Obstruction of the upper airway during sleep (OSAS) is widely treated by having patients self-administer nasal continuous positive airway pressure (CPAP). To obtain objective evidence of the patterns of CPAP use, information was gathered from two urban sites on 35 OSAS patients who were prescribed CPAP for a total of 3,743 days. Patients were given CPAP machines that contained a microprocessor and monitor that measured actual pressure at the mask for every minute of each 24-h day for an average of 106 days per patient. They were not aware of the monitor inside the CPAP machines. Monitor output was compared with patients' diagnostic status, pretreatment clinical and demographic characteristics, and follow-up self-reports of CPAP use, problems, side effects, and aspects of daytime fatigue and sleepiness. Patients attempted to use CPAP an average of 66 +/- 37% of the days monitored. When CPAP was used, the mean duration of use was 4.88 +/- 1.97 h. However, patients' reports of the duration of CPAP use overestimated actual use by 69 +/- 110 min (p < 0.002). Both frequency and duration of CPAP use in the first month reliably predicted use in the third month (p < 0.0001). Although the majority (60%) of patients claimed to use CPAP nightly, only 16 of 35 (46%) met criteria for regular use, defined by at least 4 h of CPAP administered on 70% of the days monitored. Relative to less regular users, these 16 patients had more years of education (p = 0.05), and were more likely to work in professional occupations.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep-disordered breathing is a prevalent condition associated with impairment of daytime function and may predispose individuals to metabolic abnormalities independent of obesity. The primary objective of this study was to determine the metabolic consequences and community prevalence of sleep-disordered breathing in mildly obese, but otherwise healthy, individuals. One hundred and fifty healthy men, without diabetes or cardiopulmonary disease, were recruited from the community. Measurements included polysomnography, a multiple sleep latency test, an oral glucose tolerance test, determination of body fat by hydrodensitometry, and fasting insulin and lipids. The prevalence of sleep-disordered breathing, depending on the apnea-hypopnea index (AHI) cutoff, ranged from 40 to 60%. After adjusting for body mass index (BMI) and percent body fat, an AHI gt-or-equal, slanted 5 events/h was associated with an increased risk of having impaired or diabetic glucose tolerance (odds ratio, 2.15; 95% CI, 1.05-4.38). The impairment in glucose tolerance was related to the severity of oxygen desaturation (DeltaSa(O(2))) associated with sleep-disordered breathing. For a 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% CI, 1.11 to 3.56) after adjusting for percent body fat, BMI, and AHI. Multivariable linear regression analyses revealed that increasing AHI was associated with worsening insulin resistance independent of obesity. Thus, sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.

Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Collapsibility can be increased by underlying anatomic alterations and/or disturbances in upper airway neuromuscular control, both of which play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. They can increase pharyngeal collapsibility through mechanical effects on pharyngeal soft tissues and lung volume, and through central nervous system-acting signaling proteins (adipokines) that may affect airway neuromuscular control. Specific molecular signaling pathways encode differences in the distribution and metabolic activity of adipose tissue. These differences can produce alterations in the mechanical and neural control of upper airway collapsibility, which determine sleep apnea susceptibility. Although weight loss reduces upper airway collapsibility during sleep, it is not known whether its effects are mediated primarily by improvement in upper airway mechanical properties or neuromuscular control. A variety of behavioral, pharmacologic, and surgical approaches to weight loss may be of benefit to patients with sleep apnea, through distinct effects on the mass and activity of regional adipose stores. Examining responses to specific weight loss strategies will provide critical insight into mechanisms linking obesity and sleep apnea, and will help to elucidate the humoral and molecular predictors of weight loss responses.

