Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma.

BACKGROUND: Cigarette smokers with asthma are insensitive to short term inhaled corticosteroid therapy, but efficacy when given for a longer duration at different doses is unknown. METHODS: Ninety five individuals with mild asthma were recruited to a multicentre, randomised, double blind, parallel group study comparing inhaled beclomethasone in doses of 400 microg or 2000 microg daily for 12 weeks in smokers and non-smokers. The primary end point was the change in morning peak expiratory flow (PEF). Secondary end points included evening PEF, use of reliever inhaler, number of asthma exacerbations, spirometric parameters, and asthma control score. RESULTS: After 12 weeks of inhaled beclomethasone there was a considerable difference between the morning PEF measurements of smokers and non-smokers with asthma (-18 (95% CI -35 to -1), adjusted p = 0.035). Among those receiving 400 microg daily there was a difference between the mean (95% CI) morning PEF (l/min) in smokers and non-smokers (-25 (95% CI -45 to -4), adjusted p = 0.019) and in the number of asthma exacerbations (6 v 1 in smokers and non-smokers, respectively, p = 0.007). These differences were reduced between smokers and non-smokers receiving 2000 microg inhaled beclomethasone daily. CONCLUSIONS: Compared with non-smokers, smokers with mild persistent asthma are insensitive to the therapeutic effect of low dose inhaled corticosteroid treatment administered for a 12 week period. The disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid. These findings have important implications for the management of individuals with mild asthma who smoke.

Lack of mental well-being in 15-year-olds: an undisclosed iceberg?

BACKGROUND: Young people suffer from psychiatric symptoms and illness, and the frequency of both may be higher than currently is recognized. The frequency with which young people consult GPs with emotional problems is not established. OBJECTIVE: The purpose of this study was to identify the number of 15-year-olds who consult their GP directly or indirectly with psychiatric symptoms or illness. METHODS: A two part survey was carried out involving (i) general practice casenote review; and (ii) questionnaires self-report. The subjects comprised all adolescents aged 15 years from 34 randomly selected general practices and a randomly selected subsample of these adolescents. The main outcome measures were a purpose-designed data collection sheet, General Health Questionnaire (GHQ-12) and a purpose-designed self-report questionnaire. RESULTS: In phase 1, the general practice casenotes of 2359 adolescents were examined. Five per cent of subjects were identified as attending the GP with mental health problems; 1% had attempted suicide during the year. In phase 2, 99 subjects returned completed self-report questionnaires. Although over a quarter (26%) were rated as GHQ-12 'cases' and approximately half reported having felt 'sad, unhappy or low' or 'anxious or worried' in the previous year, only one subject reported attending his/her GP with any of these concerns. CONCLUSIONS: Fifteen-year-olds rarely consult their GP about their emotional well-being, yet, with the GHQ-12, the self-reported rate of psychiatric morbidity was nearly seven times greater than that suggested by these same subjects' medical records. Although the majority of adolescents consult their GP throughout the course of a year, those with mental health problems, including those who attempt suicide, are indistinguishable in the frequency of their GP consultations from adolescents without mental health problems.

Office of Women's Health, Food and Drug Administration: future directions for women's health.

The Office of Women's Health serves as an advocate for women's health throughout the Food and Drug Administration (FDA). Through and policies, the Office supports research in gender-related issues in the regulation and use of drugs, devices, biologics, and foods; initiates outreach and disseminates health information to women; provides leadership in increasing the number of women and appropriate data analysis in all phases of clinical trials; and promotes women's health in FDA actions. This article summarizes current activities and future directions in women's health at the FDA.

Non-compliance amongst adolescents with asthma: listening to what they tell us about self-management.

BACKGROUND: Non-compliance with prescribed anti-asthma medication is considered to be a major problem. The reasons why adolescents may fail to comply with their regimen are poorly understood. OBJECTIVES: This study set out to understand better the reasons for non-compliance in adolescents with asthma. METHODS: In-depth interviews were conducted with a sample of 49 adolescents, aged 14-20 years, diagnosed as asthmatic more than a year previously and attending a hospital asthma clinic in Greater Glasgow. The interviews focused on young people's feelings about their illness and on their illness-related behaviour, including self-management. RESULTS: Most of the young people interviewed admitted that they had not always complied with their self-care regimens. Reasons given for non-compliance with prescribed medication in the past or at present were: forgetfulness, belief that the medication is ineffective, denial that one is asthmatic, difficulty using inhalers, inconvenience, fear of side effects, embarrassment and laziness. CONCLUSION: Most of those interviewed believed that compliance with prescribed medication was extremely important, with many having formed this belief following a negative experience which they attributed to their non-compliance. Nevertheless, barriers exist which mean that optimum self-care is not always achieved. It is suggested that future health care initiatives in this area be designed to provide practical information which aids the surmounting of these barriers and helps children and adolescents to be sufficiently aware of their own vulnerability at an early stage of their career as asthmatics. Peer education initiatives may meet these objectives, and more thought should be given to their development and optimum form.

