Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state.

Obstructive sleep apnoea (OSA) is a cardio-metabolic disorder. Whether metabolic syndrome (MS), insulin resistance (IR) and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV) risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP) were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA) value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF) criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence) and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p < 0.001). The prevalence of microalbuminuria in both groups was negligible. Logistic regression adjusted for age, BMI and smoking showed that the patient with OSA was 5.9 (95% CI 2.0-17.6) times more likely to have MS than non-OSA patient. Triglyceride (p = 0.031), glucose (0.023) and Epworth score (0.003) values were independently associated with OSA after adjusting for BMI and other covariates whilst IR status was found not to be significant. Using the ROC curve analysis, we found that a waist circumference of >103 cm would predict MS in patients with OSA at 75-78% sensitivity and 61-64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.

Chronic benzodiazepine treatment of cells expressing recombinant GABA(A) receptors uncouples allosteric binding: studies on possible mechanisms.

Functional and behavioral tolerance to chronic benzodiazepine (BZ) exposure has been associated with an uncoupling of the BZ and GABA binding sites. As in rats exposed to BZ for periods of a week or longer, recombinant GABA(A) receptors (GABARs) expressed in Sf9 cells lose the normally observed allosteric enhancement of [3H]flunitrazepam binding by GABA agonists, which is measured in homogenized membranes after a few hours exposure to pharmacological doses of agonist BZ. Treatment of Sf9 cells expressing recombinant GABAR with various drugs that inhibit protein kinase A (PKA), but not protein kinase C (PKC), resulted in an uncoupling of the BZ and GABA binding sites; whereas promotion of phosphorylation by PKA, but not PKC, favored coupling and recoupling. However, mutation of the only PKA phosphorylation site expressed from among the subunits proved that direct phosphorylation of the GABAR was not involved in either coupling after chronic BZ exposure or reversal of uncoupling after exposure to the competitive BZ antagonist, flumazenil. Osmotic-shock of cell membrane homogenates to lyse intracellular compartments reversed uncoupling, and uncoupling can be replicated in untreated cells by performing membrane binding assays in an acidic environment, suggesting that GABARs become internalized into an acidic intracellular environment where normal BZ binding occurs, but that potentiation by GABA is hindered. The internalization of receptors was shown by immunofluorescence after chronic exposure to either BZ or the PKA inhibitor H-89.

Sleep disordered breathing: effects of adenotonsillectomy on behaviour and psychological functioning.

UNLABELLED: Children on the adenotonsillectomy waiting list aged 6 years or more were screened by questionnaire and overnight sleep monitoring to identify 12 with a moderate sleep and breathing disorder (SBD) group. They were matched by age and sex with 11 children who had a similar history of snoring and sleep disturbance but without an obvious sleep and breathing problem when monitored (snorer group) and also with a group of ten children most of whom were refered for an unrelated surgical procedure (control group). All children were studied before and 3-6 months after surgery. Pre-operatively the SBD and snorer groups both had significantly more restless sleep than the control group. The SBD group also had significantly more (> 4%) dips in oxygen saturation than the other two groups. After surgery there were no longer any significant differences between the three groups. After adenotonsillectomy the SBD group showed a significant reduction in aggression, inattention and hyperactivity on the parent Conners scale, and an improvement in vigilance on the Continuous Performance Test. The snorer group also improved showing less hyperactive behaviour than pre-operatively and better vigilance. The control groups's behaviour and performance did not change significantly. There were no significant changes in the performance of the Matching Familiar Figures Test in any of the groups. CONCLUSION: Relief of mild to moderate sleep and breathing disorders in children is associated with improved behaviour and functioning. We confirm previous work which suggests that the relation between sleep disordered breathing and daytime problems in children is a causal one.

Bronchopulmonary infection with Pseudomonas aeruginosa in patients infected with human immunodeficiency virus.

