Ultrastructure of bronchial biopsies from patients with allergic and non-allergic asthma.

Epithelial damage is commonly found in airways of asthma patients. The aim of this study was to investigate epithelial damage in allergic and non-allergic asthma at the ultrastructural level. Bronchial biopsies obtained from patients with allergic asthma (n=11), non-allergic asthma (n=7), and healthy controls (n=5) were studied by transmission electron microscopy. Epithelial damage was found to be extensive in both asthma groups. Both in basal and in columnar cells, relative desmosome length was reduced by 30-40%. In columnar cells, half-desmosomes (i.e., desmosomes of which only one side was present) were frequently noticed. Eosinophils showing piece-meal degranulation were commonly observed in allergic asthma. Degranulating mast cells were more often observed in allergic asthma. Goblet cell hyperplasia was only found in allergic asthma. Lymphocytes were increased in both groups. In both groups, the lamina densa of the basal lamina was thicker than the control by about 40-50%. In allergic asthma the lamina densa was irregular with focal thickening. While there was always a tendency for changes (epithelial damage, desmosomes, degranulating mast cells, basal lamina) to be more extensive in allergic asthma compared to non-allergic asthma, there was no significant difference between the two groups in this respect. Reduced desmosomal contact may be an important factor in the epithelial shedding observed in patients with asthma.

Increased nitric oxide elimination from the airways after smoking cessation.

Smokers have been found to have low exhaled nitric oxide (NO) levels. The aim of the present study was to investigate where in the respiratory system the decrease in NO occurs, and whether this decrease was affected by smoking cessation. Measurements of exhaled NO were carried out in smokers (n=20) and non-smoking control subjects (n=30). In nine of the smokers, exhaled NO was analysed 1, 2 and 4 weeks after smoking cessation. The level of exhaled NO at a flow rate of 0.1 litre/s was significantly lower in smokers (4+/-2 p.p.b.) than in non-smokers (7+/-5 p.p.b.; P=0.007). A calculation of the contributions from different areas of the lung showed that the NO flux from the airways was significantly lower (14+/-10 compared with 36+/-26 nl/min; P=0.0001) and the alveolar fraction was significantly higher (2.1+/-0.8 compared with 1.5+/-0.9 p.p.b.; P=0.006) in smokers than in non-smokers. Nine smoking subjects refrained from smoking for 4 weeks, and this resulted in increased NO flux from the airways of 28+/-17 nl/min, which was no longer significantly different from controls. In conclusion, endogenous production of NO in the airways is decreased in smokers, but can be restored to normal values by 4 weeks after cessation of smoking. Smokers have an increased alveolar fraction of NO, and this might be a diagnostic sign of lung damage. Thus NO monitoring can be used to indicate improvements when a smoker decides to stop smoking.

Inflammation and structural changes in the airways of patients with primary Sjögren's syndrome.

The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.

Inhaled mannitol shifts exhaled nitric oxide in opposite directions in asthmatics and healthy subjects.

We investigated if healthy subjects could release NO upon hyperosmolar challenge as a defence mechanism, and whether asthmatics with atopy showed an altered response. A plot of NO output versus flow rate was used to calculate the alveolar level and the NO-flux from the airways. The asthmatics had a higher NO output and this was due to an increased NO-flux from the airways, 86+/-30 nl min(-1) compared with control 21+/-2 nl min(-1) (P<0.05). The alveolar NO levels showed no difference. In response to a dry powder of mannitol the exhaled NO concentration decreased in asthmatics by 37+/-7%, but increased in the control by 9+/-4% (P<0.001). The FEV(1.0) decreased 13+/-2% and airway conductance 42+/-7% in asthmatics and in the controls 2+/-1% and 0+/-7%, respectively (P<0.001). We conclude that asthmatics have an altered response to mannitol challenge in regards to exhaled NO. This may result from down regulation of constitutive NO production as a result of high levels of NO flux from the airways.

Lung function changes in relation to menstrual cycle in females with cystic fibrosis.

