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We describe the first detailed case of eosinophilic esophagitis associated with esophageal intramural pseudodiverticulosis and gastro-esophageal reflux disease in a 24-year-old man, who suffered from recurrent dysphagia since the age of 3 years. He presented with symptoms of dysphagia, food impaction and malnutrition. An esophagogram revealed a high-grade stenosis in the proximal part of the esophagus. Histological evaluation of esophageal mucosal biopsies demonstrated more than 20 eosinophil granulocytes per high power field, indicative of eosinophilic esophagitis. Additionally, esophago-gastro-duodenoscopy showed pseudodiverticulosis in the distal portion of the esophagus. A therapeutic regimen consisting of topical steroid intake, antihistamines, proton-pump-inhibition and specific food avoidance led to significant clinical improvement within 6 weeks.

A 37-year-old female never smoker with metastatic large cell carcinoma of the lung had a partial response to a second line palliative therapy with the EGF-R tyrosine kinase inhibitor erlotinib after platinum based first line therapy failed. Molecular analysis of the primary and a liver metastasis did neither find any EGF-R mutation nor an EGF-R amplification. However, both the primary and the metastasis showed an increased gene expression of vascular-endothelial growth factor-A in contrast to normal tissue, which was confirmed by immunohistochemistry. To our knowledge, this is the first report about a high vascular-endothelial growth factor-A expression in the tumor of a patient responding to an EGF-R inhibitor postulating that there might be a link between both tyrosine kinase pathways.

Background: The objective benefit of a training using the compact Erlangen Active Simulator for Interventional Endoscopy-simulator was demonstrated in two prospective educational trials (New York, France). The present study analysed whether endoscopic novices are able to reach a comparable level of endoscopic skills as in the above-described projects., Methods: Twenty-seven endoscopic novices (medical students, first year residents) were enrolled in this prospective, randomised trial. The compact Erlangen Active Simulator for Interventional Endoscopy-simulator with an upper GI-organ package and blood perfusion system was used as a training tool. Basic evaluation of endoscopic skills was performed after a practical and theoretical course in diagnostic upper GI endoscopy followed by a stratified randomisation according to the rating in endoscopic skills into intensive (n=14) and control group (n=13). The intensive group was trained 12 times every second week over 7 months in 4 endoscopic disciplines (manual skills, injection therapy, haemoclip, band ligation) by skilled endoscopist (three trainees/simulator). Assessment was performed (single steps/overall) using an analogue scale from 1 to 10 (1=worst, 10=optimal performance) by expert tutors. The control group was not trained. Blinded final evaluation of all participants was performed in January 2003., Results: We observed in all techniques applied a significant improvement of endoscopic skills and of the performance time in the intensive group compared to the control group (p<0.001). The comparison with the previous projects showed that the intensively trained novices achieved comparable levels of performance to the GI fellows in the New York and France Project (at least 80% of the median score in three out of four techniques)., Conclusion: Endoscopic novices acquired notable skills in interventional endoscopy in the simulator by an intensive, periodical training using the compactEASIE.

The role of glomerular endothelial cells in kidney fibrosis remains incompletely understood. While endothelia are indispensable for repair of acute damage, they can produce extracellular matrix proteins and profibrogenic cytokines that promote fibrogenesis. We used a murine cell line with all features of glomerular endothelial cells (glEND.2), which dissected the effects of vascular endothelial growth factor (VEGF) on cell migration, proliferation, and profibrogenic cytokine production. VEGF dose-dependently induced glEND.2 cell migration and proliferation, accompanied by up-regulation of VEGFR-2 phosphorylation and mRNA expression. VEGF induced a profibrogenic gene expression profile, including up-regulation of TGF-beta1 mRNA, enhanced TGF-beta1 secretion, and bioactivity. VEGF-induced endothelial cell migration and TGF-beta1 induction were mediated by the phosphatidyl-inositol-3 kinase pathway, while proliferation was dependent on the Erk1/2 MAP kinase pathway. This suggests that differential modulation of glomerular angiogenesis by selective inhibition of the two identified VEGF-induced signaling pathways could be a therapeutic approach to treat kidney fibrosis.