BACKGROUND: Pseudomonas aeruginosa infection is uncommon in HIV infected patients and is usually nosocomially acquired and associated with risk factors such as neutropenia or central lines. We have recently noted an increase in the number of respiratory isolates of Ps aeruginosa in hospitalised HIV positive patients and sought to describe the clinical correlates of this observation. METHODS: A retrospective case notes review of HIV positive patients admitted to a specialist unit for respiratory investigations from January 1989 to December 1993 was undertaken in order to identify those with Ps aeruginosa respiratory infection and to describe associated risk factors, patterns of presentation and radiographic abnormalities. RESULTS: Of 617 patients admitted 38 (6%) had Ps aeruginosa respiratory infection (notes were incomplete in 1 patient). All patients had advanced HIV disease; median CD4 = 0.02 x 10(9)/l. Two distinct presentations were seen; 9 patients had a fulminant course as part of a sepsis syndrome, 28 patients had an indolent presentation (18 had a single episode and 10 relapsed on one or more occasions, despite successful treatment of the initial episode). Infection was community acquired in 24 patients. Many patients had risk factors traditionally associated with Ps aeruginosa including neutropenia or indwelling central venous catheters, but 13 had no obvious risk factor. Most patients were receiving systemic pneumocystis prophylaxis and/or broad spectrum antibiotics; 20 had co-existent symptomatic sinus disease. A wide variety of chest radiographic abnormalities were seen including interstitial shadowing, mimicking pneumocystis pneumonia in 12 patients, lobar pneumonia in 2 and bronchial wall thickening in 13 patients. CONCLUSIONS: Ps aeruginosa respiratory infection occurs with increased frequency in patients with advanced HIV disease; in a significant proportion infection is community acquired. Although recognised risk factors were present in two thirds of patients it appears that advanced HIV immunosuppression, use of systemic pneumocystis prophylaxis and/or broad spectrum antibiotics and sinus disease are important risk factors. The diagnosis should be considered in patients with advanced HIV disease who present with new respiratory symptoms.

Testosterone levels during systemic and inhaled corticosteroid therapy.

Testosterone has importance both as a sex hormone and as an anabolic steroid promoting bone formation. Osteoporosis is associated with both hypogonadism and corticosteroid therapy. Testosterone levels are reduced by long term prednisolone treatment. Although high dose inhaled corticosteroid therapy may cause a variety of systemic effects including adrenal suppression, dermal thinning and a reduction in total bone calcium, its effect on testosterone levels is not known. Testosterone, luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin were therefore measured in 35 male patients with respiratory disease attending an outpatient clinic (median age 58, range 21-75 years). They were grouped according to steroid therapy and compared with 19 age matched controls. Mean (SD) testosterone levels were 33% lower in 12 men on long term oral prednisolone [14.5 (6.0) nmol 1-1] than in controls [21.7 (6.3) nmol 1-1], but were not significantly reduced in 10 patients on low dose inhaled beclomethasone [200-800 micrograms day-1: 19.7 (3.7)] nor in 13 men taking high dose inhaled beclomethasone [1500-2,250 micrograms day-1: 17.9 (5.6)]. Levels of luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin were similar in all four groups. These cross sectional data confirm that long term systemic corticosteroid therapy reduces testosterone levels. However, testosterone was reduced by only 18% (NS) by long term inhaled corticosteroids. Other mechanisms to explain the disordered bone metabolism should now be explored.

Natural history of snoring and related behaviour problems between the ages of 4 and 7 years.