Oestrogen and progesterone have been shown to have impact on cystic fibrosis transmembrane conductance regulator (CFTR) gene expression, tone of smooth muscle in the airways, immune response, exhaled nitric oxide and cytology in the tracheobronchial epithelium. The aim of this investigation was to study the influence of menstrual cyclicity on airway symptoms among cystic fibrosis (CF) females. Twelve CF women (mean age 30 years, mean Shwachman score 85) kept daily records during three menstrual cycles of lung function, sputum quality and need for intravenous antibiotics. Paired t-test was used as a statistical method to compare the airway symptoms between the time of ovulation (high levels of oestrogen and low levels of progesterone), the luteal phase (high levels of oestrogen and progesterone) and menstruation (low levels of oestrogens and progesterone). Forced expiratory volume in 1 sec (FEV1) was significantly higher during the luteal phase (66% of predicted) compared to during ovulation (63%) and menstruation (61%) (P<0.01). Forced vital capacity (FVC) showed the same pattern, being significantly higher during the luteal phase compared with during menstruation (mean 75% vs. 70%, P<0.01). In conclusion, lung function changes were found during menstrual cycles in women with cystic fibrosis. These changes are probably related to changes in progesterone levels during the menstrual cycles. This result warrants further studies to understand the complexity of CF lung disease in women.

Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group.

The aim of the present study was to compare the cellular pattern and structural changes in the airway walls of atopic and nonatopic patients with asthma. Bronchial biopsy specimens were obtained from 13 atopic subjects with asthma, nine nonatopic patients with asthma, and seven healthy control subjects and investigated using immunohistochemical methods. The number of eosinophils increased in both asthma groups, but significantly more in the atopic group. The number of mast cells increased similarly in the two asthma groups, whereas the number of neutrophils increased only in the nonatopic asthma group. The number of T-lymphocytes (CD3-, CD4-, CD8-, CD-25-positive cells) was higher in patients with atopic asthma compared with nonatopic asthma. Interleukin-4 (IL-4) and IL-5-positive cells were more frequently found in the atopic asthma group, whereas cells staining for IL-8 were more frequent in the nonatopic group. The degree of epithelial damage was significantly higher in the atopic asthma group compared with the control subjects and the nonatopic asthmatics. The tenascin and laminin layer was significantly thicker in the atopic group compared with the group of nonatopic asthmatics. In the atopic group, there was a significant negative correlation between epithelial integrity (defined as the relative length of intact epithelium) and the eosinophil count and also between the number of CD25-positive cells and epithelial integrity. The number of mast cells correlated positively with the thickness of tenascin- and laminin-positive layers. In conclusion, we provide evidence of different patterns of involvement of inflammatory cells in atopic and nonatopic patients with asthma. There were also structural differences in the bronchial mucous membrane between atopic asthma and nonatopic asthma. This suggests that there are differences in the extent of the immunopathologic response of these clinically distinct forms of asthma.

Different airway responsiveness profiles in atopic asthma, nonatopic asthma, and Sjögren's syndrome. BHR Study Group. Bronchial hyperresponsiveness.

BACKGROUND: Different mechanisms may underlie bronchial hyperresponsiveness (BHR) in different diseases. The aim of this study was to investigate the bronchial responsiveness profile produced by three different challenge tests, methacholine, a direct stimulus, and two indirect stimuli, adenosine 5'-monophosphate (AMP) and cold air, in subjects with asthma and patients with Sjögren's syndrome. METHODS: The study population comprised 40 adult patients with asthma, 18 subjects with Sjögren's syndrome, and 20 controls. Blood samples were collected before each challenge for measurements of serum eosinophil peroxidase (S-EPO) and eosinophil cationic protein (S-ECP). The investigated subjects recorded peak expiratory flow and kept a symptom diary. RESULTS: Atopic subjects with asthma were significantly more hyperresponsive to AMP than nonatopic subjects with asthma (P=0.01) and subjects with Sjögren's syndrome (P=0.02). No difference was seen between atopic and nonatopic subjects with asthma in the case of challenges with methacholine or cold air. In atopic subjects with asthma, a significant correlation was found between challenges with methacholine and AMP (r=0.91, P=0.0001) and methacholine and cold air (r=0.83, P=0.004), but, in nonatopic subjects with asthma, no significant correlation was seen between methacholine and AMP or cold air challenges. In atopic subjects with asthma, the dose-response slope for AMP was correlated to S-EPO (r= -0.56; P = 0.01) and S-ECP (r= -0.51, P = 0.02), while no correlation between BHR and inflammation markers was found in the two other patient groups. CONCLUSIONS: The results of this study suggest that patients with asthma and subjects with Sjögren's syndrome display different bronchial responsiveness profiles for different challenge agents. Atopic subjects with asthma are more hyperresponsive to AMP than nonatopic subjects and patients with Sjögren's syndrome. More than one challenge may be required to detect different aspects of bronchial responsiveness.

Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. BHR-Study Group.

