Activation of kinin B receptor triggers differentiation of cultured human keratinocytes.

BACKGROUND: Keratinocyte life span is modulated by receptors that control proliferation and differentiation, key processes during cutaneous tissue repair. The kinin B(1) receptor (B(1)R) has been reported in normal and pathological human skin, but so far there is no information about its role in keratinocyte biology. OBJECTIVES: To determine the consequence of kinin B(1)R stimulation on tyrosine phosphorylation, a key signalling mechanism involved in keratinocyte proliferation and differentiation. METHODS: Subconfluent primary cultures of human keratinocytes were used to investigate tyrosine phosphorylation, epidermal growth factor receptor (EGFR) transactivation, cell proliferation and keratinocyte differentiation. Cell proliferation was assessed by measuring bromodeoxyuridine incorporation whereas assessment of cell differentiation was based on the expression of filaggrin, cytokeratin 10 (CK10) and involucrin. RESULTS: The major proteins phosphorylated, after B(1)R stimulation, were of molecular mass 170, 125, 89 and 70 kDa. The 170- and 125-kDa proteins were identified as EGFR and p125(FAK), respectively. Phosphorylation was greatly reduced by GF109203X and by overexposure of keratinocytes to phorbol 12-myristate 13-acetate, indicating the participation of protein kinase C. B(1)R stimulation did not increase [Ca(2+)]i, but triggered EGFR transactivation, an event that involved phosphorylation of Tyr(845), Tyr(992) and Tyr(1068) of EGFR. B(1)R stimulation did not elicit keratinocyte proliferation, but triggered cell differentiation, visualized as an increase of filaggrin, CK10 and involucrin. Blockade of EGFR tyrosine kinase by AG1478, before B(1)R stimulation, produced an additional increase in filaggrin expression. CONCLUSIONS: The kinin B(1)R may contribute to keratinocyte differentiation and migration by triggering specific tyrosine signalling pathways or by interacting with the ErbB receptor family.

Clinical validation of bronchial hyperresponsiveness, allergy tests and lung function in the diagnosis of asthma in persons with dyspnea.

The aim of the study was to determine the most useful tests for decision making in the diagnosis of asthma in patients with dyspnea assessed by commonly used terms: sensitivity, specificity, positive and negative predictive values and diagnostic accuracy. In a group of 195 patients with dyspnea data were analyzed with respect to case histories and different diagnostic procedures: bronchial hyperresponsiveness (BHR), skin prick tests (SPT), total IgE, spirometry (FEV1), sputum eosinophils (SE) and blood eosinophilia (BE). Asthma was diagnosed in 141 subjects. The control group comprised 18 subjects. Sensitivity for BHR in asthma in subjects with dyspnea amounted to 97%, for SPT to 62%, while all other diagnostics were lower than 50%. Specificity was highest for SE (94%), and BHR (85%). Positive predictive value (PPV) in asthma was for BHR 94%, for SE 86%, for SPT 81%, for decreased FEV1 79%, total IgE 72% and BE 64%. The highest negative predictive value (NPV) was found for BHR (92%). Diagnostic accuracy was highest for BHR 93% and for SPT 62%, while all other tests were comparable or lower than 50%. It is not possible to conclude whether or not a person has asthma merely on the basis of data on skin sensitization to aeroallergens, total IgE, eosinophils or lung function tests. Bronchial hyperresponsiveness showed the highest values for sensitivity (97%), PPV (94%), NPV (92%) and accuracy (93%). The second most efficient test is the skin prick test, with PPV 81% and diagnostic accuracy 62%.

Diagnosis and treatment of asthma--new approach.

Asthma is a serious health problem around the world, and affects approximately 10-15% of children and 5-10% of adults. Asthma is chronic inflammatory disorder of the airways. This inflammation causes period of illness exacerbation and period without symptoms. The therapy is based on stepwise approach on the basis of clinical features of asthma before treatment and on lung function measurement (FEV1 and PEF). To control asthma help "controllers" (especially anti-inflammatory agents) which suppress the inflammation and prevent airway remodeling, and "relivers" which makes quick relief of symptoms and treat attack (shortacting bronchodilator), but all therapy must include patient education.

[Education of patients with asthma, chronic bronchitis and pulmonary emphysema]. / Poduka oboljelih od astme, kronicnog bronhitisa i emfizema pluca.

