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PubMed1981

Effect of cystic fibrosis and non-cystic fibrosis plasma on the movement and retention of 45Ca2+ and 35SO42- in guinea-pig stomach and small intestine.

The effect of cystic fibrosis plasma on the net fluxes of 45Ca2+ and 35SO42- across the guinea-pig stomach and small intestine was investigated, using an automatic short-circuit current apparatus. A significant increase in net fluxes across the stomach and small intestine for 45Ca2+ in the presence of cystic fibrosis plasma compared with non-cystic fibrosis plasma was observed. There was an increase in net flux for 35SO42- across the stomach in the presence of cystic fibrosis plasma when compared with non-cystic fibrosis plasma. However, there was a more highly significant increase in net fluxes for 35SO42- across the small intestine in the presence of cystic fibrosis plasma when compared with non-cystic fibrosis plasma. The amount of 45Ca2+ activity retained by the stomach and small intestine is more highly significant in the presence of cystic fibrosis plasma than in the presence of non-cystic fibrosis plasma. The retention of 35SO42- activity by the stomach and small intestine in the presence of cystic fibrosis plasma when compared with non-cystic fibrosis plasma was also highly significant. These findings indicate that cystic fibrosis plasma increases the net fluxes and raises retention of 45Ca2+ and 35SO42- in guinea-pig stomach and small intestine.

Animals↗
PubMed1994

Hospital care for adults with cystic fibrosis: an overview and comparison between special cystic fibrosis clinics and general clinics using a patient questionnaire.

BACKGROUND: Provision of medical care for adult patients with cystic fibrosis is an increasing problem as the number of patients surviving into adulthood increases. Recent reports have suggested that care is best provided in specialist centres because of longer survival. Recent changes in the National Health Service funding and delivery of service may adversely affect the provision of such a specialist service. The aim of this study was to assess the current pattern of medical service received by adults with cystic fibrosis and to compare the type of care between special cystic fibrosis and general clinics. METHODS: Confidential postal questionnaires were sent to all 1052 members of the Association of Cystic Fibrosis Adults (ACFA) comprising 59% of the UK population of cystic fibrosis patients over 15 years and 80% over 25 years of age. The response rate was 82%. RESULTS: Two thirds of patients were attending special cystic fibrosis clinics for either adults or adults and children. There were significant differences in the proportion of patients using special cystic fibrosis clinics between regions but not between social class groups. Significant differences between cystic fibrosis and general clinics were noted. Patients attending cystic fibrosis clinics were more likely to have had simple clinical investigations (blood tests, sputum culture, oxygen saturation, chest radiography, weight and lung function measurement) in the previous year. They were also more likely to have received intravenous antibiotics at home, and to have access to paramedical personnel. Patients attending cystic fibrosis clinics were taking higher doses of pancreatic enzyme supplements with respect to quantity and potency of preparation. Such patients also had less severe symptoms irrespective of social class, and were more likely to be satisfied with professional aspects of their care. Regardless of type of clinic, potential deficiencies were identified in overall medical care with omission of clinical investigations in severely affected patients and evidence of undertreated respiratory and digestive symptoms in patients with moderate and severe disease. CONCLUSIONS: This survey provides evidence that adults with cystic fibrosis attending special cystic fibrosis clinics receive more intensive care, have better symptom control, and are more satisfied with the service provided than those attending general clinics.

Adolescent↗
PubMed1979

Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchyma characterized by a chronic inflammatory cellular infiltration and varying degrees of interstitial fibrosis. Current data indicate that the severity of fibrosis and the degree of cellularity determine, in part, the prognosis of IPF and the response to therapy. Whereas lung biopsy gives the best assessement of fibrosis and cellularity, physiologic studies are used to stage and monitor the disease process. To determine which physiologic studies correlate best with severity of fibrosis and degree of cellularity, these parameters were graded in lung biopsies of 23 patients with IPF and compared with a variety of physiologic studies. Although vital capacity, total lung capacity, and diffusing capacity are commonly used as objective monitors of the disease process, none of these parameters correlated with either the severity of fibrosis or the degree of cellularity in biopsy specimens. In contrast, almost all parameters of lung distensibility correlated with the morphologic assessment of degree of fibrosis; compliance had the best correlation. Parameters of distensibility, however, correlated poorly with the degree of cellularity. In comparison, gas exchange during exercise correlated with both morphologic parameters; the exercise-induced changes in arterial oxygen pressure per liter of oxygen consumed had a high correlation with the degree of fibrosis (r = 0.89; P less than 0.001) and correlated to a lesser extent with the degree of cellularity (r = 0.56; P = 0.009). In contrast, neither the resting arterial oxygen tension nor the arterial oxygen tension at maximal exercise correlated with the morphologic assessment of degree of fibrosis or the degree of cellularity. These morphologic-physiologic comparisons suggest that (a) lung volumes and diffusing capacity are poor monitors of both the degree of fibrosis and the degree of cellularity; (b) the fibrotic process contributes, at least in part, to parameters of lung distensibility, and both fibrosis and cellularity contribute to gas exchange alterations during exercise; and (c) parameters of lung distensibility and exercise-induced gas exchange alterations may be useful in staging the severity of disease in IPF.