Duodenal mucosa, especially its proximal portion, is exposed to intermittent pulses of gastric acid (H+). This review summarises the mechanisms of duodenal bicarbonate (HCO3-) secretion and their role in protecting duodenal epithelium against gastric H+. Duodenal epithelium is a leaky barrier against gastric H+, which diffuses into duodenocytes, but fails to damage them due to: (a) an enhanced expression of cyclooxygenase, producing protective prostaglandins and expression of nitric oxide synthase, releasing nitric oxide, both stimulating duodenal HCO3- secretion and (b) the release of several neurotransmitters also stimulating HCO3- secretion such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, acetylcholine and melatonin. At the apical duodenocyte membrane, several HCO3-/Cl- anion exchangers operate in response to luminal H+ to extrude HCO3- into duodenal lumen. In baso-lateral duodenocyte membrane, both non-electrogenic and electrogenic Na+-HCO3- cotransporters are activated after exposure of duodenum to gastric H+, causing inward movement of HCO3- from extracellular fluid to duodenocytes. There are also at least three Na+/H+ exchangers, eliminating H+ which diffused into these cells. The Helicobacter pylori infection with gastric metaplasia in the duodenum and bacterium inoculation results in the inhibition of HCO3- secretion by its endogenous inhibitor dimethyl arginine, resulting in ulcerogenesis.

Background/aims: Medical treatment for hepatocellular carcinoma (HCC) remains elusive. While an acyclic retinoid improved tumor-free survival after hepatoma resection, tamoxifen finally proved ineffective. Combination therapy of both agents has not been investigated in vitro and in vivo., Methods: MH7777A hepatoma cells were incubated with tamoxifen (TAM) and 9-cis retinoic acid (CRA) alone or in combination. Proliferation rate and apoptosis were assessed by BrdU incorporation and flow cytometry. In vivo efficacy was studied using the Morris hepatoma model in immunocompetent rats. End points were macroscopic tumor growth, metastasis and immunohistochemistry for proliferative and apoptotic tumor cells (PCNA and TUNEL staining)., Results: In vitro, CRA and TAM monotherapy was effective only in the highest concentration. Combination therapy significantly enhanced apoptosis rate and growth inhibition in hepatoma cells. While in vivo monotherapy did not reduce tumor growth or metastasis, their combination reduced tumor size after 28 days by 64.5+/-28%. This was paralleled by an increase in TUNEL positive and a decrease in PCNA positive cells., Conclusions: The combination of TAM and CRA enhances their anti-tumoral efficacy in vitro as well as in vivo, while monotherapy is ineffective. This combination could be a promising adjunctive therapy of HCC.

Background: Chronic infections have been proposed to play a role in the aetiology or progression of atherosclerotic plaques. Increased risk of coronary artery disease has been suggested in patients seropositive for Helicobacter pylori., Aim: To analyse coronary specimens in patients with severe (coronary artery disease) for Helicobacter pylori specific DNA., Patients and Methods: Atherosclerotic plaques were obtained in 46 consecutive patients (9 female, 37 male, mean age 62.7+/-9.17 years) during coronary bypass procedures. Serum was analysed for IgG -/cagA-antibodies specific for Helicobacter pylori. Polymerase chain reaction and sequence analysis were used to identify bacterial DNA. Coronary artery biopsies from 19 autopsies without coronary artery disease were examined as a control group., Results: Of the 46 coronary artery disease patients, 32 (69.6%) were Helicobacter pylori seropositive. Positive results for Helicobacter pylori DNA showed 18 seropositive and 4 seronegative (with anamnesis of eradication therapy). A total of 22 patients (47.8%) of the coronary artery disease group but none of controls revealed positive DNA. In the coronary artery disease group, a correlation between DNA presence and prior myocardial infarction (p=0.008) and unstable angina (p<0.001) was found., Conclusion: Identification of DNA in atherosclerotic plaques of patients with severe coronary artery disease supports the hypothesis that Helicobacter pylori infection may influence the development of atherosclerosis. Our results may indicate an direct involvement of Helicobacter pylori in the progression and instability of plaques in these patients.