The structure and function of antiamoebin I, a proline-rich membrane-active polypeptide.

BACKGROUND: Antiamoebin is a member of the peptaibol family of polypeptides and has a unique antibiotic activity: it acts as an antiamoebic agent, but does not effectively haemolyze erythrocytes even though it does exhibit membrane-modifying activity. RESULTS: The structure of antiamoebin I has been determined by X-ray crystallography at 1.4 A resolution. The molecule forms a helical structure, which, as a result of the presence of a number of proline and hydroxyproline residues, has a deep bend in the middle. Circular dichroism spectroscopy, single-channel conductance studies and fluorescence diffusion studies suggest a mode of ion transport that is entirely different from that of the other two members of the peptaibol family (alamethicin and zervamicin) whose structures and functions have been examined in detail. CONCLUSIONS: The structure of the polypeptide has been determined and a functional model for its mode of action in membranes is presented. Although under some conditions antiamoebin may form ion channels, unlike the closely related alamethicin and zervamicin polypeptides, its major membrane-modifying activity appears to be as an ion carrier.

The experiential impact of head injury on adolescents: individual perspectives on long-term outcome.

Thirty-one young people, who were experiencing chronic sequelae of a head injury sustained at least 1 year previously, were interviewed in-depth about the impact head injury had had on their lives. Their functioning was also assessed using the Offer Self-Image Questionnaire (OSIQ-R). The main theme raised by subjects was that they had not received adequate explanation of the emotional problems associated with head injury and relevant support in coming to terms with their condition. Head injury had had a devastating effect on their lives, causing limitations in day-to-day activities, employment, education and relationships, and they scored significantly below norms on the OSIQ-R scale of Self-Confidence. However, these young people had a predominantly positive attitude towards life, which appeared to be related to their appreciation of how fortunate they had been to survive. They scored significantly above norms on the OSIQ-R scale of Social Functioning. Markers of poor functioning were identified and, in clinical practice, could be used as a method of highlighting those head-injured young people who potentially are most in need of support. The findings have implications for future research directions, service delivery and planning, in that particular weaknesses of current provision are demonstrated and recommendations made for improvements.

An audit of treated epilepsy in Glasgow. West of Scotland Epilepsy Research Group.

An audit of patients receiving antiepileptic drug therapy for epilepsy was carried out in 25 general practices in Glasgow. Patients were identified from computerized records of repeat prescriptions for antiepileptic drugs. Overall, 1052 (0.72%) of 145,609 screened patients had treated epilepsy. Only 5% were children, while 19% were over 65 years. Twenty-nine per cent were diagnosed by a neurologist, and in 24% no record was available of who had made the diagnosis. Fifty per cent had tonic-clonic seizures only. Partial seizures occurred in 39%, absences in 4%, and myoclonic jerks in 3%. In only 39% of case records was current seizure control documented. Seventy-four per cent and 41% of patients had surface electroencephalography and computerized tomographic brain scanning, respectively. In more than 80% of patients the presence or absence of birth injury, febrile convulsions in childhood, and a family history of epilepsy were not mentioned. Seventy-six per cent of patients were receiving anticonvulsant monotherapy. The most commonly prescribed drugs were carbamazepine (43%), phenytoin (34%), sodium valproate (22%) and phenobarbitone (15%). Eighty-four per cent had attended a hospital clinic with their epilepsy, and 19% had been admitted to hospital with seizures or complications. A standard record form for the assessment and follow-up of epileptic patients in general practice would help in providing optimal management and in facilitating the setting up of a shared-care programme.

How to do it. Get patients' consent to enter clinical trials.

Gaining patients' consent to enter clinical trials is essential, but not easy. Giving careful thought to the design of the study itself, information which patients receive, and the use of a signed consent form may all help. To be properly informed, patients need to know something about their condition, the proposed study, and alternative options. The type and amount of information will vary and investigators need to judge the level appropriate for each person. Patients should understand that taking part in a clinical trial is voluntary and that their decision will not affect the quality of care they receive. The process of obtaining consent requires time and good communication. Working with young, elderly, or mentally impaired patients, or those particularly vulnerable to coercion, requires special sensitivity to the potential dangers.

