A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Clinical features in secondary and cryptogenic organising pneumonia.

SETTING: The clinical differences between cryptogenic organising pneumonia (COP) and secondary organising pneumonia (OP) have not been studied well. OBJECTIVE: To compare clinical features in COP and secondary OP. DESIGN: Causes, clinical features, treatment, radiographic studies and pathology were studied. RESULTS: After re-evaluation, 104 patients fulfilled the diagnostic criteria, 58 for COP and 46 for secondary OP. The mean age was 68 years. Most of the patients were smokers (79/104). Infections were the most common causes of secondary OP (21/46). Cough was the most common symptom and crackles the most common sign. Crackles were more common in patients with secondary OP (P = 0.02). Transbronchial biopsy was the diagnostic test in 81/104 cases. Most patients had lowered partial oxygen pressure (PO(2)) and mildly restrictive spirometry, with no differences between the two groups. Radiographic features were similar. Corticosteroids were the treatment in 70% of the patients, but 27% received no pharmacological treatment. The average initial dose of steroids was 42 mg prednisolone, and was similar for both groups. Relapses were seen in 20% of cases, with no difference between the two groups. CONCLUSION: There were no major differences in clinical features of COP and secondary OP, except that crackles were more common in secondary OP.

Users of antiasthma drugs in Iceland: a drug utilization study.

There has been an increasing consensus worldwide on how to treat asthma, and, simultaneously, an increase in the sales of antiasthma drugs. However, little is known about actual drug use, dosage, combinations of drugs, etc., or about the clinical characteristics of patients using these drugs. All individuals with prescriptions for antiasthma drugs, who came to Icelandic pharmacies during March 1994, were invited to participate. By means of questionnaires, the pharmacists recorded the age and gender of the patient, the specialty of the prescribing doctor, as well as the name of the drug, total amount prescribed, and dosage. The patients were asked to answer another questionnaire on their clinical diagnosis, usage of other antiasthma drugs, etc. The pharmacists registered 2,026 individuals, with 2,687 prescriptions: 1,574 for beta2-agonists, 838 for inhaled corticosteroids, 208 for theophylline, 48 for anticholinergic drugs, and 19 for cromoglycates. One thousand, three hundred and fifty one patients answered the questionnaires. The majority (67%) claimed to have asthma, 18% chronic bronchitis, 11% emphysema and 5% other diseases or symptoms. Among those aged > or = 16 yrs with asthma, 93% used beta2-agonists, 62% inhaled corticosteroids, 19% theophylline, and very few used other drugs. The most commonly used combination (57%) was beta2-agonists with inhaled corticosteroids. Thirty one per cent used beta2-agonists as monotherapy, and 5% used only inhaled corticosteroids. Theophylline was used mainly in combination with beta2-agonists and inhaled corticosteroids. In conclusion, our data suggest that two thirds of antiasthma drug users have asthma and that most are treated according to present guidelines. The use of inhaled corticosteroids, however, seems somewhat less than optimal.

[Antiasthmatic drugs in Iceland - an epidemiological survey.].

The use of antiasthmatic drugs in Iceland has increased considerably during the last 15 years. The aim of this study was to assess in a well-defined epidemiological population the characteristics of those using antiasthmatic drugs; age, gender, speciality of prescribing doctor, dosage and combinations of drugs. Also their clinical diagnosis and symptoms. All individuals with prescriptions for antiasthmatic drugs that came to Icelandic pharmacies during March 1994 were invited to participate. Altogether 2026 individuals accepted (2687 prescriptions). There were proportionally more young males and middle aged females (p<0.0001). The prescriptions for beta2-adrenergic drugs were 1574, 838 for inhaled corticosteroids, 208 for theofylline, 49 for anticholinergic drugs and 19 for natrium chromoglycate. General practitioners had prescribed 68% of the drugs, 16.3% were from pulmonary physicians and/or allergists, 6.4% from pediatricians and 9.3% from other doctors. The treatment had been started by specialists other than general practitioners in more than 60% of cases. Among those using inhaled drugs 95% had been tought how to do so. The majority (66.9%) claimed that they were using the drugs because of asthma, 17.8% because of chronic bronchitis, 10.7% because of emphysema and 4.6% for other reasons. There were altogether 591 individuals (2=16 years) with asthma who answered the questionnaire. Among them 93% used beta2-adrenergic drugs, 62% inhaled corticoseroids, 19% theofylline and very few used other drugs. The most commonly used combination (57%) was beta-adrenergic drugs and inhaled corticoseroids. Altogether 31% used beta2-adrenergic drugs as monotherapy and 5% had only inhaled corticosteroids. Theofylline is mainly used in combination with beta-adrenergic drugs and inhaled corticosteroids. Its use as monotherapy is infrequent (2%). Among those 209 asthma patients who had used oral corticosteroids the last 12 months, 73% were using some kind of inhaled corticosteroids and 27% not.