Adult↗
PubMed2003

Respective roles of porto-septal fibrosis and centrilobular fibrosis in alcoholic liver disease.

In alcoholic liver disease, fibrosis classically begins around the centrilobular veins, while portal tract fibrosis is described as inconstant and septal fibrosis is a late event. The aim of this study was to compare the roles of centrilobular fibrosis (CLF) and portal tract/septal fibrosis (PTF) especially in alcoholic chronic liver disease. One hundred and sixty patients with alcoholic chronic liver disease and 83 controls with viral chronic hepatitis were included. The PTF score, derived from the Metavir score, CLF and the area of fibrosis, assessed by image analysis, were evaluated on liver biopsies in addition to blood markers of fibrosis. The correlation between the PTF score and the area of fibrosis was higher in alcoholic liver disease (r = 0.87, p < 10(-4)) than in viral chronic hepatitis (r = 0.66, p < 10(-4)). The PTF score correlated with the CLF score (r = 0.92, p < 10(-4)), serum hyaluronate (r = 0.76, p < 10(-4)), and the prothrombin index (r = -0.77, p < 10(-4)). Multiple regression analyses showed that the area of fibrosis was explained only by the PTF score and not by the CLF score. PTF appears more frequent than CLF in alcoholic chronic liver disease, suggesting that PTF may precede CLF. PTF is more responsible for the amount of fibrosis than CLF. The results of this study also validate the use of the Metavir fibrosis score in alcoholic chronic liver disease.

Biomarkers↗
PubMed2006

Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis.

Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL-40 and PIIINP and the cytokines, transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNuF-alpha). A 10-year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow-up), and true rates in the progression of fibrosis were calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-beta, and TNF-alpha were measured, as well as the expression of TGF-beta, TNF-alpha, and YKL-40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 +/- 0.13) compared with the HCV monoinfection group (0.1 +/- 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL-40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL-40 showed a linear correlation with TGF-beta (r = 0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-beta correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease.

Adipokines↗
PubMed1994

Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis.

OBJECTIVE: To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin is enhanced in cystic fibrosis. DESIGN: Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered (R)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of (R)-warfarin in plasma and the concentration of (R)-warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of (R)-warfarin was measured by ultrafiltration. RESULTS: The unbound plasma clearance of (R)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 +/- 483 ml/hr/kg; control, 788 +/- 219 ml/hr/kg). The unbound metabolic clearances of (R)-warfarin to its oxidative metabolites--6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)--were also similar (p > 0.05) in the two groups (6-hydroxywarfarin: cystic fibrosis: 124.2 +/- 72.8 ml/hr/kg, control: 99.4 +/- 37.3 ml/hr/kg; 7-hydroxywarfarin: cystic fibrosis: 43.8 +/- 32.2 ml/hr/kg, control: 34.5 +/- 10.6 ml/hr/kg; 8-hydroxywarfarin: cystic fibrosis: 80.4 +/- 85.4 ml/hr/kg, control: 69.5 +/- 39.5 ml/hr/kg; 10-hydroxywarfarin: cystic fibrosis: 4.38 +/- 2.72 ml/hr/kg, control: 16.28 +/- 13.71 ml/hr/kg). CONCLUSION: The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.

Adult↗
PubMed1995

Long term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening and treatment in a cystic fibrosis centre.