Patients' education belongs to the most efficient therapeutic measures in the management of asthma, chronic bronchitis and pulmonary emphysema. The following paper reports the experience in the educational programme at the Polyclinic for Respiratory Diseases in Zagreb. Each patient's education lasted 5 days, 3 lessons per day, in groups of 10-15 persons. The education was carried out by a teaching team consisting of pulmonologists, psychosomatologist, pharmacist, physiotherapist and biometeterologist. From March 1995 to February 1996 135 persons completed the educational programme, 65 of whom were asthma patients. Data on cough and dyspnoea, skills in inhaler and breathing technique were collected at the beginning and 3 months after the education in all asthma patients. Three months after the education the asthma patients showed a significant decrease in dyspnoea and a significant improvement in inhaler and breathing technique. A standard questionnaire was given to all patients at the end of the education and in more than 80% the education was well accepted by the patients. Initial results are encouraging and the programme should be expanded to all parts of Croatia.

[Respiratory findings in textile workers employed in dyeing wool and cotton]. / Respiracijski nalazi tekstilnih radnika zaposlenih na bojenju vune i pamuka.

The prevalence of acute and chronic respiratory symptoms and diseases and ventilatory capacity were studied in 97 textile workers employed in dyeing wool and cotton fibres and in 76 non-exposed control workers. The prevalence of chronic respiratory symptoms was significantly higher in the textile workers compared to controls. The symptoms of occupational asthma were recorded in 7.2 per cent of the textile workers. The prevalence of respiratory symptoms was higher in exposed smokers than in exposed non-smokers. The textile workers employed for more than 10 years had a higher prevalence of all respiratory symptoms than those with a shorter period of employment. The textile workers showed a high prevalence of acute symptoms which developed during work shift. Significant acute reductions of ventilatory capacity tests on maximum expiratory flow-volume curves (MEFV) in textile workers varied from 5.1% for FVC to 12.4% for FEF25. Ventilatory capacity tests in the textile workers before work shift were significantly diminished in comparison to the predicted values. Our data indicate that work in the textile dyeing industry may cause the development of respiratory symptoms and diseases as well as impairment of ventilatory capacity.

Prognostic significance of transforming growth factor alpha TGF-alpha) in human lung carcinoma: an immunohistochemical study.

Despite emerging data relating oncogene expression, growth factors and/or their receptors to the etiology of lung cancer, standard clinicopathological evaluation is still used for the diagnostic and prognostic purposes. Recent studies have shown that expression of some oncogenes and growth factors/receptors may be useful as markers in routine diagnostic and prognostic processes. For example, EGF/erb-B family of peptides may play a role in lung carcinogenesis. Similarly, expression of TGF-alpha mRNA and peptide has been shown to occur in various human lung carcinomas in vivo and in vitro. However, results concerning the role of TGF-alpha in lung carcinoma are conflicting and therefore its clinical value still remains obscure. To better evaluate the potential value of TGF-alpha in clinical application we have investigated the relationship between TGF-alpha expression in 51 lung carcinomas and 26 different clinical and clinicopathological parameters. The only significant correlation noted was between TGF-alpha and venous blood erythrocytes and eosinophils. This study suggests a relationship between metastasis and aggressive behavior of lung cancer. This data shows that TGF-alpha expression can not serve as an independent tumor marker for lung cancer.

[Pulmonary function in adolescents with idiopathic thoracic scoliosis before and after surgical correction]. / Plucna funkcija adolescenata s idiopatskom torakalnom skoliozom prije i poslije kirurske korekcije.

The purpose of this study has been to establish pulmonary function improvement achievable by surgical correction of the scoliotic curve as compared with the achieved curve correction. The study comprised two distinct groups of patients with an average age of 15 years with idiopathic thoracic scoliosis. The first group of 33 patients were treated surgically: an average Cobb angle of 72 degrees was postoperatively reduced to 32.6 degrees. The second group of 30 patients of the same age with an average Cobb angle of 33 degrees who were not treated surgically. Cardiorespiratory function parameters were tested--preoperatively and 24 months after surgery--by spirometry and plethysmography, arterial blood gas analysis, and the exercise tolerance test. The results of the tests have demonstrated that correction of the scoliotic curve improves pulmonary function: however, the improvement does not match the degree of achieved scoliotic curve correction. Statistical analysis surgically and nonsurgically treated patients with the same degree of spinal curvature disclosed a difference in cardiopulmonary function--specifically, ther VC and PaO2 variables--to the advantage of nonsurgically treated patients. This observation suggests partial irreversibility of ventilation and perfusion in surgically treated patients.

[Evaluation of ventilatory function of the small airways]. / Prilog evaluaciji funkcije ventilacije malih disnih putova.