Using color-coded Doppler sonography (CCDS), changes in the resistance index of the hepatic artery (HA-RI) and in the velocities of the hepatic artery, portal and splenic vein (HA-V, PV-V, SV-V) were measured after administration of hydroxyethyl starch (HES) in 50 intensive care patients. PV-V and SV-V increased, whereas HA-V and HA-RI remained unchanged. CCDS is suitable to assess liver perfusion in intensive care patients. Since HES enhances splanchnic perfusion, its application improves hepatic perfusion in intensive care patients.

Background/aims: Effective treatment for hepatocellular carcinoma is urgently needed. The histone-deacetylase inhibitor Trichostatin A (TSA) was shown to induce apoptosis in non-hepatic cells at submicromolar concentrations. However, the effect of TSA on hepatoma cells is unknown., Methods: The hepatoma cells HepG2, MH1C1, Hepa1-6 and Hep1B as well as human fibroblasts (control cells) were exposed to TSA (10(-6) to 10(-9)M). Cell proliferation was assessed by measuring DNA-synthesis and cell numbers. Apoptosis was quantified by flow cytometry and by the TdT-mediated dUTP nick-end labeling method. Expression patterns of cell cycle- and/or apoptosis-associated p27, p21(cip/waf), bax, bcl-2, cyclin A and (pro)-caspase 3 were studied using quantitative Western blotting. Activation of caspase 3 was analyzed via a colorimetric assay., Results: 10(-6)M TSA inhibited DNA-synthesis by 46% (HepG2) to 64% (MH1C1) after 24h, inducing a G(2)/M-phase arrest and apoptosis. TSA increased activation of caspase 3 and expression of cyclin A, p2l(cip/waf), bax and (pro)-caspase 3, while bcl-2 was downregulated. Human fibroblasts remained unaffected., Conclusions: TSA inhibits hepatoma cell growth in vitro, which are otherwise particularly resistant to chemotherapy. Its anti-proliferative activity is paralleled by a comparable rate of apoptosis. TSA may be a promising agent for treatment of hepatocellular carcinoma in vivo.

Background: In palliative first-line treatment of colorectal cancer, the secondary resection of distant metastases after downstaging has constantly gained in importance. The objective of this prospective study was to examine the tumor response rate, the toxicity, the median survival time and the prognostic impact of metastatic resection after downstaging of consecutively enrolled patients with primary nonresectable colorectal cancer treated with once weekly 24-hour (24-h) infusion of high-dose 5-fluorouracil (5-FU) and folinic acid., Patients and Methods: Between January 1995 and July 1997, 53 consecutive patients with primary nonresectable metastases were recruited for a prospective phase II study. The patients received in out-patient care 500 mg/m2 folinic acid in the form of a 1-2-hour infusion followed by 2600 mg/m2 5-FU administered as a 24-h infusion once weekly. One treatment cycle comprised six weekly infusions followed by a two week rest. Three cycles were administered, and in the event of complete remission (CR) or partial remission (PR) and good tolerability, a fourth cycle was undertaken. Thereafter, the possibility of performing a curative metastatic resection was investigated., Results: Of the 53 patients treated, 7 showed a CR (13%), 15 patients a PR (28%), 26 patients stable disease (SD) (49%), and 5 patients progressive disease (PD) (10%). As the main symptom of toxicity, diarrhea (CTC grade 3 + 4) was observed in 11 patients (21%), followed by leucocytopenia (CTC grade 3 + 4) in 2 patients (4%), and the hand-foot syndrome in 1 patient (2%). The median survival time was 17 months with a median follow-up of 41 months (range: 28-59 months). In 9 patients (17%), a secondary metastatic resection was considered; in 6 patients (11%) curative resection was performed, and 4 patients (8%) showed no evidence of disease for at least three years., Conclusion: In this phase II study, we have been able to show prospectively that, after downstaging by palliative treatment using a weekly 24-h infusion of high-dose 5-FU and folinic acid, secondary curative metastatic resection was technically feasible in 11% of the patients. For some of these patients, long-term survival is therefore possible. Secondary metastatic resection should be carried out in close interdisciplinary cooperation, and should be further investigated in prospective phase III studies.

