Donor Monoclonal Gammopathy May Cause Lymphoproliferative Disorders in Solid Organ Transplant Recipients.

Prior research on donor monoclonal gammopathy of undetermined significance (MGUS) has been inadequate regarding the risk for lymphoproliferative disease in solid organ transplantation recipients. Seven organ recipients from two different donors developed lymphoproliferative disease. The origin of the malignancy was determined by use of microsatellite analysis, and the plasma of the two donors was analyzed with the use of electrophoresis. The clinical courses of the seven recipients were followed for 36-60 months. One donor transmitted lymphoplasmacytic lymphoma to two kidney recipients and MGUS to a liver recipient, all IgMκ. A second donor caused IgGλ myeloma in two kidney and one liver recipient, and IgGλ gammopathy in a heart recipient. Transplant nephrectomy was performed in three kidney recipients and remission was achieved. The fourth kidney recipient has kept the graft and the disease has progressed. The liver recipient died from myeloma. There were no clinical signs of lymphoproliferative disease in the donors, but retrospective serum analyses showed M-components, IgMκ (37 g/L) and IgGλ (8 g/L). Donors with MGUS may cause donor-transmitted malignancies via passenger lymphocytes/plasma cells in solid organ recipients. The results call for a large register study of the incidence of donor MGUS and lymphoproliferative disease in their recipients.

Gene expression profile of colon cancer cell lines treated with SN-38.

AIM: Colorectal cancer is the third most common form of cancer in the industrial countries. Due to advances regarding the treatments, primarily development of improved surgical methods and the ability to make the earlier diagnosis, the mortality has remained constant during the past decades even though the incidence in fact has increased. To improve chemotherapy and enable personalised treatment, the need of biomarkers is of great significance. In this study, we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38, the active metabolite of topoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis. MATERIAL AND METHODS: The study included 3 colon cancer cell lines: KM12C, KM12SM and KM12l4a. The 3 cell lines were treated with SN-38, and samples were obtained after 24 and 48 hour treatments. The gene expression analyses were performed using oligonucleotide microarrays comprising of approximately 27,000 spots where the untreated controls were compared to the SN-38-treated samples. RESULTS: Unsupervised clustering clearly distinguished the treated cell lines from the untreated. Supervised analysis identified 3,974 significant genes (p = 0.05) differentiating the treated samples from the untreated, majority of which were down-regulated after treatment. The top-ranked down-regulated genes in the treated cell lines included those related to receptor and kinase activity, signal transduction, apoptosis, RNA processing, protein metabolism and transport, cell cycle and transcription. A smaller number of genes were up-regulated in the cell lines after treatment and included genes involved in apoptosis, transcription, development and differentiation. CONCLUSIONS: These results demonstrate that the expression of the genes involved in cell proliferation and apoptosis as well as RNA, DNA and protein metabolism were affected by SN-38. The impact of certain genes on colorectal cancer development needs to be further evaluated; however, these results could serve as a basis for further studies in order to find targets for irinotecan treatment.

Segmental ischemia of the liver - microdialysis in a novel porcine model.

BACKGROUND: Segmental liver ischemia is often used in rodents to study ischemia and reperfusion injuries (IRI). There are no reports of protocols using segmental ischemia in porcine models. Microdialysis (MD) provides the opportunity to study local effects of IRI in vivo. METHODS: Eight pigs received an MD catheter placed in liver segments IV and V, respectively. All circulation to segment IV was stopped for 80 min, and reperfusion was followed for 240 min. RESULTS: During ischemia the levels of lactate, glycerol and glucose increased 3-fold (p < 0.001), 40-fold (p < 0.001) and 4-fold (p < 0.01), respectively, in the ischemic segment compared to the perfused segment, whereas the levels of pyruvate fell to a tenth of the preischemic level (p < 0.001). All values returned to baseline after reperfusion. Serum levels of aspartate aminotransferase increased (p < 0.05). Polymorphonuclear cells increased in both segments, although the density was significantly higher in segment IV. CONCLUSION: Clamping of one liver segment in pigs is a simple, stable and reproducible model to study IRI with minimal systemic effects. MD revealed no signs of anaerobic metabolism in the perfused segment but still there was an increase in the number of polymorphonuclear neutrophils in this segment, although it was lower than that in the ischemic segment.