Odorants differentially enhance phosphoinositide turnover and adenylyl cyclase in olfactory receptor neuronal cultures.

Both the cAMP and the phosphoinositide (PI) second messenger systems have been implicated in olfactory signal transduction. We have developed a primary culture system of mammalian olfactory receptor neurons (ORNs; Ronnett et al., 1991a) to permit analysis of odorant-induced second messenger system activation in the intact ORN. The ability of a series of odorants to stimulate PI turnover and adenylyl cyclase was examined. All odorants stimulated both second messenger systems, although with differential potencies. Stimulation of PI turnover desensitized upon reexposure of cultures to odorant. The enhancement by single odorants of both adenylyl cyclase and PI turnover, but to varying degrees, affords a mechanism for increased specificity in olfactory signal transduction.

Cisapride in functional dyspepsia: a double-blind, placebo-controlled randomized trial in general practice patients.

This trial included patients from general practice with endoscopy-negative chronic dyspepsia and epigastric pain or discomfort. Eleven eligible patients with sufficiently severe dyspeptic symptoms after a 2-week placebo run-in period were entered into a 4-week, parallel group, double-blind randomized comparison of 10 mg cisapride three times daily and matched placebo, and were subsequently evaluable. Symptoms were comparable in the two treatment groups at the start of double-blind treatment. The cisapride group had a significantly greater reduction in the frequency of daytime epigastric pain/discomfort and the frequency and severity of nocturnal pain/discomfort after 2 weeks. After 2 weeks, all six cisapride recipients were free of nocturnal pain, compared with only one of five placebo recipients. After 4 weeks of double-blind therapy, improvements in the placebo group had reduced between-treatment differences, with five of six cisapride recipients and three of five placebo recipients being free of nocturnal pain. Cisapride was well tolerated.

Clinical experience with non-sedating antihistamines in paediatric allergic rhinitis.

This paper reviews all clinical studies involving the use of astemizole in children. The indications of seasonal allergic rhinitis, perennial rhinitis and various allergic disorders were considered in a total of 21 studies (1,008 patients). Reference compounds were placebo and other antihistamines, such as chlorpheniramine and terfenadine. Astemizole and other antihistamines were effective in the treatment of these disorders with a more favourable result for those treated with astemizole. Astemizole appeared very satisfactory as regards laboratory data and absence of side effects.

Light-dependent GTP-binding proteins in squid photoreceptors.

Previous biochemical and electrophysiological evidence suggests that in invertebrate photoreceptors, a GTP-binding protein (G-protein) mediates the actions of photoactivated rhodopsin in the initial stages of transduction. We find that squid photoreceptors contain more than one protein (molecular masses 38, 42 and 46 kDa) whose ADP-ribosylation by bacterial exotoxins is light-sensitive. Several lines of evidence suggest that these proteins represent distinct alpha subunits of G-proteins. (1) Pertussis toxin and cholera toxin react with distinct subsets of these polypeptides. (2) Only the 42 kDa protein immunoreacts with the monoclonal antibody 4A, raised against the alpha subunit of the G-protein of vertebrate rods [Hamm & Bownds (1984) J. Gen. Physiol. 84. 265-280]. (3) In terms of ADP-ribosylation, the 42 kDa protein is the least labile to freezing. (4) Of the 38 kDa and 42 kDa proteins, the former is preferentially extracted with hypo-osmotic solutions, as demonstrated by the solubility of its ADP-ribosylated state and by the solubility of the light-dependent binding of guanosine 5'-[gamma-thio]triphosphate. The specific target enzymes for the observed G-proteins have not been established.

Metabolism of inositol 1,4,5-trisphosphate in squid photoreceptors.

Inositol 1,4,5-trisphosphate (InsP3) is rapidly formed in squid photoreceptors in response to light, where it is converted sequentially into inositol bisphosphate (InsP2) and inositol monophosphate (InsP1). All of the InsP3 appears to be degraded to inositol 1,4-bisphosphate via an InsP3-phosphatase, which is characterized in this study. The enzyme is water-soluble and present in the light-transducing distal segments of squid photoreceptors. It has a Km of 50 microM for InsP3, requires Mg++ for its activity, is maximally active at neutral pH, specifically hydrolyses the 5-phosphate and is inhibited by 2,3-diphosphoglycerate. In these respects, InsP3-phosphatase of squid is very similar to the enzymes of other cells. Since no InsP4 or more highly phosphorylated inositols are found in squid photoreceptors, the InsP3-phosphatase may be important in the regulation of InsP3 concentration within these cells.