Background/aims: The liver is the major source of collagen XVIII (C18), the precursor of the angiogenesis inhibitor endostatin. In human liver C18 is mainly expressed by hepatocytes. However, its quantitative and temporospatial expression patterns during liver fibrogenesis are unknown., Methods: We used RNA quantification and in situ hybridization combined with cell-specific markers to study C18 compared to procollagen alpha1(I) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA expression in acute (single dose of CCl4) and chronic (biliary) rat liver fibrogenesis., Results: C18 transcripts were only found in hepatocytes and bile duct epithelia of normal and fibrotic livers, and occasionally in arterial myocytes and hepatic stellate cells. 72 h after CCl4 injection, C18 mRNA levels remained unchanged, while procollagen alpha1(I) mRNA was increased at 72 h and TIMP-1 mRNA peaked at 12 h (P < 0.05). In biliary fibrosis C18 mRNA levels increased 1.8-fold, contrasting with 20- and 4-fold elevated procollagen alpha1(I) and TIMP-1 transcript levels, respectively., Conclusions: Hepatocytes and bile duct epithelia are the predominant sources of C18 in normal and fibrotic rat liver. Contrary to procollagen alpha1(I) and TIMP-1, C18 expression remains constant in acute fibrogenesis and is upregulated in biliary fibrosis. Modulation of epithelial C18 expression and its processing to endostatin could allow a liver-specific anticancer therapy.

Background: Gastric infection caused by Helicobacter pylori has recently been associated with increased risk of coronary artery disease., Aim: To: 1) determine seroprevalence of Helicobacter pylori and its cytotoxin associated gene A in patients with/without coronary artery disease (group A), 2) assess influence of Helicobacter pylori eradication on coronary artery lumen reduction after percutaneous coronary angioplasty (group B) and 3) determine influence of Helicobacter pylori eradication on plasma cytokines, lipids and coagulation factors in patients subjected to percutaneous coronary angioplasty (group B)., Patients and Methods: Group A included 100 patients with coronary artery disease (subgroup 1) and 100 patients without (subgroup II). For Helicobacter pylori seroprevalence, plasma anti-Helicobacter pylori and anti-cytotoxin associated gene A IgG were examined. Group B included 40 patients with significant single-vessel coronary arterial disease and Helicobacter pylori infection confirmed by 13C-urea breath test and serologically using anti-Helicobacter pylori and anti-cytotoxin associated gene A IgG. Six months after percutaneous coronary angioplasty and triple anti-Helicobacter pylori therapy, the Helicobacter pylori status reassessed by urea breath test was negative in all but two patients of subgroup I subjected to Helicobacter pylori therapy. Coronary angiography and laboratory tests were repeated in both subgroups of group B included in the trial and reduction in coronary artery lumen in these subgroups was compared to baseline after percutaneous coronary angioplasty considered as 100%., Results: Helicobacter pylori seropositivity reached 81.5% of coronary artery disease (subgroup I) and was significantly higher than that in controls without coronary artery disease (subgroup II) (51%), the odds ratio being 4.3 for Helicobacter pylori in coronary artery disease. Cytotoxin associated gene A IgG detection was also significantly higher (47.3%) in coronary artery disease than in controls (28%) giving the odds ratio about 2.3. Mean coronary artery lumen reduction in patients undergoing percutaneous coronary angioplasty + Helicobacter pylori eradication therapy (subgroup I) was significantly (p<0.05) smaller compared to percutaneous coronary angioplasty + placebo-treated subgroup II (22% vs 41%)., Conclusions: 1) There is a significant link between coronary artery disease and infection with Helicobacter pylori, especially expressing CagA proteins, 2) Helicobacter pylori eradication significantly attenuates reduction in coronary artery lumen in coronary artery disease patients after percutaneous coronary angioplasty possibly by elimination of chronic inflammation and decline in proinflammatory cytokine release, and 3) Infection of Chlamydia pneumoniae in these percutaneous coronary angioplasty patients is not affected by eradication therapy.

Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta1 (TGF-beta1) and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-beta1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl(4)) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-beta1 and CTGF mRNA levels 6 hours after injection of CCl(4), with peak levels after 72 hours. In biliary fibrosis TGF-beta1 and CTGF mRNA levels increased fourfold and sevenfold, respectively (P: < 0.001). In situ hybridization combined with cell-specific markers revealed CTGF transcripts in desmin-positive cells after a single dose of carbon tetrachloride, whereas no transcripts were found in normal livers. In biliary fibrosis, however, proliferating bile duct epithelial cells were the predominant source of CTGF mRNA. We conclude that in rat liver fibrogenesis CTGF is up-regulated in close association with TGF-beta1 and that, contrary to a previous report, not solely hepatic stellate cells but activated bile duct epithelial cells are the main source of this profibrogenic factor.

