular risks, these findings may have clinical implications for the health of rotating shift workers. [ABSTRACT FROM AUTHOR]

Sleep apnea syndrome has been shown to be associated with decreased levels of circulating nitric oxide (NO) after waking up from sleep. In this study we investigated overnight plasma concentrations of NO in sleep apnea patients before and after nasal continuous positive airway pressure (nCPAP) treatment and the effects of nCPAP on morning levels of L-arginine. In experiment 1, NO concentrations measured hourly during sleep were found to be significantly lower in a group of eight sleep apnea patients in comparison with six age-similar snorers and six normal young adults. In experiment 2, overnight NO concentrations were compared in 5 sleep apnea patients before and 9.3±3.9 mo after treatment with nCPAP. A significant increase in NO concentrations was found in four out of five patients, and a significant increase in L-arginine was found in all five patients after treatment. In experiment 3, removal of nCPAP for a single night in seven sleep apnea patients caused a significant decrease in morning levels of NO and L-arginine. These results demonstrate that sleep apnea is associated with a chronic state of diminished circulating NO concentrations that can be ameliorated by nCPAP treatment. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of obstructive sleep apnea syndrome (OSAS) by ambulatory systems is a growing practice in view of the large number of patients awaiting correct diagnosis. The Watch PAT100 (WP100) [Itamar Medical; Caesarea, Israel] is a portable device based on the peripheral arterial tone (PAT) signal, and is designed for unattended home sleep studies. Objectives: To evaluate the efficacy, reliability, and reproducibility of the WP100 device for the diagnosis of OSAS as compared to in-laboratory, standard polysomnographic-based manual scoring. Design and methods: One hundred two subjects (78 men; 69 patients with OSAS and 33 normal volunteers; mean ± SD age, 41.4 ± 15.2 years; body mass index, 26.8 ± 5.5) underwent in laboratory full polysomnography simultaneously with WP100 recording. Fourteen subjects also underwent two additional unattended home sleep studies with the WP100 alone. The polysomnography recordings were blindly scored for apnea/hypopnea according to the American Academy of Sleep Medicine criteria (1999), and the polysomnography respiratory disturbance index (RDI) [PSG-RDI] was calculated. The WP100 data were analyzed automatically for the PAT RDI (PRDI) by a proprietary algorithm that was previously developed on an independent group of subjects. Results: Across a wide range of RDI levels, the PRDI was highly correlated with the PSG-RDI (r = 0.88, p < 0.0001), with an area under the receiver operating characteristic curve of 0.82 and 0.87 for thresholds of 10 events per hour and 20 events per hour, respectively. The PRDI scores were also highly reproducible, showing high correlation between home and in-laboratory sleep studies (r = 0.89, p < 0.001). Conclusion: The WP100 may offer an accurate, robust, and reliable ambulatory method for the detection of OSAS, with minimal patient discomfort. [ABSTRACT FROM AUTHOR]

SUMMARY Disturbed sleep is a common complaint among patients with post-traumatic stress disorder (PTSD). However, laboratory studies of sleep in PTSD have provided inconsistent evidence of objective sleep disturbances. A major shortcoming of most previous studies is the fact that they were performed retrospectively in patients with chronic PTSD, often complicated by comorbid psychiatric disorders and drug abuse. Thus, little is known about the development of sleep disturbances in recently traumatized subjects. In this study, 102 motor vehicle collision (MVC) survivors were followed from the time of collision throughout 1 year. Nineteen subjects hospitalized for elective surgery served as a comparison group. Subjective quality of sleep was assessed using the mini-Sleep Questionnaire and the Sleep Habit Questionnaire. In addition, a 48-h actigraphic recording was obtained 1 week, 3 and 12 months after the collision. At 12 months, a structured clinical interview (SCID) was administered to reach a formal diagnosis of PTSD. Twenty-six of the MVC survivors, but none of the comparison subjects, met the diagnostic criteria for PTSD. While MVC survivors with PTSD reported markedly poorer sleep as reflected by significantly higher scores on the mini-Sleep Questionnaire, there were no significant differences between the three groups on the actigraphic measures that were largely normal. These results, which were obtained in subjects with no evidence of active psychiatric symptoms at the time of trauma and free of psychotropic or hypnotic medications, further support previous polysomnographic (PSG) studies suggesting that altered sleep perception, rather than sleep disturbance per se , may be the key problem in PTSD. [ABSTRACT FROM AUTHOR]

