hepatic resection; liver metastases; colorectal cancer; guidelines; chemotherapy
Background: Oxidative stress, including the generation of reactive oxygen species (ROS), is involved in hepatofibrogenesis. The authors’ previous studies have shown that oestradiol suppresses hepatic fibrosis in animal models and attenuates the activation of cultured rat hepatic stellate cells (HSCs), which possess oestrogen receptor subtype β and are also activated by ROS.
Aims: To define the mechanisms by which female sex hormones play an antifibrogenic role in activated HSCs, the effects of oestradiol and progesterone on ROS generation processes and intracellular pathways, leading to the activation of HSCs undergoing oxidative stress, was examined.
Methods: HSCs, isolated from rats, were cultured for 7 days with oestradiol or progesterone for 24 hours as pretreatment, and oxidative stress was then induced by exposure to low doses of hydrogen peroxide for another 24 hours.
Results: Oestradiol inhibited ROS generation and antioxidant enzyme loss via the suppression of NADH/NADPH oxidase activity, and attenuated hydrogen peroxide induced transforming growth factor-β1 (TGF-β1) expression, HSC proliferation and transformation, and the activation of mitogen activated protein kinase (MAPK) pathways and transcription factors. Progesterone exerted a stimulatory effect through the progesterone receptor on the induction of ROS generation processes and intracellular pathways, resulting in TGF-β1 expression and HSC activation, and fibrogenic effects were inhibited by oestradiol.
Conclusion: These findings show for the first time that oestradiol inhibits the activation of transcription factors by suppressing ROS generation processes and the MAPK pathways, and inactivates the downstream transcription processes involved in TGF-β1 expression and HSC activation, whereas progesterone acts in opposition to the favourable effects of oestradiol and its effects are blocked by oestradiol.
oestradiol; progesterone; hepatic stellate cells; ROS; TGF-β
acute pancreatitis; diabetic ketoacidosis
Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis.
Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3).
Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER.
Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.
ghrelin; diabetic gastroparesis; pancreatic polypeptide
Crohn’s disease; antibiotics; ciprofloxacin; metronidazole
eosinophilic gastritis; Helicobacter pylori; eosinophilia
hereditary colorectal cancer; colorectal cancer
Aim: The aim of this study was to establish a method of investigating intestinal eosinophil and neutrophil granulocytes by flow cytometry, and to compare the distribution and activity of these cells in different stages of ulcerative colitis (UC).
Methods: Biopsy samples were taken from six locations of the entire colon and from the terminal ileum in 10 patients with active total UC, 10 patients with inactive total UC, eight patients with active distal UC, and 11 control subjects. Cell suspensions from biopsies and from peripheral blood were incubated with fluorophore conjugated monoclonal antibodies. The use of scatter plot-gating and specific antibodies was established in a flow cytometry assay.
Results: Eosinophils were more numerous and more active in patients with active UC than in controls. Interestingly, during inactive UC, the number of activated eosinophils was even larger. Eosinophil activity was high in the rectum of patients with distal colitis but was also slightly elevated in the proximal colon. Neutrophils were increased in number and activity during active but not inactive UC. In patients with distal colitis, activated neutrophils were only found in the sigmoid colon and rectum.
Conclusion: With this method, we confirm that neutrophils participate in the inflammatory process during active UC, and that they express a resting phenotype during remission. The finding of activated eosinophils in inflamed intestine strengthens the view of these cells as proinflammatory and tissue damaging. Nevertheless, our new finding of high eosinophil activation during inactive UC suggests that eosinophils play a role in repair of injured epithelium.
eosinophils; flow cytometry; inflammatory bowel disease; neutrophils; ulcerative colitis
Background and aims: Radiation therapy of abdominal and pelvic solid tumours results in late intestinal toxicity of a severe nature in approximately 5% of cases. These manifestations may include ischaemia and stricture formation, which may present as “webs”. These webs are likely to play a role in the pathogenesis of recurrent bowel obstruction. The mechanisms of microvascular injury to the bowel in the setting of radiation have not been defined. We hypothesised that microvascular dysfunction with impaired vasodilation to acetylcholine (Ach) would be an acquired pathophysiological abnormality in radiation and “web” formation.
Methods: A 40 year old patient treated with radiation, two years previously, for an anal squamous cell cancer presented with recurrent small bowel obstruction. “Webs” in the distal ileum were detected using wireless capsule endoscopy, after small bowel barium radiographs failed to demonstrate a lesion. Following resection, freshly isolated 50–150 μm diameter arterioles from the “web” and adjacent normal calibre bowel were analysed with histology and microvessel physiological studies.