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A partially purified preparation of the heatstable enterotoxin of EsMherichia coli caused a rapid and persistent increase in electric potential difference and short-circuit current when added in vitro to the luminal surface of isolated rabbit ileal mucosa. As little as 1 ng/ml produced an easily detectable response. Under short-circuit condition, the enterotoxin abolished net Cl-absorption; this change was half that produced by theophylline, which stimulated net secretion. The enterotoxin did not change cyclic AMP concentration but caused large and persistent increases in cyclic GMP concentration. The electrical and nucleotide responses exhibited similar and unusually broad concentration-ependences and maximal effects could not be demonstrated. Theophylline elevated cyclic GMP concentration 3fold both in the presence and absence of the enterotoxin, suggesting no effect of the toxin on cyclic GMP hosphodiesterase. Guanylate cyclase [GTP pyrophosphatelyase~cycizing); EC 4.6.1.21 activity in a crude membrane fraction from intestinal epithelial cells was stimulated 7-fold by the enterotoxin. These results suggest that guanylate cyclase stimulation is the basis for the toxin's diarrheagenic effect.Two enterotoxins have been identified among the extracellular products of Escherichia colh isolated from humans and other mammals with diarrheal disease-one heat-labile (1, 2) and the other heat-stable (1, 3, 4). The former is immunologically crossreactive with cholera toxin (5) and, like cholera toxin, stimulates adenylate cyclase (6). The latter acts more rapidly (7) and has a lower molecular weight [5000 or less (8) been equilibrated with 99% methanol/1% acetic acid. A broad peak of toxin activity appeared just behind the void volume.The eluate was reconcentrated and again filtered on Sephadex LH-20 that had been equilibrated with water. Toxin was then eluted with water and the eluate was stored in a refrigerator with preservatives. Even when stored for 6 wk at room temperature, no loss of activity could be detected. The final material was 200-to 1000-fold purified but still gave several peaks on silica gel chromatography. A detailed description of this procedure will be published elsewhere (W. J. Laird and D. M. Gill, unpublished data).Enterotoxin activity was assayed in suckling mice (9). Fifty-microliter aliquots of toxin in water were introduced by transabdominal injection into the stomachs of 2 to 4-day-old suckling mice (CD-1 Swiss white from Charles River Laboratories, Boston, MA). After 60 min the mice were killed with CHC13 and ratios of total intestinal weight to total body weight were determined. Control ratios were about 0.06 and maximal ratios were about 0.13. A mouse unit was defined as the amount of toxin producing a half-maximal increase in ratio. Serial 1:1 dilutions of toxin were assayed; three mice were used for each dilution.Three separately prepared batches of toxin were used for various phases of the present study. An aliquot from one of these batches was lyophilized and weighed: one mouse ...

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin‐deficient obese (C57BL/6J−Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl−1 on day 0 to 138 ± 10 mg dl−1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml−1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short‐term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time‐dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml−1 at baseline to 9.8 ± 1.8 ng ml−1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Human obesity leads to an increase in respiratory demands. As obesity becomes more pronounced some individuals are unable to compensate, leading to elevated arterial carbon dioxide levels (PaCO2), alveolar hypoventilation, and increased cardiorespiratory morbidity and mortality (Pickwickian syndrome). The mechanisms that link obesity and hypoventilation are unknown, but thought to involve depression of central respiratory control mechanisms. Here we report that obese C57BL/6J-Lepob mice, which lack circulating leptin, also exhibit respiratory depression and elevated PaCO2 (> 10 mm Hg; p < 0. 0001). A role for leptin in restoring ventilation in these obese, mutant mice was investigated. Three days of leptin infusion (30 microg/d) markedly increased minute ventilation (V E) across all sleep/wake states, but particularly during rapid eye movement (REM) sleep when respiration was otherwise profoundly depressed. The effect of leptin was independent of food intake, weight, and CO2 production, indicating a reversal of hypoventilation by stimulation of central respiratory control centers. Furthermore, leptin replacement in mutant mice increased CO2 chemosensitivity during non-rapid eye movement (NREM) (4.0 +/- 0.5 to 5.6 +/- 0.4 ml/min/%CO2; p < 0.01) and REM (-0.1 +/- 0.5 to 3.0 +/- 0.8 ml/min/%CO2; p < 0.01) sleep. We also demonstrate in wild-type mice that ventilation is appropriately compensated when obesity is diet-induced and endogenous leptin levels are raised more than tenfold. These results suggest that leptin can prevent respiratory depression in obesity, but a deficiency in central nervous system (CNS) leptin levels or activity may induce hypoventilation and the Pickwickian syndrome in some obese subjects. O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity.

Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established. Objectives: The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice. Methods: Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks. Measurements and Main Results: Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 ؎ 4 vs. 106 ؎ 6 mg/dl; p Ͻ 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1. Conclusions: CIH causes atherosclerosis in the presence of dietinduced dyslipidemia.Keywords: obstructive sleep apnea; lipids; hypoxia; mouse; stearoylcoenzyme A desaturaseObstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH) (1). OSA has been associated with an increased risk of hypertension, type II diabetes, angina, myocardial infarction, congestive heart failure, stroke, and fatal cardiovascular events, independent of underlying obesity (2-5).Poor cardiovascular outcomes may be related to the high prevalence of atherosclerosis in patients with OSA. Studies have shown independent associations between hypoxic stress of OSA and increased carotid artery intima-media thickness (6) as well as progressive narrowing of the coronary artery lumens (7).