Background: There have been contradictory reports on the benefit of CEA and CA 19-9 measurements in patients with metastatic colorectal cancer using palliative chemotherapy. The object of this study was to examine the diagnostic accuracy of monitoring of palliative chemotherapy by means of CEA and CA 19-9., Patients and Methods: The tumour markers CEA and CA 19-9 were subjected to serial measurement in patients with metastatic colorectal cancer (n = 90) using palliative first-line chemotherapy with weekly 24-hour infusion of high-dose 5-FU with FA and were compared with objective response according to WHO criteria. 85 patients could be evaluated. 43 patients (51%) initially had elevated CEA (> or = 10 ng/ml) and 33 patients (39%) elevated CA19-9 (> or = 50 IE/ml). In 24 patients (28%), both markers were initially increased. With CEA positive patients, 143 cycles of chemotherapy were carried out, which showed the following response in the various cycles: 21 episodes with progressions (ePD), 69 episodes with no change (eNC), 53 episodes with partial/complete remission (ePR/eCR). With CA 19-9 positive patients, 100 cycles of chemotherapy were carried out with the following results: 21 episodes with progressions (ePD), 48 episodes with eNC, and 31 episodes with ePR/eCR., Results: A CEA rise by at least 50% differentiated between ePD versus eNC/ePR/eCR with a sensitivity of 76% and specificity of 90%. With CEA decreases of at least 30% in 99% of these patient episodes (78 of 79), a tumour progression could be excluded. Patients with an initial drop in CEA after the first cycle of chemotherapy of at least 50% of the initial level had a significantly higher probability of achieving an ePR/eCR in further therapy (relative risk 2.9; P = 0.002). With an CA 19-9 increase of at least 30%, a sensitivity progression of 62% and a specifity of 90% could be calculated. A CA 19-9 decrease of at least 60% excludes a progression in 95% of the patient episodes., Conclusions: A CEA or CA 19-9 rise is only conditionally appropriate for recording progressions. A progression however, can be excluded with falling levels with high diagnostic accuracy, in which CEA offers a greater degree of certainty than CA 19-9. With a drop in CEA 79 of 143 (= 55%) of the CT scans could be saved, in which case 78 of 79 patient episodes (99%) were correctly assessed as 'no progression'. In patients with an increased CEA and CA 19-9 the CEA determination is sufficient for the further monitoring. A confirmation of these results by multicenter trials can result in a considerable decrease of monitoring costs for palliative treatment.

Upper airway dryness is a frequent side-effect of nasal continuous positive airway pressure therapy (nCPAP) in obstructive sleep apnoea (OSA). In this situation, heated or non-heated passover humidifiers are often added to the nCPAP-therapy. The efficacy of these two modes in terms of increasing the absolute humidity of the inspired air in vivo has so far not been established. The present investigation was therefore designed to compare various heated and non-heated passover humidifiers in terms of the their ability to increase the absolute humidity in the inspired air during nCPAP. In six healthy test individuals, nCPAP-therapy at pressures of 5 mbar and 10 mbar was simulated, and the relative humidity and temperature of the air within the tube at the junction between CPAP tube and mask were measured. In each test person, measurements were carried out both with and without the two heated (HC 100, Fischer&Paykel Inc., New Zealand and HumidAire, ResMed Ltd., Australia) and two non-heated (Oasis and Humidifier, both from Respironics Inc., U.S.A.) passover humidifiers under steady-state conditions. The absolute humidity was calculated from the relative humidity and temperature measurements. The mean (SD) absolute humidity (gm(-3)) in the steady-state was significantly (P<0.05 higher with each of the humidifiers than that calculated when no humidifier was used. The relevant figures were as follows: no humidifier: 10(-2) (1.8) gm(-3) (at 5 mbar)/9.8 (1.8) gm(-3) (at 10 mbar); Humidifier: 16.4 (0.97)/15.6 (1.26); Oasis: 17.3 (0.97)/ 16.7 (0.93); HC100: 26.5 (1.40)/26.2 (1.23); HumidAire: 31.8 (2.50)/30.9 (2.64). The mean increase in absolute humidity (in gm(-3)) with the aid of the heated humidifiers was 16.3 (5 mbar) gm(-3)/16.4 (10 mbar) gm(-3) with HC100 and 21.6/21.1 with HumidAire, and in both cases was clearly and significantly (P=0.028) higher in comparison with the non-heated humidifiers--6.2/5.8 with Humidifier and 7.2/6.9 with Oasis. In terms of the absolute humidity achieved within the CPAP tube system, the heated humidifiers were clearly superior to the non-heated humidifiers. These results were, however, obtained under laboratory conditions, and therefore cannot be translated unreservedly to the situation represented by long-term CPAP-treatment. Furthermore, it is possible that the smaller humidification capacity of the non-heated humidifiers may still suffice to meet the requirements of clinical use in terms of effectively preventing dry airways under CPAP treatment. This point, however, needs further investigation on the basis of long-term clinical studies.