Exhaled nitric oxide (NO) has attracted increasing interest as a non-invasive marker of airway inflammation. The purpose of this study was to determine whether exhaled nitric oxide in subjects with asthma varied according to their atopic status and to examine its correlation with airway hyperresponsiveness and lung function measurements. Forty patients with asthma and 13 controls participated in the study. Nitric oxide was measured on three occasions with intervals of at least 3 days, using a chemiluminescence method. Airway responsiveness was assessed with methacholine challenge and lung function measurements were made. All subjects recorded peak expiratory flow and kept a symptom diary during a 17-day period. There was no significant difference in lung function measurements, peak expiratory flow or symptom score between the two asthma groups. Atopic patients with asthma had a significantly higher mean amount of exhaled NO than non-atopic subjects with asthma (162 +/- 68 vs. 113 +/- 55 nl min-1; P = 0.03) and the control group (88 +/- 52 nl min-1; P = 0.004). No significant difference was found in the amount of exhaled NO between non-atopic patients with asthma and the controls. In atopic subjects with asthma the mean exhaled NO was significantly correlated to the dose-response slope for methacholine (r = -0.52; P = 0.02), while no such correlation was found in the non-atopic group. In conclusion; in this study, atopic subjects with asthma had higher levels of exhaled NO than non-atopic subjects. Atopic status should be taken into account when measuring levels of exhaled NO in subjects with asthma.

Effects of nicotine nasal spray on atherogenic and thrombogenic factors during smoking cessation.

OBJECTIVES: To investigate changes in cardiovascular risk factor parameters when stopping smoking and to identify any impact of nicotine nasal spray on these factors. DESIGN AND SUBJECTS: In a placebo-controlled, double-blind 3-month prospective study, nicotine nasal spray (NNS) or a placebo was given to 157 subjects attending a smoking cessation programme. Blood samples from 46 subjects who remained abstinent for 3 months were analysed. Nasal spray use was given on an ad libitum basis. RESULTS: The haemoglobin (Hb) decreased from 149.0 to 143.2 g L(-1) (P<0.001). The haematocrit (Hct) decreased from 44.6 to 42.4% (P<0.001). The mean corpuscular volume (MCV) decreased from 93.4 to 92.3 fl (P<0.001). The mean corpuscular haemoglobin concentration (MCHC) increased from 333.9 to 338.1 g L(-1) (P = 0.029). The white blood cell count (WBC) decreased from 8.4 to 6.6x10(9) L(-1) (P<0.001). The total cholesterol decreased from 5.92 to 5.65 mmol L(-1) (P = 0.015). The high-density lipoprotein cholesterol (HDL) increased from 1.29 to 1.44 mmol L(-1) (P = 0.48) and low-density lipoprotein cholesterol (LDL) decreased from 4.00 to 3.54 mmol L(-1) (P = 0.004). The HDL/LDL ratio increased from 0.36 to 0.46 (P = 0.011). CONCLUSION: Stopping smoking resulted in positive effects on cardiovascular risk factors. Nicotine treatment for as long as 3 months did not have any significant effect on these 'stopping smoking changes'. In smoking cessation, nicotine substitution up to 3 months seems to be safe.

Increased nitric oxide in expired air in patients with Sjögren's syndrome. BHR study group. Bronchial hyperresponsiveness.

Nitric oxide has an important role in the regulation of airway function and can have pro-inflammatory effects. Bronchial hyperresponsiveness (BHR) and respiratory symptoms are common in patients with Sjögren's syndrome (SS). The aim of this study was to determine whether patients with SS have an increased amount of exhaled NO and whether this NO correlates with respiratory symptoms and BHR. Exhaled NO was measured in 18 patients with SS and 13 normal subjects on three different occasions with intervals of at least 3 days using a chemiluminescence method. Airway responsiveness was assessed with methacholine provocation. Serum levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) were measured. Exhaled NO was significantly higher in patients with SS than in controls (147+/-82 versus 88+/-52 nL x min(-1); mean+/-SD; p=0.041). Exhaled NO was correlated with age (partial r=0.52, p=0.006) and serum HNL (partial r=0.46, p=0.014). There were no significant correlations between exhaled NO and respiratory symptoms, BHR or serum MPO, ECP or EPO. Disease duration was negatively associated with serum MPO (r=-0.47, p=0.043). In patients with SS, a positive correlation was found between symptom score and serum ECP (partial r=0.65, p=0.003) and EPO (partial r=0.62, p=0.004) and a negative correlation with age (partial r=-0.60, p=0.005). In conclusion, elevated levels of exhaled nitric oxide in patients with Sjögren's syndrome were demonstrated. The mechanism underlying this increase in exhaled nitric oxide in Sjögren's syndrome is not known.

Epidemiology of liver cirrhosis morbidity and mortality in Iceland.