Inositol trisphosphate production in squid photoreceptors. Activation by light, aluminum fluoride, and guanine nucleotides.

The light-stimulated production of inositol triphosphate (IP3), via hydrolysis of phosphatidylinositol bisphosphate (PIP2), can be demonstrated in an in vitro preparation of isolated distal segments of squid photoreceptors. The retina is labeled with [3H]inositol (Szuts, E. Z., Wood, S. F., Reid, M. S., and Fein, A. (1986) Biochem. J. 240, 929-932), and the rhodopsin-containing distal segments are isolated in artificial cytosol. Within 2 s after a flash, IP3 levels increase 200% (corresponding to an intracellular increase of approximately 5 microM), and the lipid precursor PIP2 decreases by 50%. Inositol bisphosphate (IP2) levels increase later, as a breakdown product of IP3. IP3 response is light-dependent, saturating when 0.5% of the rhodopsin is photoactivated. Guanosine-5'-O-(3-thiotriphosphate (GTP gamma S) binding demonstrates that the plasma membrane of most of the photoreceptor distal segments is intact or only transiently permeable. Membrane permeabilization enhances light-activated GTP gamma S binding but abolishes the light-activated IP3 production. Receptor-mediated production of IP3 is believed to be the result of a receptor-G-protein-phospholipase C cascade (i.e. Cockcroft, S., and Gomperts, B. D. (1985) Nature 314, 534-536). To test for G-proteins, we incubated the photoreceptors in AlF4- (an activator of G-proteins) in the dark. IP3 and IP2 were produced with a corresponding decrease in PIP2. Incubation with GTP or GTP gamma S, in hypotonic buffer, which causes transient leakiness, increased dark levels by IP3 by 50%. Addition of GTP in isotonic buffer enhanced the light-induced increase of IP3. These results localize the light-stimulated phospholipase C activity to the distal segments and suggest that a G-protein couples rhodopsin to phospholipase C.

Treatment of hay fever.

The range of treatments for hay fever available to the general practitioner has changed considerably in recent years. New antihistamines have addressed the problem of sedation and moved towards one daily dose; nasally applied corticosteroids avoid the need for systemic steroid therapy and its potential adverse effect; and regulatory decisions have set a trend away from immunotherapy in general practice. However, knowledge about the mechanism of action of immunotherapy is increasing and new developments with improved safety profiles include allergen polymers, allergoids, oral immunotherapy and nasal immunotherapy. Choice of treatment depends, as always, on the individual circumstances of the patient and his or her disease.

General practice aspects of Intal treatment.

This study analysed the type of patients receiving Intal in two Scottish practices by age, sex, type of delivery system and other therapy received. It emerged that the 'typical' Intal patient in general practice (if he actually existed) was 5-9 years old, male, and likely to be using a Spinhaler. The patient was also likely to be taking bronchodilators, but not corticosteroids.

Light stimulates the rapid formation of inositol trisphosphate in squid retinas.

To test the hypothesis that inositol trisphosphate (InsP3) mediates adaptation and excitation in invertebrate photoreceptors, we measured its formation on a rapid time scale in squid retinas. For squid, excitation and adaption occurs within 0.1 and 1-2 s respectively. We could detect an elevation in InsP3 within 200 ms of a bright flash. This increase is about 240% over dark basal levels and is maintained for at least 2 min after a flash. The increase probably occurs in the photoreceptors, which are the only neurons in squid retinas. Analysis by h.p.l.c. indicates that the light-regulated isomer is Ins(1,4,5)P3, which is formed by the hydrolysis of phosphatidylinositol bisphosphate (PtdInsP2).

Hay fever. 2. Clinical features, diagnosis, investigation and treatment.

This is the second of two reviews of hay fever. The first article dealt with prevalence and natural history, historical background and mechanisms. This article outlines the clinical features of hay fever, examines the correlation of symptoms with pollen count and describes current views of diagnosis and investigation. History and examination, skin testing, the radio-immunosorbent test (RIST) and radio allergosorbent test (RAST) and the correlation between RAST and skin testing are described. Some consideration is given to the part played by nasal challenge tests and measurements of nasal airways resistance. The section on treatment includes some general considerations, avoidance measures, anti-histamines, nasal steroids, sodium cromoglycate, systemic steroids, nasal vasoconstrictors, hyposensitisation and eye preparations. The final section is centred on future developments.