Upper airway dryness is a frequent side-effect of nasal continuous positive airway pressure (nCPAP) therapy in obstructive sleep apnoea (OSA). In this situation, heated humidification is often used. Alternatively, oily nose drops are frequently applied to relieve dryness. The present study aimed to investigate the efficacy of a heated humidifier in comparison with oily nose drops. Twenty-four OSA patients complaining of serious nCPAP-related upper airway dryness were randomized to 6 weeks of treatment either with heated humidification (HC 100, Fischer & Paykel, Inc., Auckland, New Zealand) or oily nose drops (Colda-Stop, Desitin, Inc., Germany). The patients completed questionnaires on the degree and frequency of upper airway dryness, compliance with nCPAP, intention to terminate nCPAP and comfort during the nCPAP therapy. All 12 patients treated with heated humidification improved in terms of the degree and frequency of upper airway dryness, and reported greater comfort when using the nCPAP device. All patients in the heated humidification group intending to terminate nCPAP therapy because of upper airway dryness persisted with nCPAP on addition of humidification. In contrast, only five out of 12 patients (42%) in the oily nose drops group reported their degree of upper airway dryness to be improved (P = 0.003), only three patients (25%) reported an improvement in the frequency of upper airway dryness (P < 0.001), and only five patients (42%) reported greater comfort when using the nCPAP device with oily nose drops (P < 0.001). In the group using oily nose drops none of the three patients who intended to terminate nCPAP therapy persisted with nCPAP. Heated humidification is highly effective and superior to oily nose drops in reducing the symptoms of upper airway dryness during nCPAP.

The dynamics of cognitive brain functions of 104 patients with both chronic non-cirrhotic (NC) and cirrhotic liver disease (C: C1, non-encephalopathic; C2, encephalopathic) were investigated by means of visual P300 potentials elicited in both the paradigms of transient (PI) and selective attention (PII). Conventional PVEPs, psychometric tests and quantitative liver function tests were also performed. As compared to both an age-matched control group (N) and the non-cirrhotic patients (NC), the N250 and P300 latencies of the cirrhotics (C) were equally prolonged in both P300 paradigms (P = 0.0001). By contrast, the P300 amplitudes were not different between the patient groups in either P300 paradigm. In the cirrhotics, however, the P300 amplitude differences between PII and PI (+ 3.7 +/- 2.8 muV, mean +/- 1 S.D.) were significantly (P < 0.01) smaller than in the non-cirrhotics (+ 7.5 +/- 5.2 muV) reflecting disturbances in the dynamics of visual attention. Interestingly, these P300 amplitude differences between both paradigms were positively correlated (r = 0.35; P = 0.005) with hepatic metabolic capacity, but not with liver blood flow (r = 0.23; P > 0.05). The diagnostic efficacy of the visual P300 in PI (sensitivity, 48%; specificity, 100%) was lower than that of the visual P300 in PII (79%; 100%) and that of the psychometric tests (63%; 94%), but it remained superior to that of the PVEPs (29%; 97%). It is concluded that in patients with cirrhotic liver disease visual P300 potentials can even reveal the dynamics of minor cognitive brain dysfunction and may also provide interesting pathophysiological information.

