bluuebunny/crossref_metadata_2025 huggingface dataset:
The relation between gastric vitamin C concentrations, mucosal histology, and CagA seropositivity in the human stomach
Authors: Zhang Z W , Patchett S E , Perrett D , Katelaris P H , Domizio P , Farthing M J G
Published: June 2010

Background—Vitamin C may be protective against gastric cancer though infection withHelicobacter pylori is associated with a reduction in intragastric concentrations of vitamin C.

Aims—To examine the effects ofH pylori infection, gastric juice pH, the severity and extent of gastric inflammation, and CagA antibody status of the individual on gastric juice and mucosal vitamin C concentrations.

Patients—One hundred and fifteen patients undergoing routine gastroscopy for investigation of dyspepsia.

Methods—High performance liquid chromatography was used to determine vitamin C concentrations. CagA antibody was detected by western blot analysis.

Results—Gastric juice ascorbic acid concentration was significantly lower in patients infected withH pylori compared with those uninfected (19.3 μmol/l (interquartile range (IQR) 10.7–44.5) versus 66.9 μmol/l (IQR 24.4–94.2), p=0.003). The reduction in gastric juice ascorbic acid concentration was inversely related to the severity of gastritis (p=0.01). CagA positive patients had significantly lower gastric juice ascorbic acid concentrations than CagA negative ones (14.8 μmol/l (IQR 7.9–52.2) versus 39 μmol/l (IQR 19.9–142.2), p=0.05). Decreased gastric juice dehydroascorbic acid concentrations were observed in patients with gastric atrophy and intestinal metaplasia. Mucosal ascorbic acid concentrations were also significantly lower in infected patients than uninfected patients (p=0.04).

Conclusions—The reduction in gastric vitamin C concentrations is related to gastric juice pH, the severity and extent of gastritis, the presence of H pylori, and the CagA antibody status of the individual. These findings may have implications in H pyloriassociated carcinogenesis.
On the protective mechanisms of nitric oxide in acute pancreatitis
Authors: Werner J , Castillo C Fernández-del , Rivera J A , Kollias N , Lewandrowski K B , Rattner D W , Warshaw A L
Published: June 2010

Background—Ectopic protease activation, microcirculatory changes, and leucocyte activation are the main events in the pathogenesis of acute pancreatitis. Nitric oxide (NO) is known to be a key mediator in the normal and inflamed pancreas.

Aims—To investigate the targets on which NO exerts its effect in caerulein induced pancreatitis.

Methods—Acute pancreatitis was induced in rats which additionally received either the NO synthase substrate, l-arginine; the NO donor, sodium nitroprusside; or the NO synthase inhibitor, N-nitro-l-arginine methyl ester (l-NAME). At six hours, pancreatic injury (oedema, leucocyte content, ectopic trypsinogen activation) was analysed and pancreatic oxygenation and perfusion were determined. A direct influence of NO on amylase secretion and trypsinogen activation was evaluated separately in vitro.

Results—Both NO donors reduced the grade of inflammation. l-NAME increased the severity of inflammation, while decreasing pancreatic tissue oxygenation. Although neither amylase secretion nor intracellular trypsinogen activation in caerulein stimulated pancreatic acini was influenced by either NO donors or inhibitors, both NO donors decreased intrapancreatic trypsinogen activation peptide (TAP) and pancreatic oedema in vivo, andl-NAME increased TAP.

Conclusions—NO protects against injury caused by pancreatitis in the intact animal but has no discernible effect on isolated acini. It is likely that in pancreatitis NO acts indirectly via microcirculatory changes, including inhibition of leucocyte activation and preservation of capillary perfusion.
Increased state of activation of CD4 positive T cells and elevated interferon γ production in pouchitis
Authors: Stallmach A , Schäfer F , Hoffmann S , Weber S , Müller-Molaian I , Schneider T , Köhne G , Ecker K-W , Feifel G , Zeitz M
Published: June 2010

Background—Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP).

Aims—To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied.

Patients—Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP).

Methods—Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon γ (IFN-γ) production was studied using the ELISPOT technique.

Results—In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNγ producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7–2.7) versus 0.6 (0.1–1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells (r=0.57) was shown.

Conclusion—The observed increase in activated mucosal CD4+ T cells and IFN-γ production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.
Hyperbaric oxygen: a novel modality to ameliorate experimental colitis
Authors: Rachmilewitz D , Karmeli F , Okon E , Rubenstein I , Better O S
Published: June 2010

Background—Hyperbaric oxygen (HBO) has been suggested to be beneficial in inflammatory bowel disease but the mechanisms responsible for its therapeutic effects have not been elucidated.

Aim—To assess the effect of HBO treatment on colonic damage in two models of experimental colitis, and to examine whether this effect is mediated by modulation of NO synthesis.