BACKGROUND: A study was undertaken to evaluate whether an early diagnosis by neonatal screening may improve the long term prognosis of patients with cystic fibrosis and to assess the influence of expert management started immediately after the diagnosis. METHODS: Comparative clinical follow up in three birth cohorts of patients with cystic fibrosis was performed at the Cystic Fibrosis centre in Groningen in close collaboration with paediatricians in general hospitals in the north-eastern part of the Netherlands. The first birth cohort (n = 19) was detected by screening and the two other cohorts were detected clinically, one (n = 30) consisting of patients born during the screening programme and the other (n = 32) of patients born during the six years immediately after the screening programme ended. The total number of patients in the three birth cohorts included all patients with cystic fibrosis born in this area during a 12 year period. Cumulative survival rates and the variation with time of lung function, the levels of immunoglobulins, and growth patterns were used as main outcome measures. RESULTS: Patients born during the screening programme but detected clinically appeared to have a reduced life expectancy compared with patients detected by screening. The patients detected by screening showed less deterioration in lung function (annual decrease 1.2% of FEV1 % pred), a smaller increase in immunoglobulin levels, and minimal catch-up growth compared with an annual decrease of 3.25% of FEV1 % pred in the non-screened birth cohort of the same age, a higher rise in immunoglobulins leading to increased levels at the end of the observation period, and catch-up growth for weight as well as height. Differences between patients treated in a cystic fibrosis centre and those not referred to a specialist centre were smaller but similar, in favour of treatment at a cystic fibrosis clinic. CONCLUSIONS: Expert management started immediately after an early diagnosis of cystic fibrosis by neonatal screening results in important beneficial effects on the outcome and clinical course of the condition. The institution of very early treatment may be critical for the outcome and long term prognosis for most patients with cystic fibrosis. Neonatal screening programmes for cystic fibrosis should be introduced more widely.

Age Factors↗
PubMed2002

ROC curves in evaluation of serum fibrosis indices for hepatic fibrosis.

AIM: Use Receiver operating characteristic (ROC) curves to find out the relationship between serum level of hyaluronic acid (HA), type III procollagen (PCIII), N-terminal procollagen III peptide (PIIINP), laminin (LN), type IV collagen (C-IV) and hepatic fibrosis, as well as to determine their value in clinical practice. METHODS: 114 serum samples from chronic hepatitis patients were assayed for fibrosis indices including HA, PCIII, PIIINP, LN and IV-C with radioimmunoassay (RIA). Liver biopsy was also performed in all these patients and the biopsy material was examined histopathologically. RESULTS: ROC curves analysis showed that area under the curve (AUC) of PIIINP, HA, PCIII, C-IV and LN was 0.800, 0.728, 0.727, 0.583 and 0.463, respectively. The analysis also showed that PIIINP (r=0.452), HA (r=0.497) and PCIII (r=0.404) have greater diagnosis performances than C-IV(r=0.238) and LN (r=0.128) according to fibrosis staging. The sensitivity of HA plus PIIINP was 55.1 %, it was the most sensitive combination. Combined three or more than three indices that based on HA, the specificity was 100 %. Using combination assays can improve the specificity, but its sensitivity was not high. Serum fibrosis indices increased as the grade of inflammation aggravated. But only PIIINP and PCIII had significant difference between G1 and G2 (PIIINP: 13.16+/-8.07 vs 8.32+/-5.09; PCIII: 164.22+/-65.69 vs 138.23+/-77.63). The coefficient correlation of the results of inflammation grade and fibrosis staging to HA was 0.525 and 0.553 respectively, that to PCIII, 0.446 and 0.412, that to LN, 0.234 and 0.194, and that to IV-C, 0.363 and 0.351, respectively. CONCLUSION: Serum fibrosis indices can indicate tendency of hepatic fibrosis, but it cannot replace liver biopsy. However, as diagnostic markers, more efficient serum fibrosis indices for the diagnosis of hepatic fibrosis need to be explored.

Adolescent↗
PubMed2000

[The relationship between the levels of serum fibrosis marks and morphometric quantitative measurement of hepatic histological fibrosis].