Serum concentrations of the aminoterminal propeptide of procollagen type III (PIIIP) are elevated in fibrogenic diseases of the liver, but the mechanism of elevation is not fully understood. To investigate the mechanism, we compared serum concentrations of PIIIP with total liver content of mRNA for the pro alpha 1 (III) chain, in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Adult male rats received CCl4 in mineral oil twice weekly for 8 weeks and were compared with age-matched controls. Serum concentrations of PIIIP were measured by a specific radioimmunoassay; molecular sizes of PIIIP in serum were also determined. Pro alpha 1 (III) mRNA content in the liver was quantitated by RNA slot-blot hybridization and chemical measurement of total hepatic RNA content. Total collagen content of the liver was estimated by hydroxyproline measurement. All CCl4-treated animals had septal fibrosis after 4 weeks, and evidence of cirrhosis (regenerative nodules, ascites) was seen after 7 weeks of treatment. Serum concentrations of PIIIP and pro alpha 1 (III) mRNA content in the liver were correlated well until cirrhosis has established. They increased simultaneously after 3 weeks of treatment, 1 week before any elevation of hepatic hydroxyproline could be detected. After cirrhosis has established, pro alpha 1 (III) mRNA content in the liver decreased markedly, but serum PIIIP levels continued to be elevated. Hepatic hydroxyproline plateaued after 5 weeks. The molecular sizes of serum PIIIP indicate the release of intact native procollagen peptide during the development of cirrhosis. In conclusion, at least in CCl4-induced liver fibrosis in the rats, serum PIIIP levels can be used as a fibrogenic marker for the period progressing to cirrhosis. But the use of the serum PIIIP levels in cirrhosis seems to be limited by factors other than liver fibrogenesis.

Serum concentrations of both the carboxyterminal cross-linking domain (NC1) of procollagen type IV and the aminoterminal propeptide of procollagen type III (PIIIP) were measured by specific radioimmunoassays in 60 patients with chronic liver disease and 50 healthy controls. Compared with controls (5.3 +/- 1.3 ng/ml, mean +/- S.D.), NC1 concentrations were significantly elevated in patients with chronic active hepatitis (10.2 +/- 2.0 ng/ml) and liver cirrhosis (13.5 +/- 3.0 ng/ml), but not in chronic persistent hepatitis (6.0 +/- 0.9 ng/ml). The concentrations in patients with active liver cirrhosis were significantly higher than those in patients with inactive cirrhosis. Serum concentrations of PIIIP in controls, parients with chronic persistent hepatitis, chronic active hepatitis and cirrhosis were 5.8 (4.3-7.9), 5.3 (3.5-7.9), 17.5 (10.6-28.9), 16.7 (10.4-26.7) ng/ml, respectively (logarithmic mean and range of mean +/- S.D. after retransformation). Patients with liver cirrhosis had significantly higher concentrations of NC1 in serum than those with chronic active hepatitis, but there was no difference in serum PIIIP concentrations between the two groups. These data suggest an alteration of type IV collagen metabolism in chronic liver disease. In liver cirrhosis, the metabolism of collagen IV is apparently different from that of collagen type III; serum NC1 determinations may therefore provide additional information on chronic liver disease, particularly in patients with cirrhosis with a normal level of serum PIIIP. Further follow-up studies as well as investigations related to the basic mechanism of the elevation of these peptides in serum are needed in order to understand their clinical significance fully.

Liver fibrosis is one of the most important factors of disturbed liver function, but could not be measured by simple blood tests until recently. Among several parameters used for this purpose, the aminoterminal procollagen type III peptide (PIIIP) appears to be the most widely accepted. Studies conducted in several clinical groups have shown that PIIIP effectively distinguishes between non-fibrotic and fibrotic liver disease. A reliable commercial kit is available and a wide application possible to evaluate the clinical meaning of serum PIIIP for the long-term outcome of chronic liver disease. With this novel blood test we can now assess liver fibrosis as we can measure the hepato-biliary function.