Cheyne-Stokes breathing (CSB), which is a prevalent finding in congestive heart failure (CHF) patients, has been shown to be of prognostic value. The oscillations in respiration were shown to be associated with oscillations in sympathetic nerve activation. We tested the hypothesis that the peripheral arterial tone (PAT) as measured by a novel finger plethysmograph can be used to detect CSB. Using a novel technique to measure the PAT, we monitored 10 patients with advanced CHF simultaneously with conventional polysomnographic recordings for either 1 or 2 nights. Records were scored for CSB during 3-min periods based on either respiratory effort and nasal-buccal airflow or on the PAT signal alone. The PAT sensitivity and specificity for the detection of periods containing CSB were 91 and 91% for the entire recording, 90.7 and 92.9% for non-REM sleep, 90.7 and 70% for REM sleep, and 73 and 97.3% for awake periods, respectively. PAT is a reliable marker of CSB in CHF patients. The novel finger plethysmograph can be used for screening and monitoring CSB.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

There is only scant information on sleep characteristics and long-term follow-up in patients with Kleine–Levin syndrome (KLS). This study describes the clinical course, results of polysomnography and long-term follow-up in a relatively large group of patients with KLS. During the years 1982–97, we encountered 34 patients (26 males and eight females) with KLS. We were able to obtain the original polysomnographs from 28 males and four females. In 25 patients, data regarding their present state of health were obtained. Fourteen agreed to be present at a detailed interview and examination while 11 gave the information by phone. The mean age at onset was 15.8 ± 2.8 years and the mean diagnostic delay, 3.8 ± 4.2 years. The mean duration of a single hypersomnolent attack was 11.5 ± 6.6 days. The main abnormal findings extracted out of 35 polysomnographs obtained from 32 patients during and/or in-between attacks included: decreased sleep efficiency, and frequent awakenings from sleep stage 2. All 25 patients reported present perfect health, with no evidence of behavioral or endocrine dysfunction. In adolescents with periodic hypersomnia, the diagnosis of KLS should be explored. Sleep recordings during a hypersomnolent period will often show frequent awakenings from sleep stage 2. The long-term prognosis is excellent. [ABSTRACT FROM AUTHOR]

Presents a study which compared the age-dependent severity and clinical profile of men and women with polysomnographically-documented obstructive sleep apnea syndrome. Review of related literature; Characteristics of the patients; Methods used; Results and discussion.

Objectives: Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality. Plasma levels of homocysteine are also associated with cardiovascular morbidity and mortality. We therefore investigated homocysteine and conventional cardiovascular risk factors in OSA patients with and without cardiovascular morbidity in comparison with normal control subjects and ischemic heart disease (IHD) patients without OSA. Setting: Technion Sleep Medicine Center, Haifa, Israel. Methods and participants: Levels of homocysteine, cholesterol, low-density lipoprotein, highdensity lipoprotein, triglycerides, creatinine, vitamins B[sub 12] and B[sub 6], and folic acid were determined in 345 participants after overnight fasting. These included OSA patients with IHD (n = 49), with hypertension (n = 61), or without any cardiovascular disease (n = 127). Two control groups were employed: IHD patients without or with low likelihood for sleep apnea (n = 35), and healthy control subjects (n = 73). Results: After adjustment for age, body mass index, creatinine, and existence of diabetes mellitus, OSA patients with IHD had significantly higher homocysteine levels (14.6 ± 6.77 µmol/L) than all other groups including the IHD-only patients. Hypertensive OSA patients had comparable homocysteine levels to IHD patients (11.80 ± 5.28 µmol/L and 11.92 ± 5.7 µmol/L, respectively), while patients with OSA only had comparable levels to normal control subjects (9.85 ± 2.99 µmol/L and 9.78 ± 3.49 µmol/L, respectively). No differences in conventional cardiovascular risk factors or in vitamin levels were found between groups. Conclusions: Patients with the combination of IHD and OSA have elevated homocysteine levels. We hypothesize that these results may be explained by endothelial dysfunction combined with excess free-radical formation in OSA patients. [ABSTRACT FROM AUTHOR]

Presents information on a study which assessed whether sleep apnoea syndrome is an independent risk factor for hypertension. Methodology; Results of the study; Conclusions.

