Insulin production and resistance in cystic fibrosis: effect of age, disease activity, and genotype.

AIM: To assess the major determinants of glucose tolerance between age, genotype, and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF-related diabetes (CFRD). SUBJECTS AND METHODS: One hundred and nineteen patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. Homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose/insulin ratio (FGIR) were calculated as indices of IR and insulinogenic index as a marker of pancreatic ß-cell function. All patients underwent an oral glucose tolerance test, and 57 underwent an IVGTT for the calculation of first-phase (FPIR) and acute insulin responses (AIR). RESULTS: The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMAIR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses, glucose tolerance was related to the agegroup, and to the HOMA-IR and insulinogenic indexes. CONCLUSIONS: IGT and CFRD were related mainly to genotype, although, as expected, the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, ß-cell function, and reduced insulin sensitivity to the onset of CFRD; however, further studies are warranted to better elucidate this aspect.

Three-dimensional quantitative assessment of lung parenchyma in cystic fibrosis: preliminary results.

PURPOSE: The aim of this study was to assess the feasibility of three-dimensional (3D) reconstructions and quantitative analysis of the volume of each component of the lung with cystic fibrosis (CF). MATERIALS AND METHODS: Twenty-two patients with CF (mean age 17+/-8 years) were included in the study. The patients underwent an unenhanced single-slice spiral computed tomography (CT) chest scan with the following parameters: collimation 3 mm, table feed 6 mm x rot(-1), reconstruction interval 1 mm, soft tissue reconstruction kernel. Four image data sets were obtained: native axial slices, cine-mode display, virtual bronchographic volume-rendered images with algorithm for tissue transition display and virtual endoluminal views. The lungs were segmented manually from the hilum to the visceral pleura on the axial images, and the entire lung volume was calculated. A histogram was generated representing the fractional volume of tissues, the density of which was within a preset range. A curve was then obtained from the histogram. RESULTS: Native axial images and cine-mode display allowed complete evaluation of lung volumes. Virtual bronchography allowed a better assessment of the distribution of bronchiectasis. Virtual bronchoscopy was limited by the fact that it visualised only the surface, without differentiating mucus from the bronchial wall. Manual segmentation and generation of density-volume curves required 41+/-7 min for each lung. Three curve patterns were identified depending on disease severity. CONCLUSIONS: Volume-density analysis of lungs with CF is feasible. Its main advantage is that image analysis is not analogical, as the assessment is not performed using scoring systems or similar ordinal scales. This technique cannot differentiate acute from chronic findings, and the predictive value of the curve should be assessed.

Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects.

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01). On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.

[Thirty years of activity at the center for cystic fibrosis in Parma]. / Trenta anni di attività del Centro per la fibrosi cistica di Parma.

One hundred fourteen patients (52 males, age range 1 to 40 yr, median age 16 yr) affected by Cystic Fibrosis (CF) are currently followed by the CF Centre of Parma. Forty two percent of them are adults. Most patients live in Emilia Romagna (59%) and Lombardia (19%). With respect to CF genotype, delta F508 mutation has been found in 54% of patients. Despite of the improvement in knowledge of CF, its diagnosis is still based on the clinical features and sweat test is usually used to confirm the diagnosis. Recent diagnostic tools, such as the genetic analysis and the potential difference measurement, could also be helpful in ambiguous situations. In the CF Centre of Parma, in agreement with the literature, the disease is now diagnosed earlier than in the past. Particularly, in the last year the median age of diagnosis was seven months, while it was 20 months in the 1980s. The early diagnosis and the improvement in the treatment of lung disease has significantly increased the median survival age of our patients, changing from 7.5 years in 1975 to 20 years in 1999. A significant improvement in CF prognosis could be further achieved by potential investigational agents, such as "protein-repair" addressed to CFTR activation. However, the gold standard for CF therapy is represented by gene therapy, although it is not yet available.

[Italian Cystic Fibrosis Registry: 10 years of activity]. / Registro Italiano Fibrosi Cistica: 10 anni di attività.

Cystic Fibrosis (CF) is a recessive autosomic genetic disease with an incidence in mediterranean countries of about 1:3500 born alive. In Italy the considerable genetic variability makes it difficult to identify all the homozygous subjects and, consequently, to estimate the incidence of the disease in healthy carriers. The disease is evolutive and affects various systems, most of all the respiratory and gastrointestinal systems. Not many years ago, when the clinical definition of CF was first introduced, average survival did not exceed the pediatric age. Nowadays with ever advancing diagnostic and therapeutical techniques many CF patients survive until an adult age. It is therefore necessary to plan adequate health service interventions so as to satisfy as much as possible the needs of both the patients and their families. To this end data collected since 1.1.1988 by the Italian registry for CF (year of birth, sex, region of birth and residence, diagnosis procedures, results of sweat test, pancreatic insufficiency, DNA analysis, status: alive, dead, lost to follow up) of all the patients, diagnosed in the 18 Reference Centres and the 3 local Centres for CF, have proved to be extremely useful. Since the birth of the Registry on 31.12.1997, data relating to 2458 patients alive on 1.1.1988 and 1159 born during the last ten years, for a total of 3617 subjects (1756 females and 1861 males), have been recorded. As already mentioned a considerable increase in life expectancy of CF patients (from 1988 to 1990 the average age of death was 14 years, from 1994 to 1997 it was 19) and a consequent increase in the percentage of adult patients have been observed.

