Sleep apnea in patients with myasthenia gravis.

To assess the prevalence of obstructive sleep apnea (OSA) in myasthenia gravis, the authors identified patients at risk of OSA using the multivariable apnea prediction index. OSA was diagnosed with polysomnography. The prevalence of OSA was 36% compared to an expected prevalence of 15 to 20% in the general population. When including the presence of daytime sleepiness (OSA syndrome), the prevalence was 11% compared to 3% in the general population.

Sleep. 5: Driving and automobile crashes in patients with obstructive sleep apnoea/hypopnoea syndrome.

Driving is a complex task involving distinct cognitive, perceptual, motor, and decision making skills. After placing the vehicle on the road, the driver must constantly survey the ever changing roadway environment to keep the vehicle in the lane and moving at an appropriate safe speed. This surveillance involves two distinct visual tasks: estimating and responding to the oncoming curvature and controlling lane position. Driving is therefore a divided attention task involving speed and lane control as well as monitoring. To do this in a safe manner requires careful attention and alertness which can be problematic for patients with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) or other sleep disorders.

A secreted protein from the human hookworm necator americanus binds selectively to NK cells and induces IFN-gamma production.

Parasitic helminths induce chronic infections in their hosts although, with most human helminthiases, protective immunity gradually develops with age or exposure of the host. One exception is infection with the human hookworm, Necator americanus, where virtually no protection ensues over time. Such observations suggest these parasites have developed unique mechanisms to evade host immunity, leading us to investigate the role of the excretory/secretory (ES) products of adult N. americanus in manipulating host immune responses. Specifically, we found that a protein(s) from ES products of adult N. americanus bound selectively to mouse and human NK cells. Moreover, incubation of purified NK cells with N. americanus ES products stimulated the production of augmented (4- to 30-fold) levels of IFN-gamma. This augmentation was dependent on the presence of both IL-2 and IL-12 and was endotoxin-independent. This is the first report of a pathogen protein that binds exclusively to NK cells and the first report of a nematode-derived product that induces abundant levels of cytokines from NK cells. Such an interaction could provide a means of cross-regulating deleterious Th2 immune responses in the host, thereby contributing to the long-term survival of N. americanus.

The implementation of Tomorrow's Doctors.

BACKGROUND: In 1993 the General Medical Council published its recommendations on undergraduate medical education. AIM: To study the implementation of these recommendations in UK medical schools by means of informal visitations. METHODS: Teams consisting of 3-5 members visited the 25 UK medical schools in a 3-year period commencing in early 1995. RESULTS: Substantial changes have occurred in undergraduate medical education since the publication of Tomorrow's Doctors. Of the 13 principal recommendations, 3 had been implemented in most medical schools and a further 8 substantially implemented by the majority. However, progress in health promotion and the development of appropriate assessment schemes has been slower. CONCLUSIONS: Informal visits have served a useful purpose in monitoring the implementation of the General Medical Council's recommendations on undergraduate medical education. In addition, they have encouraged dialogue with the medical schools and allowed the identification of examples of good practice including the establishment by most schools of medical education units.

Pyrazolopyrimidines.

Pharmacological therapy has an important role in the management of insomnia. Although older drugs are highly effective for initiating and maintaining sleep, tolerance and withdrawal effects as well as impairment of daytime performance are commonly troublesome and limit their use. Aided by increased knowledge of gamma-aminobutyric acid (GABA) and its receptors, new hypnotic sedatives have been developed that are increasingly selective for the various subunits of the GABA receptor. This development has produced newer agents with very favourable hypnotic profiles and side-effect profiles that provide better treatment options for medical practitioners. The pyrazolopyrimidines, the latest in this area, seem to offer some advantages over other agents.

Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP.

BACKGROUND: Patients with untreated obstructive sleep apnoea (OSA) have increased motor vehicle collisions (MVCs). When successfully treated, they report improved driving and fewer mishaps, but there are few objective data to confirm this. A study was therefore undertaken to examine actual MVC data in a large group of patients with OSA before and after treatment with continuous positive airway pressure (CPAP) compared with a control group matched for age, sex, and type of driver's licence (commercial or non-commercial). METHODS: Two hundred and ten patients of mean (SD) age 52 (11) years, body mass index (BMI) 35.5 (10) kg/m(2), apnoea/hypopnoea index (AHI) 54 (29) events/h were treated with CPAP for at least 3 years. MVC records were obtained from the Ontario Ministry of Transportation (MTO) database for patients and an equal number of randomly selected control drivers. MVC rates were compared for 3 years before and after CPAP therapy for patients and for the corresponding time frames for controls. RESULTS: Untreated patients with OSA had more MVCs than controls (mean (SD) MVCs/driver/year 0.18 (0.29) v 0.06 (0.17), p<0.001). Following CPAP treatment the number of MVCs/driver/year fell to normal (0.06 (0.17)) while, in controls, the MVC rate was unchanged over time (0.06 (0.17) v 0.07 (0.18), p=NS). Thus, the change in MVCs over time between the groups was very significant (change = -0.12 (95% CI -0.17 to -0.06), p<0.001)). The MVC rate in untreated patients (n=27) remained high over time. Driving exposure was not different following CPAP. CONCLUSIONS: The risk of MVCs due to OSA is removed when patients are treated with CPAP. As such, any restrictions on driving because of OSA could be safely removed after treatment.

Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides.

A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in delta-selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the delta address, the structural features identified to promote delta receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include hydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower mu/delta selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an overall lower delta and higher mu affinity to the piperidine-based ligands. This higher affinity for the mu receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both mu- and delta-type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the delta or mu opioid receptor.

Compliance with tricyclic antidepressants: the value of four different methods of assessment.

AIMS: To assess the advantages and disadvantages of four methods for studying compliance with antidepressants: self-report scores, tablet counts, a microprocessor (MEMS) container system and the assay of nordothiepin and dothiepin concentrations in plasma. METHODS: The techniques were used in 88 patients commencing tricyclic antidepressants in the setting of UK general practice. RESULTS: The MEMS system proved to be the most informative technique allowing identification of the precise time of container opening, the demonstration of 'drug holidays' and early cessation of therapy. Self-report scores (Morisky) proved a useful screening technique with a sensitivity of 72.2% and specificity of 74.1% for > or = 80% compliance. Although tablet counts were possible in 84 patients (95. 5%) they were unreliable in 19 (21.6%). Blood concentration assays proved the least acceptable method to patients and were possible in only 53 (60.2%). A ratio of nordothiepin:dothiepin > or = 1.1 claimed, by others, to identify noncompliance was only reliable when concentrations were low. CONCLUSIONS: Both the MEMS system and self-report scores proved useful methods for identifying noncompliant patients in the setting of UK general practice. Although compliance was higher than reported in previous studies with 70 patients (79.5%) completing 6 weeks treatment, general practitioners tended to prescribe subtherapeutic doses.

Steering simulation performance in patients with obstructive sleep apnoea and matched control subjects.

Patients with obstructive pulmonary disease (OSA) have an increased rate of driving accidents, perhaps due to poor vigilance or impaired cognitive skills that influence their driving ability. The authors have assessed whether patients with OSA perform differently to control subjects on a steering simulator which allows the separate assessment of the two visual tasks required for steering a car, immediate positioning on road with reference to the road edges, and assessment of the curve of the oncoming road which allows faster driving. Twelve patients with OSA and 12 control subjects, matched for age, sex and driving experience, performed three 30-min drives with either all the oncoming road visible, only the near part of the road visible, or only the distant part of the road visible. Steering was assessed by measuring the SD around the theoretical perfect path (steering error) and the number of times the driver went "off road". Subjects identified the appearance of target numbers at the four corners of the screen as quickly as possible, thus making the test a divided attention task. Patients with OSA performed significantly less well on the three different road fields as measured by steering error (p<0.001), time to detect the target number (p<0.03), and off road events (p<0.03). The patients appeared to be particularly impaired on the two drives when only part of the road ahead was available to guide steering. This steering simulator, with its more realistic view of the road ahead, identifies impaired performance in patients with obstructive sleep apnoea. In addition it suggests that patients with obstructive sleep apnoea may be more disadvantaged compared to normal subjects when the view of the road ahead is limited (such as in fog).

Perspectives on the management of insomnia in patients with chronic respiratory disorders.

Complaints of poor sleep are very common in people with chronic respiratory disorders. In patients with chronic obstructive pulmonary disease (COPD), poor sleep may be due to many causes, including cough, excess mucous production, and frequent arousals from sleep caused by hypercapnia, as well as secondary to medications used to manage the lung disease. Patients with obstructive sleep apnea (OSA) also complain of excessive daytime sleepiness and fatigue due to poor-quality sleep, although the mechanism of sleep disruption is somewhat different from that in patients with COPD. Although benzodiazepines are often the drugs of choice for the management of insomnia, caution is suggested with the use of these agents in patients with chronic obstructive respiratory disease due to the reduction in upper airway muscle tone and blunting of the arousal response to hypercapnia. However, controlled trials with short-acting benzodiazepine receptor antagonists, including triazolam, zolpidem, and zaleplon, suggest that these agents may be safely used in selected patients who have mild to moderate COPD without daytime hypercapnia. Less data are available on the use of these agents for patients with OSA, but a preliminary trial using zaleplon suggests that respiratory function is not adversely affected in patients with mild to moderate OSA. Studies are needed to further define the benefit-risk ratio of the use of benzodiazepine receptor agonists for the management of insomnia in patients with chronic obstructive lung disease.

Sleep apnea & automobile crashes.