In 1989-90 a survey was carried out of the prevalence of snoring and related symptoms in 782 4 to 5 year old children. Two years later, in 1992, the same group of children was studied to gather information on the natural history of snoring and the related behaviour problems. A total of 507/782 (64.8%) completed questionnaires were received. Comparison of the responses with the 1989-90 survey showed that those who did not reply to the questionnaire were no different from the respondents in terms of the prevalence of snoring, daytime sleepiness, hyperactivity, and restless sleep. The overall prevalence of habitual snoring did not change between the two surveys (12.1% in 1989-90 v 11.4% in 1992), though more than half of the children who snored habitually in the original survey no longer did so. There was little change in the prevalence of hyperactivity (24.2% in 1989-90 v 20.7% in 1992) or restless sleep (both 39%) among the 507 who responded to the present survey. The prevalence of daytime sleepiness, however, did decrease substantially (20.7% in 1989-90 v 10.2% in 1992). There was moderate agreement between the individual questionnaire responses for the 1989-90 and 1992 surveys for snoring (weighted kappa 0.52), but poor agreement for the other symptoms (daytime sleepiness 0.37, hyperactivity 0.35, and restless sleep 0.38). Trend analysis showed that the increasing prevalence of sleepiness, hyperactivity, and restless sleep across the snoring categories was highly significant. Daytime sleepiness, hyperactivity, and restless sleep were all significantly more common in the habitual snorers than in those who never snored. Relative risks (95% confidence interval) were as follows: daytime sleepiness 6.13 (2.5 to 14.9), hyperactivity 2.78 (1.6 to 4.7), and restless sleep 2.3 (1.6 to 3.2). Though habitual snoring and the associated behaviour problems resolved spontaneously over two years in about half of the children with these symptoms, there is still the same overall percentage with these problems due to the emergence of new cases.

Snoring, sleep disturbance, and behaviour in 4-5 year olds.

Parents of 996 children aged 4-5 years identified consecutively from the Oxford health visitor register were asked to complete a questionnaire about breathing disorders during sleep. A total of 782 (78.5%) was returned. Ninety five (12.1%) children were reported to snore on most nights. Habitual snoring was significantly associated with daytime sleepiness, restless sleep, and hyperactivity. The questionnaire responses were used to select two subgroups, one at high risk of a sleep and breathing disorder and a control group. These children (132 in total) were monitored at home with overnight video recording and oximetry, and had formal behavioural assessment using the Conners scale. Seven (7/66) children from the high risk group and none from the control group had obvious sleep disturbance consequent on snoring and upper airway obstruction. Thus our estimate of the prevalence of sleep and breathing disorders in this age group is 7/996 or 0.7%. The high risk group had significantly higher nocturnal movement, oxygen saturation dip rates, and overnight pulse rates than the controls. Maternal but not paternal smoking was associated with the high risk group. Parents and teachers thought those in the high risk group were more hyperactive and inattentive than the controls, but only their parents thought them more aggressive. Significant sleep and breathing disorders occur in about 0.7% of 4-5 year olds. Children whose parents report snoring and sleep disturbance have objective evidence of sleep disruption and show more behaviour problems than controls.

Arterial blood pressure responses to graded transient arousal from sleep in normal humans.

During obstructive sleep apnea, transient arousal at the resumption of breathing is coincident with a substantial rise in blood pressure. To assess the hemodynamic effect of arousal alone, 149 transient stimuli were administered to five normal subjects. Two electroencephalograms (EEG), an electrooculogram, a submental electromyogram (EMG), and beat-to-beat blood pressure (Finapres, Ohmeda) were recorded in all subjects. Stimulus length was varied to produce a range of cortical EEG arousals that were graded as follows: 0, no increase in high-frequency EEG or EMG; 1, increased high-frequency EEG and/or EMG for < 10 s; 2, increased high-frequency EEG and/or EMG for > 10 s. Overall, compared with control values, average systolic pressure rose [nonrapid-eye-movement (NREM) sleep 10.0 +/- 7.69 (SD) mmHg; rapid-eye-movement (REM) sleep 6.0 +/- 6.73 mmHg] and average diastolic pressure rose (NREM sleep 6.1 +/- 4.43 mmHg; REM sleep 3.7 +/- 3.02 mmHg) over the 10 s following the stimulus (NREM sleep, P < 0.0001; REM sleep, P < 0.002). During NREM sleep, there was a trend toward larger blood pressure rises at larger grades of arousal (systolic: r = 0.22, 95% confidence interval 0.02-0.40; diastolic: r = 0.48, 95% confidence interval 0.31-0.62). The average blood pressure rise in response to the grade 2 arousals was approximately 75% of that during obstructive sleep apnea. Arousal stimuli that did not cause EEG arousal still produced a blood pressure rise (mean systolic rise 8.6 +/- 7.0 mmHg, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone turnover during short course prednisolone treatment in patients with chronic obstructive airways disease.