Genetic history of cystic fibrosis mutations in Italy. I. Regional distribution.

Earlier analysis of the Italian population showed patterns of genetic differentiation that were interpreted as being the result of population settlements going back to pre-Roman times. DNA disease mutations may be a powerful tool in further testing this hypothesis since the analysis of diseased individuals can detect variants too rare to be resolved in normal individuals. We present data on the relative frequencies of 60 cystic fibrosis (CF) mutations in Italy and the geographical distribution of the 12 most frequent CF mutations screened in 3492 CF chromosomes originating in 13 Italian regions. The 12 most frequent mutations characterize about 73% of the Italian CF chromosomes. The most common mutation, delta F508, has an average frequency of 51%, followed by N1303K and G542X, both with average frequencies around 5%. Multivariate analyses show that the relative frequencies of CF mutations are heterogeneous among Italian regions, and that this heterogeneity is weakly correlated with the geographical pattern of non-DNA 'classical' genetic markers. The northern regions are well differentiated from the central-southern regions and within the former group the western and eastern regions are remarkably distinct. Moreover, Sardinia shows the presence of mutation T338I, which seems absent in any other European CF chromosome. The north-western regions of Italy, characterized by the mutation 1717-1G-->A, were under Celtic influence, while the north-east regions, characterized by the mutations R1162X, 2183AA-->G and 711 + 5G-->A, were under the influence of the Venetic culture.

[Circadian variations of bronchoconstriction in asthmatic children]. / Variazioni circadiane della broncoostruzione nel bambino asmatico.

In order to determine the magnitude of circadian variations in bronchoconstriction, we examined modifications of the spirometry observed during the 24-hr in a group of asthmatic (31 males, mean age = 8 years, 6 months). Particular attention was paid to the forced expiratory volume in 1 sec. (FEV1) and the forced vital capacity (FVC). We were thus able to compare in single patients 43 spirometry pairs between morning (between 8 and 10 am) and early afternoon (between 1 and 4 pm), 46 pairs between morning and evening (between 6 and 10 pm) and 54 between 2 consecutive mornings. The results of this study, substantially similar for the FEV1 and the FVC, show that the mean values obtained at different hours during the day and in two consecutive mornings were almost superimposable. On the other hand, the mean values and the standard deviations of the differences between two determinations in single patients are high. The percentage of patients who present significant modifications (greater than 10%) of FEV1 or of FVC at different hours of the day is also quite high. Moreover these variations seem directly related to the baseline spirometric value. Although the literature frequently outlines the existence of a circadian rhythm in the modifications or airways patency (maximum bronchoconstriction in the morning and minimum in the evening), in the asthmatic, however, the fast variations in the bronchial tone can be such as to mask this cyclic rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

[Respiratory physio-kinesitherapy in cystic fibrosis: the parents' viewpoint]. / La fisiochinesiterapia respiratoria nella fibrosi cistica vista dai genitori.

The aim of this study was to evaluate the problems found in performing chest physiotherapy (PKT) by patients with Cystic Fibrosis (CF) and by their families. The research has been based upon processing 389 questionnaires (46 items) that were compiled by the families. Thirteen CF centers all over the nation have participated in this study. Patients' mean age was 7.4 years (range 2 months to 14 years). Data about the socio-economic status and illness severity were available for every patient. Many graphs (line connects points with a line = n. 8; bar charts = n. 17; pie charts = n. 13) show the results and their statistical processing. Our purpose was to solve the following problems: 1) What is the extent of the compliance? 2) Who perform, or should perform, PKT in the family environment? 3) What is the kind and extent of the help request? 4) What are the mistakes made in executing PKT? 5) What is the usefulness of precursors and aerosol therapy? 6) What is the link between physical activity and PKT? 7) What are the main difficulties in performing PKT? 8) How effective is PKT? 9) What is the extent of the parents' faith in their capabilities? 10) Are there any prejudices against PKT? Three major findings emerge from this study: 1) the compliance appeared good; 2) the average family understood the meaning of PKT correctly and 3) PKT is usually executed properly. As for negative results are concerned, it is to be noted that the burden of performing PKT is usually up to the mother. This finding is linked both to the socio-economics status of the family and to the severity of the illness. On the other hand, a home PKT service is only asked in very extreme situations such as sudden worsening of the patient's illness. The difficulties met in performing PKT range from the patient's refusal to logistical and organization problems, which are correlated with the socio-economic status of the family. The relationship between PKT and sport is understood well and there is a high percentage of patients doing regular physical activity, even if it is often hindered by the severity of the disease. In conclusion, although there are many problems, there are also many methods to use in order to improve the acceptance and the effectiveness of the PKT.