The results of functional tests and the values of flow-volume and spirometric parameters were reevaluated in 1174 randomly selected patients with no evidence of heart disease. There were 533 patients with normal ventilation and 327 patients with no restrictive disorders. In the latter group 11% of the patients had normal FEV1 and lowered FEF50 and FEF75 values. In those patients obstructive changes would not have been found if expiratory flow rates had not been taken into account as one of the criteria for evaluating airway obstruction. In further 13% of the patients a mild airway obstruction would have been found had only FEV1 been evaluated without taking account of expiratory flow rates. It is concluded that expiratory flow rates along with anamnestic data and clinical status are important indicators of obstructive changes of ventilation, especially as they serve to identify functional disorders while these are still reversible and therapy can be useful.

[The effect of cigarette smoking on pulmonary diffusing capacity in asymptomatic smokers]. / Utjecaj pusenja cigareta na difuzijski kapacitet pluca u asimptomatskih pusaca.

Ninety-seven subjects of which 72 smokers and 25 nonsmokers attending the Laboratory for Respiratory Functional Diagnostics of the University Hospital for Lung Diseases, Jordanovac, Zagreb were examined. The selection criteria were normal standard spirometric test values (FEV1, FVC, FEV1/FVC) in asymptomatic healthy, young smokers/nonsmokers who showed no signs of hematological, cardiovascular and chronic or acute pulmonary symptoms or diseases (according to a standardized questionnaire), and were not exposed to harmful environmental factors. The single-breath carbon monoxide diffusing capacity was measured in all patients. The results of our study confirm the findings of those authors who report reduced values of DLCO and DL/VA in smokers in comparison with the nonsmokers. A linear value diminution has been noticed in smokers and nonsmokers with increasing age, with the values being much lower in smokers. Our results also demonstrate a significant correlation between DLCO and DL/VA in young healthy smokers vs the duration of smoking and the number of cigarettes smoked per day (p < 0.01). The possibility to detect early reversible damages of lung function in young healthy smokers is an important contribution to the prevention of all diseases in which causal consecutive relation with cigarette smoking is confirmed.

Cardiorespiratory function in surgically treated thoracic scoliosis with respect to degree and apex of scoliotic curve.

We studied the relationship of deterioration of cardiorespiratory function with respect to degree and localisation of apex of spinal curvature. The study comprised 33 patients (27 females and 6 males) aged 15 (11-21) years, surgically treated for an average scoliotic angle of 72 degrees (55-129 degrees, after Cobb) which was postoperatively reduced to 32.6 degrees (13-74 degrees). The static and dynamic cardiorespiratory function parameters were tested (pre-operatively and 24 months after surgery) by spirometry and plethysmography, arterial blood gas analysis, and the exercise tolerance test. In terms of the site and apex of the thoracic curve as determined by spine X-ray, patients were divided into two groups: upper thoracic scoliosis with the apex between T5 and T8 and lower thoracic scoliosis with the apex between T9 and T11. Only upper thoracic scoliosis with Cobb angle of more than 70 degrees correlated (r = -1) with restrictive ventilation disorder (vital capacity 68%) and latent hypoxaemia (uptake O2 ml/kg/min 63%) demonstrated during the exercise tolerance test (p > 0.05). The results of the test have demonstrated that surgically obtained 54% correction of the scoliotic curve improves pulmonary function (p < 0.05). However, the improvement does not match the degree of achieved scoliotic curve correction, what means that even in surgically treated high-angled thoracic scoliosis exists an increased risk of morbidity and mortality.

Pulmonary function in adolescents with idiopathic scoliosis.

Two groups of patients, with an average age of 15 years, have been studied to establish the improvement in pulmonary function after surgical correction in relation to the amount of correction achieved. The first group of 33 patients were treated surgically; an average Cobb angle of 72 degrees was reduced to 32.6 degrees. The second group of 30 patients with an average Cobb angle of 33 degrees were not operated on. Results of tests undertaken have shown that pulmonary function was improved by surgical correction, but the improvement does not match the degree of correction achieved. Statistical analysis of the two groups shows a difference in cardiopulmonary function to the advantage of those who were not operated on. This suggests that there is partial irreversibility of ventilation and perfusion in those who are treated surgically.

[How should pharmacodynamic tests for respiratory tract obstruction be evaluated?]. / Kako procijeniti farmakodinamski test pri opstrukciji disnih putova?