BACKGROUND: Although osteoporosis is a well known side effect of long term prednisolone, the effects of a short course are less clear. Biochemical markers of bone turnover were therefore studied in 10 men with chronic obstructive airways disease who required assessment of "steroid reversibility" (mean age 65 years, mean FEV1 1.2 1). METHOD: Patients received, single blind, two weeks of placebo, four weeks of prednisolone 20 mg/day, and then two further weeks of placebo. RESULTS: The mean (SD) fasting urinary hydroxyproline:creatinine ratio, a marker of bone resorption, increased by 65% with prednisolone (from 8.9 (5.7) to 14.7 (8.5) mumol/mmol) and returned to baseline after placebo. Serum alkaline phosphatase, a marker of net bone formation, fell after prednisolone by 28% (from 113 (41) to 81 (30) IU/1). Substantial changes occurred after only two weeks of prednisolone. Serum osteocalcin, calcium, and phosphate concentrations did not change significantly. CONCLUSIONS: Short courses of prednisolone increased bone resorption and inhibited bone formation after two and four weeks.

The acute effects of continuous positive airway pressure and oxygen administration on blood pressure during obstructive sleep apnea.

We have measured blood pressure continuously with a digital artery blood pressure monitor in eight patients with severe obstructive sleep apnea (OSA) during 30 min each of wakefulness, OSA, OSA with added oxygen to keep saturation above 96 percent at all times (OSA+O2), and nasal continuous positive airway pressure (CPAP) therapy. Mean blood pressures were not different between wakefulness, OSA, OSA+O2, and CPAP, although the variability in blood pressure was significantly greater during OSA and OSA+O2 than during wakefulness and CPAP. The addition of oxygen did not attenuate the variability in blood pressure. Using multiple linear regression modeling to further dissect out the principal variables determining the postapneic blood pressure rise, we found that only apnea length (r2 = 0.28, p less than 0.0001) and pulse rate changes (r2 = 0.15, p less than 0.0001) remained significantly related to SBPmax, while hypoxemia did not. We found the same trends in the other variables SBPten, DBPmax, and DBPten. Hypoxemia made a small contribution to the size of DBPmax, although this was small by comparison with apnea length. We conclude that CPAP treatment of OSA does not lower mean blood pressure acutely, although it significantly reduces the large oscillations in blood pressure seen in patients with untreated OSA. The rise in blood pressure following each apnea is not primarily due to arterial desaturation but is related to apnea length and may be caused by increased sympathetic activity secondary to arousal.

Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome.

BACKGROUND: Neck circumference has been suggested to be more predictive of obstructive sleep apnoea than general obesity, but the statistical validity of this conclusion has been questioned. Combining neck circumference with other signs and symptoms may allow the clinical diagnosis or exclusion of sleep apnoea to be made with reasonable confidence. This study examines these issues. METHODS: One hundred and fifty patients referred to a sleep clinic for investigation of sleep related breathing disorders completed a questionnaire covering daytime sleepiness, snoring, driving, and nasal disease. Body mass index and neck circumference corrected for height were measured and obstructive sleep apnoea severity was quantified as number of dips in arterial oxygen saturation (SaO2) of more than 4% per hour of polysomnography. Multiple linear regression was used retrospectively to identify independent predictors of SaO2 dip rate, and the model derived was then prospectively tested in a further 85 subjects. RESULTS: The retrospective analysis showed that the question "Do you fall asleep during the day, particularly when not busy?" was the best questionnaire predictor of variance in the SaO2 dip rate (r2 = 0.13); no other question improved this correlation. This analysis also showed that neither body mass index nor any of the questionnaire variables improved the amount of variance explained by height corrected neck circumference alone (r2 = 0.35). A statistically similar prospective analysis confirmed this relationship (r2 = 0.38). CONCLUSIONS: Prospective study of these patients referred to a sleep clinic with symptoms suggesting sleep apnoea shows that neck circumference corrected for height is more useful as a predictor of obstructive sleep apnoea than general obesity. None of the questionnaire variables examined add to its predictive power, but alone it is inadequate to avoid the need for sleep studies to diagnose this disease.