OBJECTIVE: To study the relationship between the levels of serum fibrosis marks hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV) and the degree of hepatic fibrosis, and the clinical significance of HA, PCIII, CIV in the diagnosis of hepatic fibrosis to the chronic viral hepatitis. METHODS: The concentrations of serum HA, PCIII, CIV in 151 patients with chronic viral hepatitis were measured by radioimmunoassay. Liver biopsies were performed in all of the patients at the same time. Morphometric quantitative measurements of hepatic fibrosis were performed in 4mum sections stained with masson stain using a fully automated image-analysis system. RESULTS: The levels of serum HA, PCIII, CIV were all increased steadily with the progression of hepatic fibrosis, and the highest levels were in stage 4. They were all positively correlated with staging of the liver pathology and morphometric measurement of hepatic fibrosis (P<0.001). The coefficient value (r) with staging were 0.694, 0.493, 0.552 (P<0.001), respectively and with morphometric measurement of hepatic fibrosis were 0.715, 0.596, 0.537 (P<0.001), respectively. CONCLUSION: The levels of serum HA, PCIII, CIV are in concert with the degree of hepatic fibrosis, and the determination of these marks may be valuable for diagnosing hepatic fibrosis.

Adolescent↗
PubMed2005

[A quantitative study of the relationship between levels of liver fibrosis markers in sera and fibrosis stages of liver tissues of patients with chronic hepatic diseases].

OBJECTIVES: To study the quantitative relationship between the levels of serum liver fibrosis markers and fibrosis stages of liver tissues in patients with chronic hepatic diseases. METHODS: In 118 patients with chronic hepatitis, fatty liver or cirrhosis, their Serum levels of LN, HA, PCIII and CIV were investigated by EIA and their liver histological changes were studied. The relationship between the levels of serum LN, HA, PCIII and CIV and the degrees of liver tissue fibrosis was analyzed quantitatively by using the SPSS11.0. RESULTS: A correlation between the levels of serum LN, HA, PCIII and CIV and the histologically assessed grades of inflammatory activity was found (r = 0.394, 0.449, 0.443, 0.351, respectively, P <0.01). The correlation between the levels of serum LN, HA, PCIII and CIV and the histological assessed stages of liver fibrosis was strong (r = 0.456, 0.564, 0.476, 0.421 respectively, P <0.01). The levels of serum LN, HA, PCIII and CIV of the patients with a stage 2 liver fibrosis were 110 ng/ml, 110 ng/ml, 100 ng/ml and 70 ng/ml respectively, with sensibilities of diagnosing stage 2 liver fibrosis at 70%, 79%, 79% and 74% respectively. Their specificities in diagnosing stage 2 liver fibrosis were 68%, 72%, 64% and 73% respectively. The levels of LN, HA, PCIII and CIV in serum of these patients diagnosing cut-off value in stage 4 liver fibrosis (early cirrhosis) were 130 ng/ml, 140 ng/ml, 120 ng/ml and 70 ng/ml respectively. Their sensibility of diagnosing liver cirrhosis was 79%, 93%, 79% and 86% respectively. Their specificity of diagnosing liver cirrhosis was 66%, 82%, 72% and 61% respectively. As shown by the ROC curves in these patients, differentiating patients with cirrhosis or without cirrhosis, serum HA level was more valuable than LN, PCIII, CIV (the areas under the curves = 0.938 vs 0.775, 0.787, 0.791 ) When serum HA was higher than 190 ng/ml, the veracity of diagnosing liver cirrhosis was 93%. CONCLUSIONS: There is a certain quantitative relationship between the levels of LN, HA, PCIII and CIV in serum and the degrees of liver tissue fibrosis. The level of HA in serum is an important reference datum for early diagnosing liver cirrhosis.

Adolescent↗
PubMed1990

Effects of inflammation and fibrosis on pulmonary function in diffuse lung fibrosis.

To investigate the relation between lung function and inflammation and fibrosis in patients with diffuse lung fibrosis, a study was made of untreated patients without appreciable airway obstruction (14 patients with cryptogenic fibrosing alveolitis and seven with pneumoconiosis). Quantitative assessment of inflammatory infiltration and fibrosis was carried out on open lung biopsy specimens and compared with lung volumes, carbon monoxide transfer factor (TLCO), TLCO corrected for alveolar volume (TLCO/VA), and arterial blood gases at rest and during exercise. The degree of fibrosis and the degree of cellular infiltration were positively correlated. Lung volumes and TLCO were correlated with the grades of fibrosis and cellular infiltration of alveoli; arterial blood gases during exercise tended to correlate with both fibrosis and infiltration (p less than 0.06). In contrast, morphological data were not correlated with gas exchange at rest or with TLCO/VA. It is concluded that, in untreated patients with diffuse lung fibrosis, lung volumes, TLCO, and arterial blood gases during exercise reflect the lung lesions, and that the pulmonary function tests used cannot discriminate between fibrosis and infiltration of the lung by inflammatory cells.