A specific and sensitive radioimmunoassay for the rat aminoterminal procollagen type III peptide (PIIIP) was developed which allowed easy and sequential measurement of this peptide in the serum of individual animals. PIIIP in sera of 1-week-old rats was high (60 +/- 15.4 ng, 1 SD) falling to 15.7 +/- 4.3 ng/ml (1 SD) at 7 weeks and 6.7 +/- 2.6 ng/ml (1 SD) at 12 weeks of age. Adult animals (above 6 months of age) showed serum PIIIP levels in the narrow range of 2.5 +/- 2.33 ng/ml (2.5 SD). CCl4-induced liver damage in adult rats produced an elevated serum PIIIP (median 9.1; range 2.6-45.2 ng/ml) already after 2 weeks, rising to a mean of 33.8 ng/ml (range 22.0-47 ng/ml) after 6 weeks of continued CCl4-intoxication. In the same animals at 6 weeks, hepatic hydroxyproline was almost 5 times higher in the CCl4-group (mean 493.2; range 343.1-582.3 micrograms/100 mg dry weight) when compared with controls (109 +/- 14 micrograms/100 mg dry weight, 1 SD). These results are in complete analogy to those reported for PIIIP in sera of growing children, healthy human adults and patients with fibrogenic liver disease. Elevated serum PIIIP in rats with experimental liver fibrosis predicts the deposition of excess hepatic collagen. This novel serum test allows, for the first time, to assess altered PIIIP metabolism and hepatic fibrogenesis in individual animals as early as 2 weeks after the start of the experiment. It also reflects growth-related changes of type III collagen metabolism.

A liquid phase radioimmunoassay (RIA) was developed for pepsin-solubilized human type VI collagen, allowing quantitative analysis of this protein down to a concentration of 3 ng/ml. No cross-reactivity was observed with human collagens type I, III, IV (triple helical portion and 7-S domain), and V, nor with laminin fragment Pl and plasma fibronectin. Significant amounts of closely related antigenic material were detected in serum, bile, ascites, and mesenchymal cell culture media. Type VI collagen could be completely solubilized from several tissues by a repeated pepsin digest, and its content as determined by RIA was found to be less than 0.1% of total collagen (55-70 micrograms/g protein). In fibrotic liver tissue type VI collagen was elevated up to 10-fold (620 micrograms/g protein) when compared to normal liver. Sera of patients with fibrotic liver disease, however, revealed antigen levels usually below the narrow normal range of 22 +/- 7.8 ng/ml (mean +/- 2.5 SD). We conclude that, although type VI collagen represents a minor fraction of the interstitial collagens, its comparatively high serum levels point to a considerable turnover in the normal individual. Our data suggest that in fibrosis as exemplified in fibrotic liver disease, the metabolism of this collagen is down-regulated, while at the same time, it accumulates in the interstitial matrix.

We measured the serum concentration of the aminoterminal propeptide of collagen type III (PIIIP) in 22 patients with acute viral hepatitis (19 hepatitis B, 3 hepatitis non-A, non-B). Nine patients showed persistent biochemical remission, 13 patients developed chronic active hepatitis (CAH); 6 of those underwent therapy with methylprednisolone and azathioprine. Thirteen patients with chronic persistent viral hepatitis (CPH) and 38 healthy individuals were also investigated. In the control group, PIIIP values were 9.5 +/- 2.25 ng/ml (chi +/- SD; range 4-14 ng/ml). All patients with acute hepatitis showed elevated PIIIP values (range 20-125 ng/ml). In the 9 patients with biochemical resolution, PIIIP normalized after a maximum of 6.5 months (range 7.5-14 ng/ml). In CAH, PIIIP was persistently elevated on the day of the diagnostic biopsy (range 15.6-35.7 ng/ml). In comparison, the patients with chronic persistent hepatitis showed a range of 5.0-15.4 ng/ml. Differences between controls and CAH and CPH/CAH were statistically highly significant (P less than 0.001). Treatment of patients with CAH by immunosuppression resulted in normal PIIIP values in 3 and persistently elevated values in 3. One additional patient had normal PIIIP after treatment with an increased dose of methylprednisolone of 16 mg p.d. Serum concentrations of PIIIP offer a non-invasive index for the development of chronic active hepatitis from acute viral hepatitis. This blood test may also be useful for monitoring immunosuppressive treatment in CAH.