Methods—Colitis was induced by either flushing the colon with 2 ml 5% acetic acid or intracolonic administration of 30 mg trinitrobenzenesulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol. Rats were exposed to HBO (100% oxygen at 2.4 atmosphere absolute) for one hour twice on the day of colitis induction and once daily thereafter. Control rats were treated only with acetic acid or TNB. Rats were killed 24 hours after acetic acid administration or one and seven days after TNB treatment. The colon was isolated, washed, and weighed, the lesion area was measured, and mucosal scrapings were processed for determination of myeloperoxidase (MPO) and NO synthase (NOS) activities, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) generation.

Results—In control rats exposed for seven days to HBO, colonic NOS activity was significantly decreased by 61%, compared with its activity in untreated rats (2.93 (0.17) nmol/g/min). HBO significantly reduced by 51 and 62% the extent of injury induced by acetic acid and TNB respectively. The protection provided by HBO was accompanied by a significant decrease in colonic weight, PGE2 generation, MPO, and NOS activities. In acetic acid colitis, LTB4 generation was also significantly decreased.

Conclusions—(1) HBO effectively decreases colitis induced by acetic acid and TNB. (2) The decreased NOS activity induced by HBO suggests that reduction in NO generation may be among the mechanisms responsible for the anti-inflammatory effect of HBO. (3) HBO may be considered in the treatment of patients with refractory inflammatory bowel disease.
Effect of chronic and acute cigarette smoking on the pharyngo-upper oesophageal sphincter contractile reflex and reflexive pharyngeal swallow
Authors: Dua K , Bardan E , Ren J , Sui Z , Shaker R
Published: June 2010

Background—Cigarette smoking is known to affect adversely the defence mechanisms against gastro-oesophageal reflux. The effect of smoking on the supraoesophageal reflexes that prevent aspiration of gastric contents has not been previously studied.

Aims—To elucidate the effect of cigarette smoking on two of the supraoesophageal reflexes: the pharyngo-upper oesophageal sphincter (UOS) contractile reflex; and the reflexive pharyngeal swallow.

Methods—Ten chronic smokers and 10 non-smokers were studied, before and 10 minutes after real or simulated smoking, respectively. UOS pressure and threshold volume for the reflexes were determined using a UOS sleeve assembly. Two modes of fluid delivery into the pharynx were tested: rapid injection and slow injection.

Results—For both rapid and slow injections, the threshold volume for triggering the pharyngo-UOS contractile reflex was significantly higher in smokers than in non-smokers (rapid: smokers 0.42 (SE 0.07) ml, non-smokers 0.16 (0.04) ml; slow: smokers 0.86 (0.06) ml, non-smokers 0.38 (0.1) ml; p<0.05). During rapid injection, the threshold volume for reflexive pharyngeal swallow was higher in smokers (smokers 0.94 (0.09) ml, non-smokers 0.46 (0.05) ml; p<0.05). Acute smoking further increased the threshold volume for the pharyngo-UOS contractile reflex and reflexive pharyngeal swallow during rapid injection.

Conclusions—Smoking adversely affects stimulation of the pharyngo-UOS contractile reflex and pharyngeal reflexive swallow. These findings may have implications in the development of reflux related respiratory complications among smokers.
Urokinase and the intestinal mucosa: evidence for a role in epithelial cell turnover
Authors: Gibson P R , Birchall I , Rosella O , Albert V , Finch C F , Barkla D H , Young G P
Published: June 2010

Background—The functions of urokinase in intestinal epithelia are unknown.

Aims—To determine the relation of urokinase expressed by intestinal epithelial cells to their position in the crypt-villus/surface axis and of mucosal urokinase activity to epithelial proliferative kinetics in the distal colon.

Methods—Urokinase expression was examined immunohistochemically in human intestinal mucosa. Urokinase activity was measured colorimetrically in epithelial cells isolated sequentially from the crypt-villus axis of the rat small intestine. In separate experiments, urokinase activity and epithelial kinetics (measured stathmokinetically) were measured in homogenates of distal colonic mucosa of 14 groups of eight rats fed diets known to alter epithelial turnover.

Results—From the crypt base, an ascending gradient of expression and activity of urokinase was associated with the epithelial cells. Median mucosal urokinase activities in each of the dietary groups of rats correlated positively with autologous median number of metaphase arrests per crypt (r=0.68; p<0.005) and per 100 crypt cells (r=0.75; p<0.001), but not with crypt column height.

Conclusions—Localisation of an enzyme capable of leading to digestion of cell substratum in the region where cells are loosely attached to their basement membrane, and the association of its activity with indexes of cell turnover, suggest a role for urokinase in facilitating epithelial cell loss in the intestine.
A prospective evaluation of magnetic resonance cholangiopancreatography in patients with suspected bile duct obstruction
Authors: Adamek H E , Albert J , Weitz M , Breer H , Schilling D , Riemann J F
Published: June 2010

Background—The value of magnetic resonance cholangiopancreatography (MRCP) is under debate.

Aims—To assess the diagnostic accuracy of MRCP and endoscopic retrograde cholangiopancreatography (ERCP) and to determine whether MRCP may help to prevent unnecessary interventional procedures.