The role of melatonin in the regulation of reproduction in humans is still controversial. In the present study the effects of melatonin were examined, 6 mg given orally every day at 1700 h for 1 month in a double-blind, placebo controlled fashion, on the nocturnal secretory profiles of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and inhibin β in six healthy adult men. Serum concentrations of LH, FSH, testosterone and inhibin β were determined before and after treatment every 15 min from 1900 to 0700 h over 3 nights in a controlled dark-light environment with simultaneous polysomnographic sleep recordings. The following sleep parameters were determined: total recording time, sleep latency, actual sleep time, sleep efficiency, rapid eye movement (REM) sleep latency and percentages of sleep stages 2, 3/4 and REM. There were no statistically significant differences in all sleep parameters between baseline and placebo or between baseline and melatonin except for longer REM latency and lower percentage REM at baseline than under melatonin treatment. These are explained as reflecting first-night effect at baseline. The mean nocturnal LH, FSH, testosterone and inhibin β integrated nocturnal secretion values did not change during the treatment period. Likewise, their pulsatile characteristics during melatonin treatment were not different from baseline values. Taken together, these data suggest that long-term melatonin administration does not alter the secretory patterns of reproductive hormones in normal men. [ABSTRACT FROM PUBLISHER]

The role of melatonin in the regulation of human reproduction remains unclear. In the present study, we examined the influence of exogenous melatonin on pulsatile luteinizing hormone (LH), diurnal rhythm of testosterone, and endogenous melatonin profile in six healthy young adult males. To test the hypothesis that the effect of melatonin on LH or testosterone secretory patterns may be mediated through the benzodiazepine-(BNZ) γ-amino-butyric acid (GABA) receptor complex, a benzodiazepine receptor antagonist (Flumazenil) was administered. The study design comprised four 10-h (4:00 pm–2:00 am) testing periods. During each experimental period, subjects were given an oral dose of placebo, or 3 mg melatonin or 10 mg flumazenil, at 5:00 pm, in a randomized, double-blind, partially repeated Latin square design in the following combinations: placebo-placebo, placebo-melatonin, flumazenil-placebo, and flumazenil-melatonin. The following day, serum samples were obtained every 20 min between 4:00 pm and 2:00 am in a controlled light-dark environment for the determination of LH and melatonin levels. Serum testosterone concentrations were determined every 20 min between 7:00 and 8:00 am and 7:00 and 8:00 pm. A significant decrease in mean serum LH levels ( p < 0.02) was observed in the melatonin-treated groups as compared with placebo-flumazenil groups. There was no change in LH pulse frequency, testosterone levels, or in melatonin onset time and amplitude. No additional effect of flumazenil on LH or testosterone levels was observed. These data indicate that an evening melatonin administration decrease the next-day LH secretion in normal adult males without altering testosterone levels or the endogenous nocturnal melatonin secretory pattern. This effect of melatonin is not mediated through the benzodiazepine-GABA receptor complex. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop an inexpensive, simplified home monitoring system for prescreening certain sleep complaints and for long-term home-based experiments. Four subjects slept in the laboratory for 3-4 nights. In addition to a standard polysomnogram, piezoelectric ceramic transducers were attached to both hands, both feet, and over the right eyelid. The sleep from 2 nights of each subject was staged according to the standard criteria. The limb transducers identified major and minor body shifts and were used to signal possible state changes. The data from the eye movement sensor was used to develop a REM-state algorithm. Using this algorithm, REM and NREM sleep were identified with 92% (SD=0.091) and 91% (SD=0.076) accuracy, respectively. The ultimate goal is to have a bedside device programmed with the algorithm that would either store information or score the data on-line for waking, NREM, and REM states. We conclude that a system monitoring eye movements and major body shifts is a promising approach to an economical and accurate home recording system. [ABSTRACT FROM AUTHOR]

Several investigators have observed ultradian rhythmicities in physiological indices of arousal. Although EEG biofeedback has been widely explored as a means of auto-regulating cortical arousal, alpha or theta enhancement has not yet been convincingly demonstrated in comparison to continuous baseline controls for the possible effect of endogenous cyclical arousal trends. Diurnal EEG and subjectively appraised arousal measures were recorded from 11 subjects on a 5-min recording, 5- min recovery schedule, continuously over 7½ hrs. Subjects returned to the laboratory for an equal amount of recording during which they attempted to either raise or lower the frequency of their EEG with the aid of biofeedback. Significant ultradian rhythmicity centered at about 200 min/cycle was observed in EEG measures and in subjectively appraised arousal. Although eyes-open frequency- raising and frequency-lowering biofeedback training was efficacious in comparison to long-day baselines, eyes-closed frequency-lowering training was not, lending support to other studies which have failed to achieve overall eyes-closed alpha or theta enhancement even with many hours of training. Because the observed ultradian and circadian EEG rhythmicities could be spuriously interpreted as learning curves under a biofeedback paradigm, it is argued that future designs should incorporate continuous baseline controls. [ABSTRACT FROM AUTHOR]