The factors that could influence the results of pharmacodynamic testing with beta 2 agonists in lung function diagnostics are discussed. These are: hypersecretion of the mucus, acute respiratory infection, tachyphylaxis of the adrenoceptors, therapy in the past 48 hours, patient's cooperation, and ambient or environmental pollution. The correct application, by inhalation, of selective sympathomimetics is described and differences between the basic values of lung function parameters and those following the salbutamol test are discussed.

[Pharmacokinetic testing of patients with bronchial asthma]. / Farmakodinamsko testiranje bolesnika s bronhalnom astmom.

The study represents the investigation on pharmacodynamic lung function testing in 40 patients (21 with extrinsic asthma and 19 with intrinsic asthma). Skin prick tests on common inhalation allergens, IgE antibodies, spirometry, flow-volume curve, body plethysmography and pharmacodynamic testing with salbutamol spray were performed in each person. The greatest changes after beta 2 agonist were established by plethysmographic parameters SGaw (mean increase 117%) and Raw (mean decrease 45%), than by the expiratory flow rates from flow-volume curve: FEF25%-75% and FEF50% (mean increase 26%), than the FEV1 (+ 15%), the PEF (also + 15%), the RV (mean decrease 17%) and the FVC (mean increase 8%). The aim of this study was to represent the necessity of the complex analysis and interpretation of the results of pharmacodynamic testings because of many factors that might change the values of the tests.

[Rare causes of bronchial asthma]. / Rijedi uzroci nastanka bronhalne astme.

Historical perspectives, incidence, clinical presentation, immunopathogenesis, aspirin challenge and sulfiting provocation test are presented together with the hyposensitization, complications, diagnosis and differential diagnosis and treatment of these forms of bronchial asthma. Many patients with aspirin bronchial asthma can tolerate acetaminophen. Over 90% of patients with allergic bronchopulmonary aspergillosis have extrinsic form of bronchial asthma. Criteria for the diagnosis of allergic bronchopulmonary aspergillosis are described. About 5-10 percent of all asthmatic patients may have some degree of sulfite sensitivity. The principle of etiologic differentiation is reasonable when the therapy is indicated by confirmed bronchial asthma. In some cases the invasive methods of diagnostics should be applied (provocation, BAL, transbronchial biopsy, transthoracic biopsy).

[Determination of blood volume in pulmonary capillaries in patients with chronic obstructive lung disease]. / Odredivanje volumena krvi plucnih kapilara bolesnika s kronicnom opstruktivnom bolescu pluca.

The subjects were divided into four groups, three of which consisted of patients with various degrees of lung obstruction, while the fourth was the control group. The patients were divided according to the spirometric values: VC, FEV1, FEV1/VC%. The diffusing capacity was determined on the basis of the single breath method and graphical separation of the diffusion components was performed. It was found that the diffusing lung capacity was slightly lower in patients with mild to severe obstructive lung disease. The capillary blood volume was also slightly lower. Correlations between the degree of obstruction of the respiratory system and the diffusing lung capacity or the lung capillary blood volume was not statistically significant (p greater than 0.5). In studying patients with obstructive lung disease we were unable to establish which of the diffusion components significantly affected the value of the total diffusing lung capacity.

[A computer program for the interpretation of the acid-base status and respiratory gases]. / Kompjutorski program za interpretaciju acido-baznog statusa i respiratornih plinova.

A computer program for analysing the parameters of the acid-base status and respiratory gases has been designed. The program separates cases which are included into classical picture of certain respiratory, metabolic and mixed disorders. Out of a test series of 200 findings, 93% findings have been accurately interpreted. The program is written in BASIC, translated into machine code and occupies about 25 Kbyte computer memory. The main parts of the program use commands which do not favorize any version of BASIC increasing the program portability to other systems. The classification of respiratory gases and acid-base status was based on the already known facts.

[Study of bronchial reactivity using dry, cold air and eucapnic hyperventilation]. / Ispitivanje bronhalne reaktibilnosti pomocu suhog hladnog zraka i eukapnicne hiperventilacije.

