Butyrate produced by colonic bacterial fermentation is the main fuel for colonocytes, glucose bei... more Butyrate produced by colonic bacterial fermentation is the main fuel for colonocytes, glucose being an alternative fuel. During inflammatory bowel disease, butyrate oxidation by colonocytes is impaired, and increased production of proinflammatory cytokines is detected in the colonic mucosa. We hypothesized that proinflammatory cytokines might reduce butyrate oxidation, and we assessed the in vitro effects of 3 proinflammatory cytokines on butyrate and glucose oxidation in colonic mucosa. Colonic biopsies were obtained from normal mucosa in 42 patients who underwent a colonoscopy. Biopsies were incubated in RPMI 1640 with [1-14C]-butyrate or [U-14C]-glucose with or without 1 of the 3 following proinflammatory cytokines: tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, and IL-6. For each cytokine, 4 different concentrations were tested in 8 subjects. Concentrations overlapped those commonly found in inflamed mucosa and had no cytotoxicity as assessed in preliminary experiments using both the trypan blue exclusion test and lactate dehydrogenase release. Production of 14CO2 (picomoles per microgram dry weight per hour) was measured after a 2-hour incubation and expressed as a percentage of the control [14C]-substrate oxidation without cytokines. Whereas glucose oxidation was not affected, butyrate oxidation was reduced significantly (P < 0.05) by TNFalpha at concentrations of 100 (-26 +/- 6%), 1000 (-32 +/- 7%), and 5000 pg/mL (-34 +/- 5%). IL-1beta (0, 500, 5000, and 25,000 pg/mL) and IL-6 (0, 100, 1000, and 5000 pg/mL) did not affect either substrate oxidation. TNFalpha at concentrations found in inflamed mucosa reduces butyrate oxidation in vitro in mucosa from healthy controls. This result is not caused by a cytotoxic effect of TNFalpha and is not balanced by an increased oxidation of glucose. Reduced butyrate oxidation results in a decreased energy supply to colonocytes and may explain, in part, mucosal damage occurring during attacks of inflammatory bowel disease.
Auto-immune pancreatitis is rare and its evolution includes both the usual complications of chron... more Auto-immune pancreatitis is rare and its evolution includes both the usual complications of chronic pancreatites, such as diabetes and specific consequences and complications including extension of inflammatory lesions of the extra or intrahepatic biliary tract. One particular characteristic of these complications is that they are sensitive to cortisone therapy, as illustrated by the case we report here.
The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Cr... more The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Crohn's disease (CD) is not well elucidated. Twenty healthy volunteers and 94 consecutive patients with CD (44 in relapse and 50 in remission) were studied. Plasma IL-6 concentrations in patients with active disease [80 +/- 9 pg/ml; mean +/- standard error of the mean (SEM)] were significantly higher than in patients with inactive disease (50 +/- 4 pg/ml; P < 0.001) or controls (3 +/- 1 pg/ml; P < 0.001). However, concentrations did not vary with the severity of CD attacks. Plasma concentrations of soluble interleukin-6 receptor (sIL-6R) in active-CD patients (77 +/- 5 ng/ml) did not differ significantly from those with inactive disease (82 +/- 5 ng/ml), while both groups had significantly raised concentrations compared with those of controls (58 +/- 6 ng/ml; P < 0.03 and P < 0.01, respectively). Plasma IL-6 concentrations correlated significantly with serum C-reactive protein (CRP) (r = 0.34; P < 0.001), whereas plasma sIL-6R concentrations did not. Taken together, these data suggest that, although IL6 and sIL6-R are both involved in the inflammatory process of CD, they are poor markers of disease activity.
Hepar lobatum carcinomatosum is an unusual cause of chronic liver failure, usually maskerading as... more Hepar lobatum carcinomatosum is an unusual cause of chronic liver failure, usually maskerading as cirrhosis. The pathogenesis of this syndrome is unclear. We report a case of liver failure revealing an occult lobular carcinoma of the breast, which offers the opportunity to gain further insight into the mechanisms of this rare cause of chronic liver disease. A 57-year-old woman, without history of malignancy, presented with hepatomegaly, ascites and altered liver tests (serum transaminase activity >5 N and hyperbilirubinemia). The transjugular liver biopsy performed at diagnosis showed an extensive fibrosis, containing scattered tumor cells, typical of metastatic lobular carcinoma of the breast. Four months later, after discovery of a rectal adenocarcinoma, a laparoscopy was performed; peritoneal carcinomatosis was discovered. A surgical biopsy of the liver was taken during the procedure: it showed histological features suggestive of chronic Budd-Chiari syndrome, with venocentric fibrosis and reversed lobulation. Intraluminal invasion of small hepatic veins and sinusoidal obstruction by neoplastic cells were observed. A small focus of lobular carcinoma was eventually discovered in the left mammary gland. The present case report expands the spectrum of clinical presentations associated with hepar lobatum carcinomatosum and points out to the importance of vascular injury in the pathogenesis of this rare cause of chronic liver disease.