Abstract. Two studies were conducted to evaluate actigraphic home-monitoring for the assessment of infants' and children's sleep patterns. In the first study, 11 children (aged 12 to 48 months) were monitored in the laboratory by traditional polysomnography and by actigraphy for one night. Actigraphic automatic sleep-wake scorings were compared with those of the polysomnograph; total agreement rate was 85.3%. In the second study, sleep patterns of 63 sleep-disturbed and 34 control healthy children (aged 9 to 27 months) were compared. These children were home-monitored by actigraph for a mean of 4.45 nights (total 482 nights). Actigraphic data were analyzed by an automated scoring procedure. Sleep quality of the sleep-disturbed children, measured by actigraphically derived sleep percent and number of longer-than-5-minute wakings, was significantly lower than that of the control subjects (P < .0001). Sleep measures showed significant night-to-night stability in both groups. The stability of specific measures and their age trends were different between the groups. Actigraphic sleep measures alone could discriminate between sleep-disturbed and control children with a highly correct assignment rate of 79.4% and 91.2%, respectively. Pediatrics 1991;87:494-499; infants, sleep problems, home-monitoring, actigraph. [ABSTRACT FROM AUTHOR]

Recently we have demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. Testosterone administration to these patients decreased melatonin secretion to normal levels. These data, however, did not exclude a gonadotropic effect on melatonin secretion. To further elucidate whether gonadal steroids and/or gonadotropins modulate melatonin secretion in humans we compared untreated young males with hypogonadotropic hypogonadism (IGD, n=6), and hypergonadotropic hypogonadism caused by Kleinfelter's syndrome (KS, n=11) to normal pubertal male controls ( n=7). KS patients were subdivided into two groups: KS-1, with low testosterone; and KS-2, with normal testosterone levels. Serum samples for melatonin concentrations were obtained every 15 min from 7 pm to 7 am in a controlled lightdark environment with simultaneous sleep recordings. All KS patients had elevated gonadotropin levels and decreased melatonin levels. Mean (±SD) darktime nocturnal melatonin levels in KS-1 were 92±21 pmol/L and were 146±46 pmol/L in KS-2 compared with 178±64 pmol/L in controls. Integrated nocturnal melatonin secretion values (AUC) were 64±14 pmol/min×L×10 in KS-1 and 96±29 pmol/min×L×10 in KS-2 compared with 116±42 pmol/min×L×10 in controls. All IGD patients had low gonadotropin and testosterone levels. Their darktime melatonin levels (286±26 pmol/L) and the AUC values (184±15 pmol/min/L×10) were increased. These data indicate that melatonin secretion is increased in male patients with GnRH deficiency and decreased in low testosterone hypergonadotropic hypogonadal patients. Taken together, our results suggest that both gonadotropins and gonadal steroids modulate melatonin secretion in humans. [ABSTRACT FROM AUTHOR]

The effect of two dosages of sarmazenil (RO 15-3505) on sleep propensity and performance was investigated in a double-blind, placebo-controlled paradigm. The design included three 24-h testing periods, separated by at least one 7-day rest period, commencing after 24-h of sleep deprivation. Twelve normal, healthy, adult males (mean age 27±2.8 years) were paid to participate. During the experimental periods, they came to the sleep laboratory at 2100 hours and spent the night awake under close supervision. At 0700 hours, a schedule of 7 min 'attempting' sleep in bed, 13 min awake outside the bedroom, began. This schedule was maintained for 24 h. Repeated administrations of 1 mg and 2 mg sarmazenil significantly reduced the 24-h levels of total sleep. This was particularly evident during the period 0700-2300 hours. Sarmazenil also significantly improved reaction time and tended to increase the number of correct responses in the 'categories search' task. Sarmazenil tended to improve reaction time in the 'Stroop' test but this was significant only for the 'easy' version of the test during the night. [ABSTRACT FROM AUTHOR]

Sleep data were obtained on 11 patients who had survived traumatic events and who complained of sleep disturbances. Each was awakened from REM and non-REM sleep for dream recall. The patients bad lower sleep efficiency indices (because of prolonged sleep latency and larger amounts of "awake" plus "movement" time within sleep periods), shorter REM time, and longer REM latencies than did control subjects. Four of the 11 patients had REM- and non-REM-related nightmares, which, in two sea disaster patients, were associated with REM-related motor activity. The rest of the patients bad unusually low dream recall in spite of high eye movement density. [ABSTRACT FROM AUTHOR]

The article discusses an association between cardiovascular diseases and obstructive sleep apnea (OSA). It shows the effect of reactive oxygen species (ROS) and oxidative stress on patients with OSA. It assesses the inducement of cardiovascular consequences of OSA by sympathoexcitation and oxidative stress/inflammation. Other risk factors of OSA are identified, including hypertension, insulin resistance and diabetes mellitus.