Methods—Eighty six patients with suspected common bile duct obstruction who presented between January and December 1996 were enrolled. Twenty six were excluded due to anatomical reasons or because MRCP or ERCP could not be performed successfully. Results of MRCP were interpreted by two radiologists and a gastroenterologist unaware of clinical diagnosis. Final diagnosis was determined by ERCP and histopathological findings or a follow up of at least 12 months.

Results—MRCP images of diagnostic quality were obtained in all 60 patients. Thirteen patients had a clear bile duct. Sensitivity and specificity for the detection of any abnormality (n=47) were 89% and 92%, and for the detection of malignancy (n=27) 81% and 100%, respectively. These results were equivalent to the respective figures of ERCP (91% and 92% for any abnormality, and 93% and 94% for malignant diseases).

Conclusions—MRCP is as sensitive as ERCP in the evaluation of bilary tract diseases. As the specificity of this non-invasive technique is close to 100%, MRCP may prevent inappropriate invasive explorations of the common bile duct and pancreatic duct.
Fatigue in primary biliary cirrhosis
Authors: Cauch-Dudek K , Abbey S , Stewart D E , Heathcote E J
Published: June 2010

Background—Fatigue is a frequent and debilitating symptom in patients with primary biliary cirrhosis (PBC).

Aims—To study fatigue in relation to sleep, depression, and liver disease severity.

Methods—Patients with PBC completed validated self report questionnaires measuring fatigue, sleep quality, depression, and functional capacity. Verbally reported fatigue and observer rated measure of depression and ursodeoxycholic acid (UDCA) use were recorded. Liver biochemistry and tests to rule out metabolic causes of fatigue were performed.

Results—Mean age of the 88 patients enrolled was 57 years; 86% were female and mean duration of disease was 6.6 years. Median bilirubin was 13 μmol/l (mean 18.6). Verbally reported fatigue (for more than six months) was present in 60 patients (68%). The self rated Fatigue Severity Score (FSS) correlated well with verbally reported fatigue (p=0.0001). The FSS did not correlate with age, duration of disease, serum bilirubin, Mayo Risk Score, or UDCA use, but correlation was seen with sleep quality. Fatigued patients had more sleep problems and higher depression scores than non-fatigued patients. Self rated depression was present in 28% (17/60) of fatigued compared with 4% (1/28) of non-fatigued patients.

Conclusions—Long term fatigue affected 68% of the patients with PBC but it was not related to the severity of their liver disease. Poor sleep quality and depression were commonly associated with fatigue.
Laser lithotripsy of difficult bile duct stones: results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system
Authors: Hochberger J , Bayer J , May A , Mühldorfer S , Maiss J , Hahn E G , Ell C
Published: June 2010

Introduction—Laser lithotripsy of bile duct stones has become a widely accepted endoscopic treatment modality for giant, impacted, or very hard stones. The procedure is usually carried out under direct endoscopic control in view of the potential risk of bile duct injuries in “blind” laser application.

Aims—To investigate the use of a rhodamine 6G laser lithotriptor with an integrated optical stone tissue detection system (oSTDS).

Methods—From 1 September 1991 to 7 March 1997, 60 patients with giant or impacted common bile duct stones refractory to endoscopic papillotomy stone extraction, and mechanical lithotripsy were treated via the endoscopic retrograde route using a rhodamine 6G dye laser (595 nm, 2.5 μs, 80–150 mJ pp, Lithognost Telemit/Baasel Corp., Germany) with integrated oSTDS. In case of tissue contact oSTDS cuts off the laser pulse after 190 ns (transmission of 5–8% of the total pulse energy). 47 patients (78.3%) were subjected tox ray targeting (oSTDS) alone, five (8.3%) to choledochoscope targeting alone, and eight (13.3%) to both techniques.

Results—At the end of treatment 52 (87%) patients were completely stone-free. The only major complications included transient haemobilia, cholangitis, and pancreatitis in five patients. All five were successfully treated by conservative methods.

Conclusions—Laser lithotripsy using the described rhodamine 6G dye laser with oSTDS seems to be safe and effective and allows “blind” fragmentation of difficult common bile duct stones under radiological control only.
The significance of haemochromatosis gene mutations in the general population: implications for screening
Authors: Burt M J , George P M , Upton J D , Collett J A , Frampton C M A , Chapman T M , Walmsley T A , Chapman B A
Published: June 2010

Background—Haemochromatosis is associated with mutations in the HFE gene but the significance of these mutations in the general population is unknown.

Aims—To determine the frequency ofHFE gene mutations in the general population, their effect on serum iron indexes, and their role in screening for haemochromatosis.

Methods—Deoxyribonucleic acid (DNA) from 1064 randomly selected subjects was analysed for the C282Y and H63D mutations in the HFE gene. Serum iron, transferrin saturation, and ferritin were measured and individuals with increased iron indexes were investigated to confirm or exclude a clinical diagnosis of haemochromatosis.