The effect of acetylsalicylic acid in 3 different formulations on in vitro and in vivo platelet function tests. An experimental study on healthy male volunteers.

The template bleeding time (TBT), ADP-induced platelet aggregation, and serum production of TXB2 were measured in healthy young male subjects immediately before, and on days 1, 4 and 6 after the ingestion of 1 single dose of 500 mg acetylsalicylic acid (ASA) in 3 different formulations: Aspirin (Bayer), and the 2 enteric-coated formulations Reumyl (Hässle) and Premaspin (Lääke). The ingestion of Aspirin resulted in a significant prolongation of the TBT over a period of 6 d. However, after the ingestion of the same amount of ASA in the 2 enteric coated formulations, the TBT as measured on day 6 had become normalized. After the ingestion of Aspirin, there was no reappearance of the second wave of ADP-induced platelet aggregation during the study period; however, after the ingestion of the 2 enteric-coated formulations, secondary platelet aggregation occasionally returned on day 6. In response to the intake of each of the 3 ASA formulations, the serum TXB2 production as measured 24 h later was almost completely inhibited. In each of the 3 study groups, the TXB2 formation as measured on day 6 was still significantly impaired.

Plasma concentrations of platelet-specific proteins in young female acute myocardial infarction survivors and their age-matched female controls.

The steady state plasma concentrations of the two platelet-specific proteins beta-thromboglobulin (BTG) and platelet factor 4 (PF4) were determined in two groups of females: 36 acute myocardial infarction (AMI) survivors, and 38 age-matched control subjects. For the AMI patients the mean BTG and PF4 values were 57 +/- 4 and 14.1 +/- 1.7 ng/ml, respectively. These two means significantly exceeded the corresponding means for the controls, 40 +/- 2 and 10.3 +/- 0.6 ng/ml, respectively. Similar results have recently been reported by other workers who investigated patients with coronary artery disease; however, in no previous study were the values for BTG and PF4 related to those obtained for control subjects matched with respect to sex and age. The present results therefore further support the concept that increased platelet activation and secretion is taking place in steady state patients who previously have sustained an AMI.

Interstitial pneumonia due to sulfasalazine.

A 45-year old man with ulcerative colitis developed a dry cough, dyspnoea and pulmonary infiltrates after two months of sulfasalazine treatment. Transbronchial lung biopsy showed interstitial pneumonia. Withdrawal of the drug and institution of corticosteroids resulted in rapid recovery. After challenge with sulfasalazine, symptoms and signs of interstitial pneumonia reappeared.

Plasma platelet factor 4: a potentially useful predictor of ischaemic heart disease?

The aim was to investigate whether plasma platelet factor 4 (PF-4) in suspected acute myocardial infarction (AMI) patients could serve as a prognostic tool and identify patients at risk for future death from AMI or ischaemic heart disease (IHD). Therefore, upon admission to our coronary care unit plasma PF-4 was measured on 109 consecutive patients. 53 of them proved to have AMI, and 50 IHD but no AMI; the remaining 6 had no evidence of IHD. 24 patients died in hospital or during the follow-up period which was an average of 16.7 +/- 2.4 months. The decreased were subgrouped into those dying of AMI (n = 16), and those dying of IHD but with no AMI (n = 8). No deaths from other causes were recorded. As compared with survivors there was a tendency towards higher PF-4 values among those who died of AMI. However, patients who during follow-up suffered death from IHD proved to have significantly (p less than 0.05) higher PF-4 levels than survivors.

Platelet activation in response to phlebotomy. An experimental study of healthy blood donors.

Plasma concentration of beta-thromboglobulin (BTG) and platelet factor 4 (PF4) were measured in three consecutive blood samples from 29 healthy male blood donors. The first sample was collected after 15 min of rest, the second immediately after a phlebotomy of 450 ml blood and the third after a further 15 min of rest. The mean baseline plasma BTG and PF4 values were 68 x 5 and 13.8 +/- 0.7 ng/ml, respectively. The second sample's mean plasma values of these two platelet-specific proteins were significantly higher (88 +/- ( and 24.1 +/- 4.1 ng/ml, respectively). The plasma concentrations of BTG and PF4 in the last sample, however, had returned to baseline levels. It is concluded that significant but short-lasting platelet activation and secretion take place in healthy subjects in response to an acute but comparatively mild blood loss even though the platelets do not participate in the process of hemostasis.