[Criteria for discontinuation of sustained-release theophylline in children with chronic asthma]. / Criteri per la sospensione della teofillina ritardo nel bambino con asma cronico.

Aim of the study was to ascertain when it is advisable to discontinue the treatment with sustained release theophylline in chronic asthmatic subjects. The population consisted of 23 patients under continuous therapy with Theo-dur since at least 9 months, and free from bronchoobstructive episodes during the last three months. Upon stopping the treatment, instrumental controls showed a statistically significant reduction of mean values of PEF (checked by patients at home three times a day), VC, FEV1, MMEF or FEF25-75, FEV1/VC. The worsening of the physical examinations and anamnestic score is also significant, whilst the exstemporary use of beta 2 agonists increases. Dividing the cases into two populations, formed by worsened patients (11) and by stationary ones (12), it can be observed that the only distinctive features are that the former have been ill for longer, and are older in age. As the majority of patients (12/23) did not exhibit substantial modifications, we consider as proposable the standards we have adopted that means to try a suspension of theophylline in patients free from symptoms for at least 3 months.

[Aspiration bronchopneumopathies]. / Le broncopneumopatie da aspirazione.

Diagnosis of pulmonary disease due to inhalation (PDI) is based on the assumption that not all paediatric pulmonary disease is attributable to infection. Moreover, an accurate investigation of all typical signs of PDI is necessary: drooling, pouring of food from the nose, choking, frequent vomiting and regurgitation. Specific aetiological diagnosis is not difficult when PDI represents only the epiphenomenon of well defined diseases which have disturbed deglutition (e.g. premature birth, cerebral palsy, muscle disease). It is difficult but more important to find the cause of dysphagia when dysphagia itself represents the first sign of dysfunction of the autonomic nervous system (e.g. familial dysautonomy). There are different PDI due to oesophageal dysphagia, e.g. the anomalous artery which presses the oesophagus against the trachea, oesophageal duplication, achalasia. The most frequent cause is gastro-oesophageal reflux, although recently its role in producing symptoms at night in the asthmatic child in much less. Gastro-oesophageal reflux is increased by the Beta2, agonists, the corticosteroids and theophylline. Therefore these drugs, especially theophylline, have to be used with discretion, also if gastro-oesophageal reflux is only suspected (e.g. frequent vomiting by the infant). Anomalous communication between the oesophagus and airways, particularly the laryngotracheo-oesophageal cleft and the isolated tracheoesophageal fistula, are rare diseases and difficult to diagnose. Therefore diagnosis can be delayed for months or even years. Prognosis is extremely variable: repeated inhalation will, however, cause diffuse interstitial fibrosis or, more rarely, a bronchiectasic lesion.

[Aerosol administration in antibiotic therapy of cystic fibrosis]. / La via areosolica nella terapia antibiotica della fibrosi cistica.

The aim of this research was to evaluate the response to aerosol antibiotic therapy in Cystic Fibrosis (CF) patients, who because of severe lung disease, were obligated to frequent hospitalizations to undergo intravenous antibiotic therapy. Ten patients, aged 2 to 20 years were submitted to 4 months cycles of aerosol antibiotic therapy for a total of 18 cycles. The daily treatment consisted of carbenicillin 1 g b.d. and gentamicin 80 mgs b.d. At the end of treatment there was a statistically significant improvement of the modified Huang score and of single clinical parameters such as body growth, apetite, physical activity, clinical thoracic evaluation, appearance of sputum. Almost all of the radiographic items remained unchanged: in only 4 cases there was an improvement of the atelectasis-broncopneumonia type lesions. Regarding lung function, there was a statistically significant increase of maximum midexpiratory flow rate (MMEF) from 40% predicted before treatment to 50% predicted after. The reduction of residual volume (RV) from 270% predicted before 170% predicted after treatment was quantitatively more important. Furthermore, the treatment brought about a drastic reduction in number of hospitalizations: from an average of 1,7 hospitalizations/year before to an average of 0,3 hospitalizations/year during treatment. The increased number of isolations of isolations of candida albicans is the only report which favors possible adverse effects, in particular the possibility that this type of treatment favors lung mycosis.