Results—Mutations were identified in 409 individuals (38.4%) with heterozygote (carrier) frequencies of 13.2% and 24.3% for the C282Y and H63D mutations respectively. Heterozygosity for either mutation significantly increased serum iron and transferrin saturation but despite a similar trend for ferritin, this was only significant for C282Y homozygotes. Five individuals (0.47%) were homozygous for the C282Y mutation, three of whom had haemochromatosis confirmed by liver biopsy (0.28%). The other two C282Y homozygotes would not have been detected by phenotypic screening alone.

Conclusions—HFE mutations are present in 38.4% of the population, affect serum iron indexes, and are important determinants of iron status. The population frequency of genetically defined haemochromatosis (C282Y homozygosity) is approximately one in 200 and is higher than the prevalence of clinically apparent haemochromatosis.
Dietary polyamines are essential luminal growth factors for small intestinal and colonic mucosal growth and development
Authors: Löser Chr , Eisel A , Harms D , Fölsch U R
Published: June 2010

Background

Polyamines are essential for cell growth. Dietary and probably gut bacterial derived polyamines contribute significantly to the polyamine body pool.

Aims

To evaluate the influence of dietary, luminal polyamines on growth and development of different gastrointestinal organs in normally growing rats.

Methods

Male suckling Wistar rats were randomly allocated to four treatment groups: polyamine deficient diet (PDD); PDD plus antibiotics (neomycin 2 g/kg and metronidazole 34 mg/kg); PDD plus polyamine supplementation at normal concentrations; or normal standard laboratory chow. After a six month feeding period 7–10 animals/group were sacrificed.

Results

No differences in body weight gain, food consumption, or general behaviour could be observed between the four groups of animals. Feeding of PDD alone or PDD plus antibiotics resulted in a highly significant decrease in organ weight, protein content, and DNA content in small intestinal and colonic mucosa whereas no alterations were found in the liver.

Conclusions

Long term feeding of polyamine deficient diets resulted in a significant hypoplasia of small intestinal and colonic mucosa. Dietary, luminal polyamines are important local factors for growth and the development of small intestinal and colonic mucosa.
Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer
Authors: Bennett M W , O’Connell J , O’Sullivan G C , Roche D , Brady C , Kelly J , Collins J K , Shanahan F
Published: June 2010

Background

Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a “Fas counterattack” against antitumour immune effector cells may contribute to tumour immune escape.

Aim

To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer.

Specimens

Thirty paraffin wax embedded human gastric adenocarcinomas.

Methods

FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL).

Results

Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour.

Conclusions

Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.
Increased gastric Pco
2 during exercise is indicative of gastric ischaemia: a tonometric study
Authors: Kolkman J J , Groeneveld A B J , van der Berg F G , Rauwerda J A , Meuwissen S G M
Published: June 2010

Background

Diagnosis of gastric ischaemia is difficult and angiography is an invasive procedure. Angiographic findings may not correlate with clinical importance.

Aims

To investigate whether tonometric measurement of intragastric Pco2during exercise can be used to detect clinically important gastric ischaemia.

Methods

Fourteen patients with unexplained abdominal pain or weight loss were studied. Splanchnic angiography served as the gold standard. Three patients were studied again after a revascularisation procedure. Gastric Pco2 was measured from a nasogastric tonometer, with 10 minute dwell times, and after acid suppression. Gastric and capillary Pco2 were measured before, during, and after submaximal exercise of 10 minutes duration.

Results

Seven patients had normal angiograms; seven had more than 50% stenosis in the coeliac (n=7) or superior mesenteric artery (n=4). Normal subjects showed no changes in tonometry. In patients with stenoses, the median intragastric Pco2(Pico2) at rest was 5.2 kPa (range 4.8–11.2) and rose to 6.4 kPa (range 5.7–15.7) at peak exercise; the median intragastric blood Pco2 gradient increased from 0.0 kPa (range −0.8 to 5.9) to 1.7 kPa (range 0.9 to 10.3; p<0.01). Only two subjects had abnormal tonometry at rest; all had supernormal values at peak exercise. The Pco2 gradient correlated with clinical and gastroscopic severity; in patients reexamined after revascularisation (n=3), exercise tonometry returned to normal.

Conclusion

Gastric tonometry during exercise is a promising non-invasive tool for diagnosing and grading gastrointestinal ischaemia and evaluating the results of revascularisation surgery for symptomatic gastric ischaemia.
Cisplatin impairs fluid and electrolyte absorption in rat small intestine: a role for 5-hydroxytryptamine
Authors: Bearcroft C P , Domizio P , Mourad F H , André E A , Farthing M J G
Published: June 2010

Background

The antineoplastic drug cisplatin has been widely used for the treatment of cancer in humans but its use has been limited by vomiting and diarrhoea. Cisplatin releases 5-hydroxytryptamine into the gut which is thought to be the major mediator of cisplatin induced vomiting.

Aim

To determine whether cisplatin affects fluid and electrolyte transport in rat jejunum and whether this change can be modulated by the 5-hydroxytryptamine3 receptor antagonist, ondansetron.