Adult↗
PubMed1993

Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis.

Enhanced metabolism of theophylline in subjects with cystic fibrosis suggests that the activity of certain cytochrome P450 isoforms is affected in subjects with this genetic disease. To determine whether this effect on the P450 enzymes is selective, the in vivo activity of the cytochrome P450 isoform CYP2C9 was determined in adult subjects with cystic fibrosis (n = 6) and in control subjects (n = 8). Subjects were administered (S)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 96 hours. Plasma (S)-warfarin concentrations were determined by HPLC; urinary concentrations of (S)-warfarin and its metabolites were determined by gas chromatography-mass spectrometry. The total plasma clearance of (S)-warfarin (subjects with cystic fibrosis, 3.6 +/- 0.48 ml/hr/kg; control subjects, 3.82 +/- 0.73 ml/hr/kg), elimination half-life (subjects with cystic fibrosis, 29.5 +/- 4.2 hours; control subjects, 25.9 +/- 5.4 hours); and steady-state volume of distribution (subjects with cystic fibrosis, 153 +/- 18 ml/kg; control subjects, 138 +/- 22 ml/kg) were similar in the two groups (p > 0.05). The metabolic clearance of (S)-warfarin to its major metabolites mediated by CYP2C9, 6-hydroxywarfarin and 7-hydroxywarfarin, was not significantly (p > 0.05) different between the two groups (6-hydroxywarfarin: subjects with cystic fibrosis, 0.33 +/- 0.1 ml/hr/kg; control subjects, 0.41 +/- 0.1 ml/hr/kg; 7-hydroxywarfarin: subjects with cystic fibrosis, 1.34 +/- 0.49 ml/hr/kg; control subjects, 1.8 +/- 0.45 ml/hr/kg). On the basis of these data, we conclude that the in vivo cytochrome P450 activity is selectively affected in persons with cystic fibrosis.

Adult↗
PubMed1995

The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group.

BACKGROUND: Anecdotal reports suggest an increased frequency of certain cancers in patients with cystic fibrosis, the commonest genetic disorder of whites. One third of patients with cystic fibrosis now reach adulthood, when cancer is more frequent, implying that cancer rates in these patients will increase over time. We investigated the relation between cystic fibrosis and cancer in North American and European patients with cystic fibrosis. Methods. We performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. We also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. RESULTS: Thirty-seven cancers were observed in the North American cohort during 164,764 person-years of follow-up, as compared with an expected number of 45.6, yielding a ratio of observed to expected cancers of 0.8 (95 percent confidence interval, 0.6 to 1.1). Thirteen digestive tract tumors were observed, as compared with an expected number of two, for a ratio of observed to expected cancers of 6.5 (95 percent confidence interval, 3.5 to 11.1). In Europe, 11 of 39 cancers originated in the digestive tract, yielding a positive association between digestive tract tumors and cystic fibrosis (odds ratio, 6.4; 95 percent confidence interval, 2.9 to 14.0). CONCLUSIONS: Although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. Persistent or unexplained gastrointestinal symptoms in these patients should be carefully investigated.

Adolescent↗
PubMed2001

Study on free radicals and pancreatic fibrosis--pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor.

The exact mechanisms of the development of pancreatic fibrosis are still unknown. To clarify the relationship between pancreatic fibrosis and free radicals, the effect of the administration of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC), on pancreatic fibrosis in rats was studied. A single intraperitoneal injection of 500 mg/kg of DDC significantly reduced SOD activity and significantly increased lipid peroxidation products in the pancreas, showing no histologic changes of inflammation or necrosis. Repeated administration of 500 mg/kg DDC, twice a week, caused inter- and intralobular fibrosis with atrophy of acinar cells in the pancreas for at least 2 weeks without fibrosis of the liver and kidney. Administration of allopurinol showed preventive effects against DDC-induced pancreatic fibrosis. In conclusion, repeated administration of DDC, which caused pancreatic fibrosis, is a new experimental model of pancreatic fibrosis from the viewpoint of oxidative stress.

Allopurinol↗