Butyrate produced by colonic bacterial fermentation is the main fuel for colonocytes, glucose bei... more Butyrate produced by colonic bacterial fermentation is the main fuel for colonocytes, glucose being an alternative fuel. During inflammatory bowel disease, butyrate oxidation by colonocytes is impaired, and increased production of proinflammatory cytokines is detected in the colonic mucosa. We hypothesized that proinflammatory cytokines might reduce butyrate oxidation, and we assessed the in vitro effects of 3 proinflammatory cytokines on butyrate and glucose oxidation in colonic mucosa. Colonic biopsies were obtained from normal mucosa in 42 patients who underwent a colonoscopy. Biopsies were incubated in RPMI 1640 with [1-14C]-butyrate or [U-14C]-glucose with or without 1 of the 3 following proinflammatory cytokines: tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, and IL-6. For each cytokine, 4 different concentrations were tested in 8 subjects. Concentrations overlapped those commonly found in inflamed mucosa and had no cytotoxicity as assessed in preliminary experiments using both the trypan blue exclusion test and lactate dehydrogenase release. Production of 14CO2 (picomoles per microgram dry weight per hour) was measured after a 2-hour incubation and expressed as a percentage of the control [14C]-substrate oxidation without cytokines. Whereas glucose oxidation was not affected, butyrate oxidation was reduced significantly (P < 0.05) by TNFalpha at concentrations of 100 (-26 +/- 6%), 1000 (-32 +/- 7%), and 5000 pg/mL (-34 +/- 5%). IL-1beta (0, 500, 5000, and 25,000 pg/mL) and IL-6 (0, 100, 1000, and 5000 pg/mL) did not affect either substrate oxidation. TNFalpha at concentrations found in inflamed mucosa reduces butyrate oxidation in vitro in mucosa from healthy controls. This result is not caused by a cytotoxic effect of TNFalpha and is not balanced by an increased oxidation of glucose. Reduced butyrate oxidation results in a decreased energy supply to colonocytes and may explain, in part, mucosal damage occurring during attacks of inflammatory bowel disease.
Auto-immune pancreatitis is rare and its evolution includes both the usual complications of chron... more Auto-immune pancreatitis is rare and its evolution includes both the usual complications of chronic pancreatites, such as diabetes and specific consequences and complications including extension of inflammatory lesions of the extra or intrahepatic biliary tract. One particular characteristic of these complications is that they are sensitive to cortisone therapy, as illustrated by the case we report here.
The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Cr... more The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Crohn's disease (CD) is not well elucidated. Twenty healthy volunteers and 94 consecutive patients with CD (44 in relapse and 50 in remission) were studied. Plasma IL-6 concentrations in patients with active disease [80 +/- 9 pg/ml; mean +/- standard error of the mean (SEM)] were significantly higher than in patients with inactive disease (50 +/- 4 pg/ml; P < 0.001) or controls (3 +/- 1 pg/ml; P < 0.001). However, concentrations did not vary with the severity of CD attacks. Plasma concentrations of soluble interleukin-6 receptor (sIL-6R) in active-CD patients (77 +/- 5 ng/ml) did not differ significantly from those with inactive disease (82 +/- 5 ng/ml), while both groups had significantly raised concentrations compared with those of controls (58 +/- 6 ng/ml; P < 0.03 and P < 0.01, respectively). Plasma IL-6 concentrations correlated significantly with serum C-reactive protein (CRP) (r = 0.34; P < 0.001), whereas plasma sIL-6R concentrations did not. Taken together, these data suggest that, although IL6 and sIL6-R are both involved in the inflammatory process of CD, they are poor markers of disease activity.
Hepar lobatum carcinomatosum is an unusual cause of chronic liver failure, usually maskerading as... more Hepar lobatum carcinomatosum is an unusual cause of chronic liver failure, usually maskerading as cirrhosis. The pathogenesis of this syndrome is unclear. We report a case of liver failure revealing an occult lobular carcinoma of the breast, which offers the opportunity to gain further insight into the mechanisms of this rare cause of chronic liver disease. A 57-year-old woman, without history of malignancy, presented with hepatomegaly, ascites and altered liver tests (serum transaminase activity >5 N and hyperbilirubinemia). The transjugular liver biopsy performed at diagnosis showed an extensive fibrosis, containing scattered tumor cells, typical of metastatic lobular carcinoma of the breast. Four months later, after discovery of a rectal adenocarcinoma, a laparoscopy was performed; peritoneal carcinomatosis was discovered. A surgical biopsy of the liver was taken during the procedure: it showed histological features suggestive of chronic Budd-Chiari syndrome, with venocentric fibrosis and reversed lobulation. Intraluminal invasion of small hepatic veins and sinusoidal obstruction by neoplastic cells were observed. A small focus of lobular carcinoma was eventually discovered in the left mammary gland. The present case report expands the spectrum of clinical presentations associated with hepar lobatum carcinomatosum and points out to the importance of vascular injury in the pathogenesis of this rare cause of chronic liver disease.
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Papers by Ivan Graber