Methods

Jejunal perfusion in rats in vivo was performed one hour after intraperitoneal cisplatin (5 and 10 mg/kg) administration. The effect of pretreatment with subcutaneous ondansetron 300 μg/kg was investigated.

Results

Median net fluid absorption after cisplatin 10 mg/kg (67 μl/min/g dry intestinal weight (interquartile range 46 to 100); n = 15) was reduced compared with controls (120 (107 to 151) μl/min/g; n = 13; p<0.001). Ondansetron reversed the impairment of jejunal fluid absorption produced by cisplatin to normal (161 (130 to 176) μl/min/g; n = 11; p<0.001). Electrolyte movement paralleled fluid movement. Jejunal histological examination of sections from cisplatin treated animals showed villus damage, which was not prevented by pretreatment with ondansetron.

Conclusion

These findings suggest that diarrhoea during cisplatin therapy may be due to altered fluid transport in the small bowel. The reversal of fluid transport to normal in the presence of a 5-hydroxytryptamine3 receptor antagonist suggests that 5-hydroxytryptamine is a local mediator in the small intestine.
Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds
Authors: Mori N , Horie Y , Gerritsen M E , Anderson D C , Granger D N
Published: June 2010

Background

Inflammatory bowel diseases (IBD) are characterised by an intense infiltration of leucocytes that is mediated by adhesion molecules expressed on the surface of activated endothelial cells.

Aims

To determine whether drugs used in the treatment of IBD, specifically dexamethasone (DEX), 5-aminosalicylic acid (5-ASA), methotrexate (MTX), and 6-mercaptopurine (6-MP), alter the expression of endothelial cell adhesion molecules (ECAMs).

Methods

The expression of P-selectin, E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular CAM 1 (VCAM-1) in different vascular beds of C57Bl/6J mice was measured using the dual radiolabelled monoclonal antibody technique.

Results

Lipopolysaccharide (LPS) elicited a profound increase in the expression of all ECAMs in the mesentery, small intestine, caecum, and distal colon. The LPS induced increase in CAM expression was not significantly affected by prior treatment with either MTX or 6-MP. However, pretreatment with either DEX or 5-ASA significantly attenuated LPS induced increases in expression of P- and E-selectin, and VCAM-1 in the majority of tissues evaluated. DEX also blunted the LPS induced increase in ICAM-1 expression in the caecum and distal colon. DEX, but not 5-ASA, largely abolished the rise in plasma tumour necrosis factor α elicited by LPS.

Conclusions

These findings suggest that DEX and 5-ASA may exert their beneficial therapeutic action in IBD, at least in part, by inhibiting the expression of ECAMs which mediate leucocyte adhesion and transmigration in the microvasculature.
Mutations in exons 2 and 3 of the cationic trypsinogen gene in Japanese families with hereditary pancreatitis
Authors: Nishimori I , Kamakura M , Fujikawa-Adachi K , Morita M , Onishi S , Yokoyama K , Makino I , Ishida H , Yamamoto M , Watanabe S , Ogawa M
Published: June 2010

Background/Aims

Single-point mutations in the cationic trypsinogen gene have been reported in hereditary pancreatitis kindreds in the white population. The aim of the present study was to investigate whether similar gene mutations are present in Japanese hereditary pancreatitis kindreds.

Methods

All five exons of the cationic trypsinogen gene were amplified by polymerase chain reaction and sequenced in six Japanese families with hereditary pancreatitis.

Results

Two types of single-point mutation in the cationic trypsinogen gene, which were identical with those reported in white families with hereditary pancreatitis, were observed in separate Japanese families with hereditary pancreatitis: 21Asn (AAC) to Ile (ATC) (N21I) in exon 2 and 117Arg (CGC) to His (CAC) (R117H) in exon 3. Pancreatitis occurred at more advanced ages in patients with the N21I mutation than in those with the R117H mutation. Besides normal polymorphisms in exons 4 and 5, no mutation was found in patients in the remaining four families with hereditary pancreatitis, 21 patients with sporadic chronic pancreatitis, or five normal subjects.

Conclusions

These results show heterogeneity, but no racial specificity, in the cationic trypsinogen gene mutations in hereditary pancreatitis kindreds. A distinctive clinical feature for each of the mutation types is suggested: adult onset for the N21I mutation and childhood onset for the R117H mutation.
Single portal pressure measurement predicts survival in cirrhotic patients with recent bleeding
Authors: Patch D , Armonis A , Sabin C , Christopoulou K , Greenslade L , McCormick A , Dick R , Burroughs A K
Published: June 2010

Background

Height of portal pressure correlates with severity of alcoholic cirrhosis. Portal pressure indices are not however used routinely as predictors of survival.

Aims

To examine the clinical value of a single portal pressure measurement in predicting outcome in cirrhotic patients who have bled.

Methods

A series of 105 cirrhotic patients who consecutively underwent hepatic venous pressure measurement were investigated. The main cause of cirrhosis was alcoholic (64.8%) and prior to admission all patients had bled from varices.