Results: After constriction (30–50%) with endothelin, dilation to graded doses of Ach (10−9–10−4 M) was observed in vessels dissected from the stricture and the adjacent normal calibre area. Ach dilation was reduced in vessels from “web” (mean diameter 7 (2)%; n = 3, p<0.01) compared with the adjacent unaffected bowel (mean diameter 85 (5)%). Dihydroethidine and dichlorofluorescein diacetate intravital staining demonstrated increased reactive oxygen species production in microvessels from “web” compared with adjacent normal calibre bowel. Histology from the strictured bowel demonstrated narrowing of the arterial lumen due to intimal and muscularis propria fibrosis, with endothelial preservation.
Conclusions: External radiation is associated with acquired microvascular endothelial dysfunction and “web” formation in the small bowel.
radiation therapy; radiation toxicity; small bowel obstruction; microvascular dysfunction
family history; molecular features; children; adolescents; young adults; colorectal carcinoma
neutrophils; ulcerative colitis; eosinophils; inflammatory bowel disease; inflammatory cells; Crohn’s disease
endoscopic gastroplication; Endocinch; gastro-oesophageal reflux disease
Objective: To study whether birth size influences colorectal cancer risk in adulthood.
Design: A cohort of Norwegian men and women identified from midwives’ birth records with long term cancer follow up through the Norwegian Cancer Registry.
Setting: St Olav’s University Hospital, Trondheim, Norway.
Participants: 16 016 women and 19 681 men born between 1920 and 1958 and alive in 1960.
Outcome measures: Incidence rate ratios (RRs) for colorectal cancer with 95% confidence intervals (CIs) and two sided p values for trend across categories of birth dimensions.
Results: Men whose birth length was less than 51 cm had a nearly twofold higher risk of colorectal cancer (RR 1.9 (95% CI 1.0–3.7)) compared with men who were 53 cm or more, after adjustment for birth cohort, maternal age at childbearing, length of gestation, gestational hypertension or pre-eclampsia, birth order, maternal height, and indicators of maternal socioeconomic status. The association displayed a linear trend across categories of birth length (ptrend = 0.03). Among men, similar associations were found for birth weight and head circumference, but for women there was no association between any of these birth dimensions and risk of colorectal cancer.
Conclusion: The results suggest that among men, but not women, being relatively short at birth is associated with increased risk of colorectal cancer in adulthood, indicating that intrauterine growth could be important for colorectal carcinogenesis.
colorectal cancer; birth weight; birth length; head circumference; early life
tuberculous colitis; Crohn’s disease
Paneth cells; innate immunity; inflammatory bowel disease
migraine; faecal incontinence
gastro-oesophageal reflux disease; pH monitoring; diagnosis; ambulatory recordings; reflux events
Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibutyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study.
Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model.
Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 µg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically.
Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, α-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines.
Conclusions: : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.
anti-monocyte chemoattractant protein 1; gene therapy; chronic pancreatitis; dibutyltin dichloride; rats; C-C chemokine receptor; pancreatic fibrosis
Background: Budd-Chiari syndrome (BCS) is associated with parenchymal changes leading to major architecture remodelling. In order to gain further insight into the pathogenesis of BCS, we investigated expression of a set of genes involved in the course of chronic liver diseases.
Methods: Quantitative expression of 35 selected genes involved in extracellular matrix regulation, growth factors, and angiogenesis was investigated in 13 cases of BCS and compared with 10 normal livers and 13 cirrhosis cases by real time reverse transcription-polymerase chain reaction. Differential gene expression was considered significant for genes showing at least a twofold variation, with p<0.05.
Results: Expression of 14 genes was significantly increased in BCS versus normal liver, with the highest increase in superior cervical ganglion 10 (SCG10) gene. BCS cases were classified according to their evolution and morphological pattern as either acute or chronic in six and seven cases, respectively. Unsupervised hierarchical clustering of acute and chronic BCS cases on the basis of similarity in gene expression pattern led to distinction between the two groups. Expression of three genes was significantly different in acute versus chronic BCS (increase in matrix metalloproteinase 7 and SCG10, decrease in thrombospondin-1 for chronic BCS). Seventeen and 10 genes, mainly involved in extracellular matrix and vascular remodelling, were significantly deregulated in acute BCS versus normal liver and cirrhosis, respectively.
Conclusion: These results show that BCS cases display a specific gene expression profile that is different from that of normal liver and cirrhosis; the molecular configuration of BCS can be readily distinguished by its evolution and morphological pattern.
liver fibrosis; thrombosis; tissue factor; SCG10; Budd-Chiari syndrome
diarrhoea; carcinoid syndrome