The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy.

BACKGROUND: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM: To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS: Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS: Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION: The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.

Update of genetics in colorectal carcinomas: genomic instability and somatic evolution.

INTRODUCTION: Currently, there are two contrasting viewpoints on what drives the process of carcinogenesis. The genomic (DNA or chromosomal) instability model contends that an increased mutation rate early in carcinogenesis is necessary for the multistage process, while the somatic evolution model postulates that normal mutation rate with selective advantage and clonal expansion is sufficient to cause cancer. METHODS: Evidence from colorectal carcinoma (CRC) for and against the two models are compared and contrasted. RESULTS: With the exception of hereditary non-polyposis colorectal carcinoma (HNPCC) where DNA instability attributable to mismatch repair deficiency is clearly demonstrated, the majority of CRC appear to progress through the selection of a series of mutations without the need of first acquiring a mutator phenotype. Aneuploidy or chromosomal instability is more likely to be a consequence of non-random selection of mutations in genes residing on the chromosome rather than the direct cause of cancer. Nevertheless, aneuploidy and/or DNA alterations can lead to secondary instability, hence, contributing to the phenotypes associated with carcinoma. CONCLUSIONS: Present knowledge, thus, points to multiple, mutually non-exclusive pathways for different cancer populations, further emphasising tumour heterogeneity.

The effect of dosing with omeprazole on the accuracy of the 13C-urea breath test in Helicobacter pylori-infected subjects.

BACKGROUND: The 13C-urea breath test (13C-UBT) is an accurate means of Helicobacter pylori diagnosis. However, proton pump inhibitors may suppress H. pylori and cause false negative results. AIM: To study the kinetics of H. pylori suppression by omeprazole during and after short-term use. METHODS: Volunteers underwent a baseline 13C-UBT (13C-urea 100 mg). H. pylori-positive subjects took omeprazole 20 mg daily for 14 days. Those who remained 13C-UBT positive (delta13CO2 >/= 5) continued omeprazole for a further 14 days. 13C-UBTs were performed weekly on omeprazole and then every second day after it was stopped. False negatives occurred when delta13CO2 fell to < 5. RESULTS: In 25 H. pylori-positive subjects (mean age 43.9 +/- 2.4 years; 21 females, 4 males) the mean baseline delta13CO2 was 28.1 +/- 3.4. False negative breath tests occurred in three subjects after 7 days of omeprazole and in a further four subjects after 14 days. A further six subjects developed negative tests between Days 14 and 28. Following cessation of omeprazole, the 13C-UBT became positive again in 12/13 subjects within 4 days and in all within 6 days, with a mean recovery to 99.9 +/- 18.6% of baseline delta13CO2. CONCLUSIONS: False negative 13C-UBTs are common during treatment with omeprazole and occur after as little as 7 days. Return to positive test results is rapid after cessation of omeprazole. These findings are relevant to the timing of testing in clinical practice.

Dynamic decision analysis in medicine: a data-driven approach.

Dynamic decision analysis concerns decision problems in which both time and uncertainty are explicitly considered. Two major challenges in dynamic decision analysis are on proper formulation of a model for the problem and effective elicitation of the numerous time-dependent conditional probabilities for the model. Based on a new, general dynamic decision modeling framework called DynaMoL (Dynamic decision Modeling Language), we propose a data-driven approach to addressing these issues. Our approach uses available problem data from large medical databases, guides the decision modeling at a proper level of abstraction and establishes a Bayesian learning method for automatic extraction of the probabilistic parameters. We demonstrate the theoretical implications and practical promises of this new approach to dynamic decision analysis in medicine through a comprehensive case study in the optimal follow-up of patients after curative colorectal cancer surgery.

Effect of age, Helicobacter pylori infection, and gastritis with atrophy on serum gastrin and gastric acid secretion in healthy men.