Results

During the follow up period (median 566 days, range 10–2555), 33 patients died, and 54 developed variceal haemorrhage. Applying Cox regression analysis, hepatic venous pressure gradient, bilirubin, prothrombin time, ascites, and previous long term endoscopic treatment were the only statistically independent predictors of survival, irrespective of cirrhotic aetiology. The predictive value of the pressure gradient was much higher if the measurement was taken within the first or the second week from the bleeding and there was no association after 15 days. A hepatic venous pressure gradient of at least 16 mm Hg appeared to identify patients with a greatly increased risk of dying.

Conclusions

Indirectly measured portal pressure is an independent predictor of survival in patients with both alcoholic and non-alcoholic cirrhosis. In patients with a previous variceal bleeding episode this predictive value seems to be better if the measurement is taken within the first two weeks from the bleeding episode. A greater use of this technique is recommended for the prognostic assessment and management of patients with chronic liver disease.
Ciprofloxacin decreases the rate of ethanol elimination in humans
Authors: Tillonen J , Homann N , Rautio M , Jousimies-Somer H , Salaspuro M
Published: June 2010

BACKGROUND

Extrahepatic ethanol metabolism is postulated to take place via microbial oxidation in the colon, mediated by aerobic and facultative anaerobic bacteria.

AIMS

To evaluate the role of microbial ethanol oxidation in the total elimination rate of ethanol in humans by reducing gut flora with ciprofloxacin.

METHODS

Ethanol was administered intravenously at the beginning and end of a one week period to eight male volunteers. Between ethanol doses volunteers received 750 mg ciprofloxacin twice daily.

RESULTS

A highly significant (p=0.001) reduction in the ethanol elimination rate (EER) was detected after ciprofloxacin medication. Mean (SEM) EER was 107.0 (5.3) and 96.9 (4.8) mg/kg/h before and after ciprofloxacin, respectively. Faecal Enterobacteriaceae and Enterococcus sp. were totally absent after medication, and faecal acetaldehyde production capacity was significantly (p<0.05) decreased from 0.91 (0.15) to 0.39 (0.08) nmol/min/mg protein. Mean faecal alcohol dehydrogenase (ADH) activity was significantly (p<0.05) decreased after medication, but ciprofloxacin did not inhibit human hepatic ADH activity in vitro.

CONCLUSIONS

Ciprofloxacin treatment decreased the ethanol elimination rate by 9.4%, with a concomitant decrease in intestinal aerobic and facultative anaerobic bacteria, faecal ADH activity, and acetaldehyde production. As ciprofloxacin has no effect on liver blood flow, hepatic ADH activity, or cytochrome CYP2E1 activity, these effects are probably caused by the reduction in intestinal flora.
Incidence of rectosigmoid adenomatous polyps in subjects without prior colorectal adenoma or cancer: a prospective cohort study
Authors: Paillot B , Czernichow P , Michel P , Merle V , Queuniet A-M , Duval C , Daubert H
Published: June 2010

BACKGROUND

Subjects without known colorectal adenomas or cancer constitute a large majority of the population where 85% of all cases of colorectal cancer are thought to occur. Consequently these people should be considered for screening to decrease mortality from colorectal cancer in the general population.

AIMS

To estimate the incidence rate of rectosigmoid adenomas in these subjects.

METHODS

Subjects without adenomas or cancer at a previous examination which had visualised the rectosigmoid underwent a fibre endoscopy every three years. Endoscopic data and population characteristics were collected prospectively.

RESULTS

A total of 450 subjects fulfilled the selection criteria; 287 (64%) underwent at least two examinations, and 163 had three or more. At the second examination, with a mean delay of 39 months, the incidence rate of rectosigmoïd adenomas was 1.50% per patient year. The rate was 1.75% per patient year (95% CI 0.80–3.33) at the third endoscopy with an additional mean delay of 38 months. The cumulative incidence rate at six years was 7.3% (95% CI 4.3–10.3), representing a mean of 1.2% per patient year. This rate increased with age and was higher for men than for women after age adjustment (p< 0.03).

CONCLUSIONS

The incidence rates are very low compared with those of patients with prior adenomas. These results should be considered in establishing rectosigmoid adenoma screening strategies.
Vagotomy inhibits the jejunal fluid secretion activated by luminal ileal Escherichia coli STa in the rat in vivo
Authors: Rolfe V E , Levin R J
Published: June 2010

BACKGROUND

Escherichia coli heat stable enterotoxin (STa) is a major cause of secretory diarrhoea in humans.

AIMS

To assess the effects of instilling STa into the ileum on remote fluid secretion in the jejunum and colon in rats in vivo by a gravimetric technique.