The paper is concerned with diagnostic value provocation test with cold dry air and eucapnic hyperventilation for testing bronchial reactivity. Forty healthy subjects, 90 patients with bronchial asthma, 20 with chronic bronchitis, 2 with sarcoidosis, 14 with pollenosis, one with mucoviscidosis and 22 with dispnoa or long-lasting dry cough were tested. The total of 149 provocations have been carried out in patients and 40 in healthy subjects. Airways resistance after provocation with cold dry air and eucapnic hyperventilation in patients with bronchial asthma is increased over 100% in 13 (14%), over 200% in 12 (13%), over 300% in 25 (26%) and over 500% in 40 (47%) patients. Less intensive asthmatic attack was provoked in 14 (15%), moderate attack in 18 (20%) and severe attack in 58 (65%) patients with asthma. Provocation time lasted from 2 to 9.9 min. Inspired air temperature ranged from -23 degrees C to -26 degrees C. Airway resistance was measured before and after provocation by means of Bronchoscreen. Central airway resistance was increased in 2 patients, peripheral resistance in 78, and both resistances in 10 patients with bronchial asthma. The results pointed out that provocation with cold dry air and eucapnic hyperventilation resulted in bronchial hyperreactivity exclusively in patients with bronchial asthma, and the test was positive in 100% of patients with bronchial asthma.

[Evaluation of allergologic diagnosis in patients with bronchial asthma]. / Evaluacija alergoloske dijagnostike u bolesnika s bronhialnom astmom.

The present paper deals with 16 patients who were referred to the Clinical Hospital for Lung Disease "Jordanovac", Zagreb. On admission they were supposed to have or had already been diagnosed to have bronchial asthma. Numerous data from the patients' history were evaluated as well as the results of allergy tests (skin tests, RIST, RAST, eosinophils in the blood and sputum) and parameters of the functional lung diagnostics (blood gas analysis during rest and exercise, spirometry, flow-volume, body plethysmography). It was established that allergy diagnostics is not carried out as required, even though it is necessary in all chronic obstructive lung diseases. Skin tests, inspite of the problems on the standardization of allergens and the average number of positive reactions in healthy volunteers, represent a significant diagnostic method for the determination of the role of allergic reaction in bronchial asthma. It is necessary to combine them with the determining level for specific IgE in serum (RAST), which would, if the other conditions are satisfactory, be a basis for specific immunotherapy. The value of skin tests is greater since a good correlation between them and bronchial sensibility was found established by specific broncho-provocative testing. The correlation between eosinophils in the blood and the sputum with allergic sensibilization in asthma was not confirmed in this work. For evaluation the localisation and degree of obstruction as well as the effect of therapy in asthma patients the best functional test was found to be the flow-volume.

[Functional diagnosis of pulmonary sarcoidosis]. / Funkcionalna dijagnostika plucne sarkoidoze.

Restrictive disturbances of ventilation of various degree and disorders in diffusing capacity of the lung have been reported as the most frequent disorders in pulmonary sarcoidosis. Recently, however, several authors have found the obstructive disorders of ventilation being present as well, especially in the second stage of disease, and pointed out a possibility of the airways being affected very early at the onset of disease. Present study shows the results of functional tests carried out in 70 patients with histologically verified pulmonary sarcoidosis at all three stages of the disease (classification by Würm). All of them were nonsmokers, aged 20 to 55 years, and had no symptoms of chronic bronchitis, asthma or emphysema, either in case history or clinical findings. They included spirometry, flow-volume loop, body-plethysmography, blood gas analyses at rest and after exercise and pulmonary diffusing capacity for carbon monoxide obtained by single-breath method. Results from the study show the obstructive disorders of ventilation to be dominant in the early stage, while restrictive disturbances dominate in the third stage in pulmonary sarcoidosis. Diffusing capacity of the lung should be measured in the early stage of the disease as well as in those more advanced because of a possibility that interstitial space is being affected, although there is no visible damage on a radiograph. Measurement of pulmonary diffusing capacity together with radiological findings provide a highly valuable data which is of great importance in monitoring the dynamics of this disease.

[Correlation of the size of the residual volume measured by whole body plethysmography and the single breath helium dilution method]. / Korelacija velicina rezidualnih volumena mjerenih pletizmografijom cijelog tijela i dilucijom helija metodom jednog udaha.

The value of residual volume, intrathoracic gas volume, functional residual capacity and total lung capacity obtained by the method of body plethysmography and helium dilution method was correlated by single-breath diffusing capacity. These parameters were correlated in 22 patients who had had complete functional diagnostics of the lung: spirometry, flow volume curve, body plethysmography and single-breath diffusing capacity. All findings were within normal limits, which was a condition for selection of patients for our group. Statistically significant differences (p = 0.01) of t-test were established between residual volumes by the plethysmographic and helium dilution method of single-breath diffusing capacity. The residual volume obtained by body plethysmography showed higher values for 526 ml, or 30%. The intrathoracic gas volume showed higher values for 682 ml, or 17%. Inspite of the fact that values of RV obtained by two methods had statistically significant differences, they were still within normal limits, if presented as percent of the predicted value.