Gastric acid secretion has been considered to decline with increasing age but this view is being re-evaluated as the importance of Helicobacter pylori infection emerges. This study aimed to determine the effect of age, H pylori, and gastritis with atrophy on the serum gastrin concentration, gastric secretory volumes, and acid output in healthy, asymptomatic men. Young men (mean (SD) age 22.9 (0.6) years; n = 22) were compared with old men (72.9 (1.2) years; n = 28) in respect of basal serum gastrin and basal, sham fed, pentagastrin stimulated maximal and peak acid secretion. Antral, corpus, and fundal biopsy specimens were taken for histology and H pylori status (histology, culture, and rapid urease test). H pylori associated gastritis was present in three of 22 young (13.6%) and 16 of 28 old (57.1%) men. Gastritis with atrophy was present in 11 old subjects, 10 of whom were H pylori positive. These subjects had higher mean (SD) serum gastrin concentrations than old subjects without atrophy and young subjects (61.8 (9.2); 40.0 (2.9); 36.8 (2.3) pmol/l respectively; p < 0.001). H pylori infected subjects had higher gastrin values than uninfected subjects, overall (55.3 (5.9); 36.0 (1.8) pmol/l; p < 0.001) and in subjects without atrophy (45.3 (4.2); 36.0 (1.8) pmol/l; p < 0.03). In subjects without H pylori infection, gastrin values did not differ with age (old 37.1 (1.7); young 35.4 (2.1) pmol/l). The maximal gastric secretory volume was lower in old subjects with atrophy. Acid output (mmol/h) in subjects with atrophy was lower than in subjects with no atrophy (basal: 3.0(1.1); 5.1(0.7); p=NS; sham led: 5.4 (1.4); 9.3 (0.8); p<0.02; maximal: 18.9 (4.0); 31.4(1.8); p<0.002; peak: 25.1(5.3); 43.4(2.7); p<0.003). However, acid secretion in old subjects without atrophy was not different to that in young subjects, irrespective of H pylori status. These results did not differ when acid output was expressed as mmol/h/kg lean body mass or mmol/h/kg fat free body weight. Using multiple linear regression analysis, gastritis with atrophy was the only factor that had an independent negative effect on acid secretion. In healthy men without atrophy, gastric acid secretion is preserved with ageing and is independent of H pylori status. Atrophy, which is closely related to H pylori infection, is associated with a decline in acid secretion. Increased basal serum gastrin is related to both atrophy and H pylori infection but not to ageing per se.

The effect of Giardia lamblia trophozoites on trypsin, chymotrypsin and amylase in vitro.

Giardia lamblia localize and multiply in the small intestine and may cause acute or chronic diarrhoea with malabsorption of fat, protein and other nutrients. Abnormal pancreatic function has been documented in giardiasis and trophozoites directly inhibit pancreatic lipase activity in vitro. The aim of this study was to examine the effect of Giardia trophozoites on pancreatic trypsin, chymotrypsin and amylase activity in vitro. Axenically cultured Giardia trophozoites (Portland-1 stock) were incubated with a range of concentrations of trypsin, chymotrypsin and amylase and enzyme activity assayed over time. Tryptic activity was decreased after incubation with Giardia trophozoites. This reduction was time dependent and linear over the incubation period of 2 h. At a trypsin concentration of 18 BAEE units/ml, there was a 35.5 +/- 4% reduction in enzyme activity after 2 h compared to controls. The total amount of activity lost was proportional to the initial trypsin concentration up to 185 BAEE units/ml. At this initial concentration, the activity was reduced by 46.5 +/- 3 units/ml after 2 h. Above this concentration, little further loss of enzyme activity was seen. To investigate the nature and specificity of this effect, similar experiments were conducted using killed trophozoites and with a related protozoan, Trichomonas vaginalis. No loss of enzyme activity was evident. Media previously incubated for 2 h with trophozoites did not diminish tryptic activity. Trophozoites had no effect on chymotrypsin or amylase activities over the range of concentrations tested.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of Giardia lamblia trophozoites on lipolysis in vitro.