METHODS AND RESULTS

Ileal STa (55 ng/ml) stimulated fluid secretion in both ileal and jejunal loops but not in the colon. The fluid secretion induced by ileal STa was inhibited by l-NAME (Nω-nitro-l-arginine methyl ester, 40 mg/kg intraperitoneally) but not by d-NAME (Nω-nitro-d-arginine methyl ester). Ileal carbachol (183 mg/ml) instilled into the lumen stimulated ileal secretion but not jejunal secretion, and was unaffected by l-NAME. Capsaicin (10 μM), instilled luminally with STa in the ileum, blocked both the ileal and jejunal fluid secretion. Acute bilateral vagotomy prevented luminal ileal STa from inducing jejunal fluid secretion but not from activating ileal fluid secretion.

CONCLUSION

IlealE coli STa stimulates remote secretion in the rat jejunum but not in the colon, probably by a nitrinergic, vagal reflex mediated by C fibres. This neural pathway will amplify the action of the toxin in its generation of secretory diarrhoea.
Characterisation of penicillin G uptake in human small intestinal brush border membrane vesicles
Authors: Poschet J F , Hammond S M , Fairclough P D
Published: June 2010

BACKGROUND

Many β lactams are well absorbed by the small intestine, although the reasons for this are poorly understood.

AIMS

To characterise the uptake of penicillin G into human small intestinal brush border membrane vesicles (BBMV) and to compare the uptake characteristics to those of rabbit BBMV.

METHODS AND RESULTS

Uptake of penicillin G was studied in human BBMV. Penicillin G was actively transported into the lumen of BBMV via an H+ dependent, Na+ independent uptake system. The carrier mediated process was saturable and adhered to Michaelis-Menten kinetics (Vmax 52 nmol penicillin G per mg protein per 30 seconds,Km 13.9 mM). These results are similar to those previously reported in rabbit BBMV.

CONCLUSIONS

It is suggested that penicillin G can be used as a model molecule for peptide and β lactam transport studies as it is cheap and readily available in isotopically labelled form. Furthermore, rabbit BBMV may be used as an acceptable substitute for human BBMV for the study of penicillin transport.
Acquired interferon γ responsiveness during Caco-2 cell differentiation: effects on iNOS gene expression
Authors: Chavez A M , Morin M J , Unno N , Fink M P , Hodin R A
Published: June 2010

BACKGROUND

Impairment of intestinal barrier function occurs under a variety of inflammatory conditions and is mediated at least in part by interferon γ (IFN-γ) induced nitric oxide (NO) production. Previous in vivo studies have shown that systemic lipopolysaccharide treatment caused an induction of the rat inducible nitric oxide synthase (iNOS) mRNA primarily in villus cells, rather than in undifferentiated crypt cells.

AIMS

To examine iNOS induction by IFN-γ in vitro as a function of enterocyte differentiation.

METHODS

Preconfluent and postconfluent Caco-2 cells were treated with IFN-γ in the presence or absence of various inhibitors. Northern analyses were performed to assess the magnitude of iNOS mRNA induction. IFN-γ receptor mRNA and protein levels were determined.

RESULTS

iNOS mRNA induction by IFN-γ occurred at two hours and was not blocked by cycloheximide, indicating that it is an immediate early response. iNOS induction and nitrite/nitrate increases were inhibited by dexamethasone and pyrrolidine dithiocarbamate, supporting an important role for the NF-κB transcription factor in this process. The stimulated iNOS induction was seen almost exclusively under conditions of cellular differentiation—that is, in postconfluent Caco-2 cells. This increased IFN-γ responsiveness seen in postconfluent Caco-2 cells correlated with an increased expression of IFN-γ receptor, whereas T84 and HT-29 cells did not show any significant alterations in either iNOS induction or IFN-γ receptor levels as a function of postconfluent growth.

CONCLUSIONS

With regard to iNOS mRNA induction, IFN-γ responsiveness is acquired during Caco-2 cell differentiation, perhaps related to an increase in the numbers of IFN-γ receptors.
The natural history of histologically proved drug induced liver disease
Authors: Aithal P G , Day C P
Published: June 2010

BACKGROUND

The long term outcome of drug related liver disease is unknown.

AIMS

To study the natural history of histologically proved drug induced hepatotoxicity.

METHODS

110 patients with liver biopsies coded either as drug induced liver disease or hepatitis/cholestasis of unknown aetiology were identified from hospital records 1978–1996. Review of case notes and histology identified 44 patients with definite drug induced hepatotoxicity. Forty surviving patients were invited to attend a follow up clinic. History, examination, full liver screen, and isotope and ultrasound liver scans were repeated in all patients. Repeat liver biopsies were offered to patients with abnormal liver tests.

RESULTS

Presentation at index biopsy was jaundice in 24 patients, abnormal liver tests in 17, and hepatic failure in three. Antibiotics (n=13) and non-steroidal anti-inflammatory drugs (n=11) were the most common drugs implicated. Initial histology showed acute hepatitis in six, chronic hepatitis in 20, and cholestasis in 18. At 1–19 years (median 5 years) follow up, 13/33 (39%) patients had persistent significant abnormalities in their liver blood tests and/or scans. Three of the five repeat liver biopsies performed showed significant abnormalities. Factors predicting persistence or development of chronic liver disease were fibrosis and continued exposure to the drug.