BACKGROUND: As a group, patients with obstructive sleep apnea (OSA) are at increased risk of having automobile accidents. Previous studies using actual accident data have used only small numbers of subjects. OBJECTIVE: To determine the rate of automobile accidents in a large population of OSA patients using objective data from the Ministry of Transportation of Ontario (MTO). DESIGN: Retrospective study SETTING: Academic sleep disorders clinic and laboratory. PARTICIPANTS: All cases of OSA polygraphically confirmed between June 1990 and June 1994. INTERVENTIONS: Cases of OSA were a priori divided into groups based on apnea-hypopnea index (AHI): (OSA1 - AHI 10-25, OSA2 - AHI 26-40, OSA3 - AHI>40) and driving records were obtained from the MTO. Age and sex matched controls were selected at random from drivers in the MTO driver database who hold passenger vehicle licences. Analysis was restricted to drivers with the same licence class. MAIN OUTCOME MEASURES: Primary outcome measure was accidents in the five years preceding diagnosis. Secondary outcome was citations during the same period. RESULTS: There were 155 of 460 OSA patients with one or more accidents compared with 150 of 581 Controls for the same time period (x2=7.7,p<0.01). The rate of accidents/year, for the preceding five years, was 0.07+/-0.14 for Controls versus 0.09+/-0.14 for OSA (p <0.05). This difference could all be accounted for by increased accident rate in OSA patients with the highest AHI (OSA3) (MVA/yr: 0.11+/-0.15, 0.08+/-0.12, 0.06+/-0.14 for OSA groups 3,2,1 respectively) as there was no differences among Control, OSA1 and OSA2 accident rates. OSA patients had twice as many citations as Controls (1.74+/-2.13 vs 0.86+/-1.43 p<0.001) although the types of citation were the same. CONCLUSIONS: Increased automobile accidents in OSA may be restricted to cases with more severe apnea (AHI >40). Despite the large sample size (an order of magnitude greater than previous reports using accident data) further study is needed with even larger numbers, including more measures of disease severity and rigorously controlling for driving exposure.

Measuring social responsiveness: a view from the United Kingdom.

In the United Kingdom, the Education Committee of the General Medical Council has a statutory responsibility to promote high standards in medical education and does so by producing recommendations for undergraduate medical training. The last set were published in 1993, and five of the 13 principal recommendations were aimed at improving social responsiveness of medical schools. The Education Committee has been measuring responsiveness of the medical schools by means of written inquiries and visits. Twenty-three visits have been made, and the Education Committee is, with minor exceptions, well satisfied with the schools' progress. The social responsiveness of the School of Medicine at the University of Southampton is discussed.

Neural network prediction of obstructive sleep apnea from clinical criteria.

STUDY OBJECTIVES: Clinical prediction models for the diagnosis of obstructive sleep apnea (OSA) have lacked the accuracy necessary to confidently replace polysomnography (PSG). Artificial neural networks are computer programs that can be trained to predict outcomes based on experience. This study was conducted to test the hypothesis that a generalized regression neural network (GRNN) could accurately classify patients with OSA from clinical data. STUDY DESIGN: Retrospective review. SETTING: Regional sleep referral center. PATIENTS: Randomly selected records of patients referred for possible OSA. MEASUREMENTS: The neural network was trained using 23 clinical variables from 255 patients, and the predictive performance was evaluated using 150 other patients. RESULTS: The prevalence of OSA in this series of 405 patients (293 men and 112 women) was 69%. The trained GRNN had an accuracy of 91.3% (95% confidence interval [CI], 86.8 to 95.8). The sensitivity was 98.9% for having OSA (95% CI, 96.7 to 100), and the specificity was 80% (95% CI, 70 to 90). The positive predictive value that the patient would have OSA was 88.1% (95% CI, 81.8 to 94.4), whereas the negative predictive value that the patient would not have OSA (if so classified) was 98% (95% CI, 94 to 100). CONCLUSIONS: Appropriately trained GRNN has the ability to accurately rule in OSA from clinical data, and GRNN did not misclassify patients with moderate to severe OSA. In this study, use of the neural network could have reduced the number of PSG studies performed. Prospective validation of the neural network for the diagnosis of OSA is now required.

Diagnostic techniques in obstructive sleep apnea.

Only in the last 25 years has sleep apnea been recognized as a very common disorder and important cause of mortality. Overnight, attended polysomnography remains the reference diagnostic tool for sleep apnea, although the technology for diagnosis continues to evolve rapidly. In many instances, screening and ambulatory monitoring devices can provide similar, clinically relevant information, but larger validation studies including long-term clinical outcomes are necessary.

N-Substituted 9beta-methyl-5-(3-hydroxyphenyl)morphans are opioid receptor pure antagonists.

The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.

N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines are opioid receptor pure antagonists.

N-Methyl- and N-phenylethyl-(+/-)-1,2,3,4,4a,5,10,10a- octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines (4 and 5, respectively) were found to be pure opioid antagonists. These compounds were shown to share many of the characteristics identified with the N-methyl- and N-phenylethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1 and 2, respectively) including N-substituent mediated potency and a lack of N-substituent mediated antagonism. These data suggest that compounds 4 and 5 and the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (1 and 2) may interact with opioid receptors similarly.