BACKGROUND: The mortality from liver cirrhosis in Iceland is the lowest in the Western world. OBJECTIVE: To study the epidemiology of liver cirrhosis mortality and morbidity in Iceland and to obtain a reliable separation between alcoholic cirrhosis (AC) and non-alcoholic cirrhosis (NAC) by using multiple data sources. METHODS: The study included the whole population of Iceland. Mortality was studied through death certificate data for the period 1951-90 and morbidity (clinical incidence) through hospital, autopsy and biopsy records for the period 1971-90. RESULTS: The average mortality for AC in age group 20 years and older was 8.6 and for NAC 19.2 per 10(6)/year and the average clinical incidence was 22.1 per 10(6)/year for AC and 25.9 per 10(6)/year for NAC. In the morbidity study 44% of cases were due to AC. In the mortality study 24% of cases were due to AC but the data suggested an underreporting of AC for males at a rate of 30%. There was a significant decrease in AC mortality with time but no change in NAC. Average alcohol consumption of inhabitants aged over 15 years increased from 2.1 to 4.9 litres per year (130%) during the period 1951-90. CONCLUSION: The incidence of cirrhosis in Iceland is very low for both AC and NAC, accounting for only 0.2% of total deaths. The reasons are unknown. The low incidence of AC in Iceland is probably partly due to low alcohol consumption. The decreasing incidence of AC despite 130% increase in alcohol consumption is thought to be due to intensive treatment of alcoholism. A low prevalence of hepatitis B and C probably contributes to the low incidence of NAC.

Habitual coughing and its associations with asthma, anxiety, and gastroesophageal reflux.

STUDY OBJECTIVE: Coughing was studied in relation to different disorders and objective variables indicative of airway inflammation. SETTING: A random sample of 800 persons, aged 20 to 44 years, was chosen from a larger cohort of participants in the European Community Respiratory Health Survey in Uppsala Sweden; of these, 623 participated. This sample was enriched with 201 individuals who reported asthma-related symptoms or the use of asthma medication. METHODS: The study comprised a structured interview, including questions about habitual (productive and nonproductive) and nocturnal coughing and spirometry, methacholine challenge, peak flow diary, skin prick tests, and measurements of blood eosinophil count and serum eosinophil cationic protein (S-ECP). RESULTS: A significant positive correlation was found between productive coughing and asthma (adjusted odds ratios [OR] = 2.0), allergic rhinitis (OR = 1.9), gastroesophageal reflux (OR = 4.4), smoking (OR = 1.9), and anxiety (OR = 1.8), while nonproductive coughing was related to female gender (OR = 1.8) and anxiety (OR = 1.7). Nocturnal coughing was positively correlated to female gender (OR = 1.8), smoking (OR = 1.9), and asthma (OR = 2.2). Bronchial hyperresponsiveness was positively related to productive coughing (p < 0.001), nonproductive coughing, and nocturnal coughing (p < 0.05). S-ECP was significantly higher in individuals with nonproductive coughing compared with subjects without habitual coughing (p < 0.01). CONCLUSIONS: We conclude that habitual coughing has a significant association with different disease categories.

[Epidemiology of liver cirrhosis morbitity and mortality in Iceland.].

BACKGROUND: The mortality from liver cirrhosis in Iceland is the lowest in the Western world. OBJECTIVE: To study the epidemiology of liver cirrhosis mortality and morbitity in Iceland and to obtain a reliable separation between alcoholic cirrhosis (AC) and non alcoholic cirrhosis (NAC) by using multiple data sources. METHODS: The study included the whole population of Iceland. Mortality was studied through death certificate data for the period 1951-1990 and morbidity (clinical incidence) through hospital, autopsy and biopsy records for the period 1971-1990. RESULTS: 1) The average mortality for AC in age group 20 years and older was 8.6 and for NAC 19.2 per 106 per year and the average clinical incidence was 22.1 for AC and 25.9 for NAC. 2) In the morbitity study 44% were due to AC. In the mortality study 24% were due to AC but the data suggested an underreporting of AC for males at a rate of 30%. 3) There was a significant decrease in AC mortality with time but no change in NAC. 4) Alcohol consumption per inhabitant over 15 years increased from 2.1 to 4.9 litre (130%) during the period 1951-1990. CONCLUSION: The incidence of cirrhosis in Iceland is very low for both AC and NAC accounting for only 0.2% of total deaths. The reasons are unknown. The low incidence of AC in Iceland is probably partly due to a low population alcohol consumption. The decreasing incidence of AC despite 130% increase in alcohol consumption is thought to be due to intensive treatment of alcoholism. A low prevalence of hepatitis B and C probably contributes to the low incidence of NAC.