CONCLUSIONS

Drugs should be considered in the differential diagnosis of abnormal liver function and/or histology, as failure to withdraw the offending drug is associated with a high risk of persistent liver damage.
Molecular screening of patients with long standing extensive ulcerative colitis: detection of p53 and Ki-ras mutations by single strand conformation polymorphism analysis and differential hybridisation in colonic lavage fluid
Authors: Lang S M , Stratakis D F , Heinzlmann M , Heldwein W , Wiebecke B , Loeschke K
Published: June 2010

BACKGROUND

In patients with long standing ulcerative colitis at risk of developing malignancy, mutations of the p53 and Ki-ras gene were investigated in lavage solution obtained at surveillance colonoscopy.

METHODS

DNA was isolated from 31 consecutive patients with total or subtotal ulcerative colitis and a disease duration of between seven and 26 years. Twenty seven control patients showed no macroscopic or microscopic inflammation on colonoscopy. Exons 5–8 of the p53 gene and exon 1 of the Ki-ras gene were amplified by polymerase chain reaction. Mutations of the p53 gene were detected by single strand conformation polymorphism analysis. Point mutations of the Ki-ras gene were hybridised on dot blots with oligonucleotides marked with digoxigenin.

RESULTS

In all cases of ulcerative colitis and in all of the 27 control patients, wild type p53 and wild type Ki-ras could be detected. In four patients with ulcerative colitis, a mutation in exon 5 to 7 of the p53 gene was found, and two patients had a mutation of the Ki-ras gene (Gly to Asp-12, Gly to Val-12). None of these patients had dysplasia in serial biopsy specimens, and all but one had had the disease for more than 10 years. One control patient had a mutation.

CONCLUSIONS

Mutations were more frequent in patients with long standing ulcerative colitis (19%) than in control patients (3%, p = 0.07). The technique may be useful for screening for early malignancy in ulcerative colitis.
Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study
Authors: Bellentani S , Pozzato G , Saccoccio G , Crovatto M , Crocè L S , Mazzoran L , Masutti F , Cristianini G , Tiribelli C
Published: June 2010

BACKGROUND

The severity, clinical course, and risk of hepatitis C virus (HCV) related chronic liver disease are still rather poorly defined.

AIMS

To investigate the prevalence, risk factors, and severity of HCV related liver disease in the general population, and investigate whether infection with a specific genotype is associated with an increased risk of cirrhosis or hepatocellular carcinoma.

METHODS

HCV RNA determination by polymerase chain reaction (PCR) and HCV genotyping were performed in all anti-HCV positive subjects belonging to the Dionysos study (6917 subjects). Diagnosis of cirrhosis and hepatocellular carcinoma was established by liver biopsy in all cases. All the data were analysed by univariate and multivariate statistics in all the cohort. To investigate the natural history of HCV infection, anti-HCV positive subjects were followed up every six months for three years with liver function tests and ultrasonograms.

RESULTS

The overall prevalence of HCV RNA positivity was 2.3%. Positivity increased progressively with age, and was higher in women (ratio of men to women = 0.7). Genotypes 1b and 2a were the most frequent (42 and 24% of HCV RNA positive patients), with a prevalence of 1 and 0.6% respectively. Intravenous drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabiting, and history of animal (mainly dogs) bites were significantly (p<0.05) associated with HCV infection, independently of age and sex. Multivariate analysis showed that, independently of age, sex, and alcohol intake, genotype 1b infection, with or without coinfection with other genotypes, is the major risk factor associated with the presence of cirrhosis and/or hepatocellular carcinoma. During the three years of follow up, 57 (35%) of the HCV RNA positive subjects had consistently normal alanine aminotransferase and γ-glutamyltransferase values. Two of the 22 HCV RNA positive cirrhotic patients, all drinking more than 90 g of alcohol a day, developed hepatocellular carcinoma (incidence rate = 3.0% per year).

CONCLUSIONS

In the general population of Northern Italy, HCV infection is widespread, but only less than 50% of the anti-HCV positive subjects, particularly those infected with genotype 1b, are associated with a more severe liver disease. Alcohol consumption greater that 30 g a day significantly aggravates the natural course of the disease.
Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes
Authors: Hearing S D , Norman M , Probert C S J , Haslam N , Dayan C M
Published: June 2010

BACKGROUND

Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown.

AIM

To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes.

METHODS

Eighteen patients with severe UC were studied. After seven days’ treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured.

RESULTS

In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups.

CONCLUSIONS

Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.
Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications
Authors: Mahmud N , Molloy A , McPartlin J , Corbally R , Whitehead A S , Scott J M , Weir D G
Published: June 2010

BACKGROUND

Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD.

AIMS

To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD.

METHODS

Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC).

RESULTS

Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn’s disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B12 levels were lower in patients with IBD irrespective of MTHFR genotype.

CONCLUSIONS

There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B12 therapy to protect against the thromboembolic complications of raised tHcy.