Infection with Giardia lamblia often causes only minor mucosal changes to the small intestine yet frank fat malabsorption may still occur. Some evidence suggests abnormal pancreatic exocrine function in subjects with giardiasis although the mechanism and significance of this is unclear. Studies were conducted in vitro to determine the effect of G. lamblia trophozoites or culture filtrates from the organism on lipolysis of triglyceride by porcine pancreatic lipase. Live trophozoites significantly inhibited lipolysis. The degree of inhibition increased with longer duration of lipase exposure to trophozoites. Total amounts of enzyme inhibited were proportional to enzyme concentration, while the percentage inhibition was greatest at lowest concentration. At a lipase concentration of 1.7 i.u./ml, enzyme activity was reduced by 89.7% compared to controls after incubation for 4 h with trophozoites. The effect was abolished using killed, intact trophozoites. Culture filtrates of G. lamblia did not inhibit lipolysis. Specificity of the effect was suggested by the failure of another flagellate protozoan, Trichomonas vaginalis, to inhibit lipase. In this assay system the inhibition of lipolysis was not dependent on the bile salt concentration present. The impact of this effect in vivo remains to be determined but it may contribute to fat malabsorption in giardiasis.

Acute cisplatin nephrotoxicity in the rat. Evidence for impaired entry of sodium into proximal tubule cells.

The earliest phase of cisplatin nephrotoxicity involves natriuresis due to impaired sodium reabsorption by the proximal tubule. To define the cell mechanism of this transport lesion, electron microprobe X-ray analysis was used to determine changes in the electrolyte composition of proximal tubule cells in kidneys taken from rats treated acutely with cisplatin (1 mg/100 g body weight). Compared to control animals injected with vehicle, cisplatin treated rats developed significant natriuresis, the fractional excretion of sodium rising over sevenfold. In kidneys removed 90 min following cisplatin, sodium concentration in proximal tubule cells was reduced by 4.2 mmol/kg wet weight, or 19%, compared to control values. When allowance was made for cell shrinkage in cisplatin-treated kidneys by deriving the cell content of sodium (mmol/kg dry weight), the reduction was even greater (28%). These data suggest that cisplatin reduces proximal tubule sodium reabsorption by inhibiting the entry of sodium into the cells across the apical membrane.

Micropuncture comparison of nephron function during acute and chronic ADH excess in the rat.

1. The aim of this study was to compare the effect of acute versus chronic ADH administration on the handling of sodium, potassium and water by the nephron. Simultaneous clearance and free-flow micropuncture experiments were performed on rats, infused with hypotonic Ringer solution, following either 1-3 h ('acute') or 10-12 days ('chronic') of continuous treatment with arginine vasopressin, 50 mU/h. A third group of animals receiving no exogenous ADH acted as controls. 2. Chronic ADH treatment led to more profound concentration of the urine and antidiuresis than acute treatment, due to enhanced extraction of water in the renal medulla. 3. Fractional sodium excretion during this protocol was increased after 'acute' but not 'chronic' ADH treatment. The acute natriuretic response was brought about principally along the length of the proximal tubule, probably due to volume expansion and increased arterial blood pressure. 4. Fractional excretion of potassium was also increased by 'acute' ADH, but this response was due to stimulation of potassium secretion in the late distal tubule. 5. It is concluded that acute and chronic exposure to ADH have different effects on nephron function, as a result of both direct and indirect actions.

The effect of chronic acid/base disturbances on renal amino acid clearances in the rat.

Since the few data available concerning the effect of acid/base disturbances on renal amino acid reabsorption were conflicting, and there were sound theoretical reasons for an effect, we have studied the clearance of endogenous amino acids in the rat in vivo under control conditions and after induction of either metabolic acidosis or alkalosis by administration of NH4Cl or NaHCO3, respectively. The effectiveness of treatment was assessed by examination of plasma and urinary levels of HCO3, Cl, Na and K. It was found that the renal clearance of amino acids, measured during acidosis or alkalosis, did not differ from those found under control conditions, the majority of values being less than 1% of the glomerular filtration rate. Thus, the amino acid reabsorptive mechanism appears unaffected by changes in the pH of the glomerular filtrate and/or by changes in tubular hydrogen ion secretion which would accompany such disturbances. These data are thus in agreement with findings during acidosis in man and in both acidosis and alkalosis in the dog. The findings are contrary to earlier reports from in vitro studies in the rat, and suggest the presence of severe functional impairment in the isolated perfused kidneys used in these earlier studies where very large changes in amino acid clearance were obtained.