Periodic movements of the legs during sleep associated with rises in systemic blood pressure.

We report the relationship between periodic leg movements during sleep and recurrent rises in systemic blood pressure in a patient with narcolepsy. The mean increase in systolic blood pressure following leg movements was 23%, which is of the same order as the rises seen in patients with obstructive sleep apnea. Following treatment with temazepam, the swings in blood pressure were unchanged despite considerably less electroencephalographic evidence of cortical arousal.

Bone turnover during high dose inhaled corticosteroid treatment.

This study was performed to determine the effects of high doses of two inhaled corticosteroids, beclomethasone dipropionate and budesonide, on biochemical indices of bone turnover (urinary hydroxyproline:creatine and calcium:creatinine ratios, plasma alkaline phosphatase, and parathyroid hormone). Twelve healthy male doctors, aged 25-36 (mean 30) years, were studied. After a week's run in period eight subjects inhaled beclomethasone dipropionate 2000 micrograms/day and eight inhaled budesonide 1800 micrograms/day for 28 days; this was followed by a week without any treatment. During treatment with beclomethasone dipropionate there was a significant increase in the hydroxyproline:creatinine ratio (a 46% increase at 28 days), and a fall in serum alkaline phosphatase activity (a 7.4% fall at 28 days). There were no significant changes during budesonide treatment. Thus high dose inhaled beclomethasone dipropionate increased biochemical markers of bone resorption and reduced serum alkaline phosphatase, a marker of bone mineralisation. A prospective study in asthmatic patients is indicated to assess the long term effects of high dose inhaled corticosteroids on bone mass.

The clinical spectrum and diagnosis of Mycoplasma pneumoniae infection.

The clinical, radiographic and microbiological data of 47 patients with Mycoplasma pneumoniae infection admitted to three Norfolk hospitals during a 20-month period between 1982 and 1983 have been reviewed. Thirty-nine presented with pneumonia and eight with non-pulmonary infection. The M. pneumoniae specific IgM test was positive in 42 of 45 patients tested (89 per cent); in 39 the levels were diagnostic on admission. Cold agglutinins were detected in 27 (57 per cent) and a fourfold rise in complement fixation titre was demonstrated in 13 (29 per cent). Sputum culture was positive in 12 (26 per cent). The extrapulmonary manifestations observed were haemolytic anaemia (17 per cent), Stevens Johnson syndrome (4.1 per cent), neurological abnormalities (4.1 per cent), arthritis (2.1 per cent), hepatitis (2.1 per cent) and pericarditis (2.1 per cent). One patient with multilobe pneumonia, pericardial effusion and haemolytic anaemia died. Six patients presented with a history of illness longer than a month; in three the clinical and radiographic picture suggested chronic disease (pulmonary tuberculosis, lymphoma and unresolving pneumonia). There were no distinctive clinical or radiographic features of M. pneumoniae infection. Diagnosis, therefore, relies on serological tests of which the most useful is the rapid, specific IgM test, positive in 86 per cent of the admission sera.

Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure.

52 severely ill asthmatic patients requiring acute admission to hospital entered a double-blind placebo-controlled trial to determine whether intravenous hydrocortisone given in addition to high-dose oral prednisolone and standard bronchodilator therapy accelerated recovery. Patients who had been given parenteral steroids before admission, by comparison with those who had not received such treatment, had been deteriorating for a shorter period before admission, had received more injected or nebulised bronchodilator therapy, and had higher admission peak flows. As judged by peak flow measurements 24 h after admission, parenteral steroids had no effect on the outcome, irrespective of whether they were given before or after (ie, intravenous hydrocortisone) admission. There is no evidence for the continued use of intravenous hydrocortisone in addition to oral prednisolone and bronchodilator therapy in patients admitted to hospital with severe asthma without ventilatory failure.