Serum amino acid profile in patients with acute pancreatitis.

Patients in the early phase of acute pancreatitis (AP) have reduced serum levels of arginine and citrulline. This may be of patho-biological importance, since arginine is the substrate for nitric oxide, which in turn is involved in normal pancreatic physiology and in the inflammatory process. Serum amino acid spectrum was measured daily for five days and after recovery six weeks later in 19 patients admitted to the hospital for acute pancreatitis. These patients had abnormal levels of most amino acids including arginine, citrulline, glutamine and glutamate. Phenylalanine and glutamate were increased, while arginine, citrulline, ornithine and glutamine were decreased compared to levels after recovery. NO(2)/NO(3) concentration in the urine, but not serum arginase activity, was significantly increased day 1 compared to day 5 after admission. Acute pancreatitis causes a disturbance of the serum amino acid spectrum, with possible implications for the inflammatory process and organ function both in the pancreas and the gut. Supplementation of selected amino acids could possibly be of value in this severe condition.

Selective iNOS inhibition enhances spontaneous gallbladder motility in the Australian possum.

Gallbladder inflammation is a common and painful disease. Inducible nitric oxide synthase (iNOS) plays a major role in inflammatory diseases, and iNOS inhibitors are being developed as therapeutic agents. Reports are inconsistent regarding iNOS expression in normal gallbladder. The aim of this study was to determine the effect of iNOS inhibition on spontaneous gallbladder motility. mRNA extracted from normal possum gallbladders was analysed by PCR. Gallbladder contractility was evaluated using a highly selective iNOS inhibitor AR-C102222AA (AR-C) in in vitro muscle strips (0.1-10 000 microm) and in vivo (0.1-30 micromol kg(-1)) experiments. Gene expression analysis revealed the presence of iNOS mRNA in normal gallbladder (n = 3). In vitro, AR-C (0.1-1000 micromol L(-1)) produced a concentration-dependent increase in spontaneous gallbladder contractile activity and basal tension (P < 0.05; n = 6). The maximum effect was a 1.8-fold increase in activity and 2.1-fold increase in basal tension. Pretreatment of muscle strips with tetrodotoxin (1 micromol L(-1)) did not block the AR-C-induced response (n = 5). In vivo, AR-C (30 micromol kg(-1), i.v.) increased gallbladder contraction frequency (P < 0.05; n = 8). These data suggest that iNOS is continually expressed in the normal gallbladder, which presumably releases low levels of nitric oxide and in turn may modulate spontaneous gallbladder motility. AR-C may be a beneficial treatment for patients suffering from acute cholecystitis.

Indomethacin intravenously--a new way for effective relief of biliary pain: a double-blind study in man.

Prostaglandins have been demonstrated to contract the gallbladder and induce fluid secretion into its lumen in experimental animals. Indomethacin is an effective inhibitor of prostaglandin synthetase and has recently been demonstrated to inhibit inflammatory fluid secretion into the gallbladder in experimental cholecystitis. A mechanism by which an increased prostaglandin synthesis will result in a raised intraluminal pressure in the gallbladder in patients with gallstone disease has been suggested. By inhibiting the synthesis of prostaglandins with indomethacin the intraluminal pressure is reduced and the biliary pain relieved. In a double-blind study with a placebo in 40 separate attacks of biliary pain in 37 patients with verified gallstone disease intravenous indomethacin was found to effectively relieve pain within 5 to 30 minutes. No serious side effects were seen, but nausea and vertigo of short duration were noticed in 10 of 21 cases of indomethacin treatment. The drug did not affect blood pressure, but a reduction of the pulse rate was usually seen.

Gallbladder function in experimental cholecystitis.

Experimental cholecystitis was induced by implanting gallstones from human beings into the gallbladder of the cat. Three months later the concentrating function of the gallbladder, the motility, and hepatic bile flow were studied by a perfusion technique in the anesthetized animal. Gallbladder function was correlated to morphologic changes. After 3 months, the cystic duct was patent in nine animals and bile was found in the gallbladder. In 17 animals the cystic duct was obstructed and colorless contents were found in the gallbladder. Animals with a patent cystic duct showed slight or moderate inflammation and intact concentrating activity in the gallbladder, whereas animals with obstructed animals had pronounced inflammation and continuous fluid "secretion" into the lumen. Both groups had increased bile outflow from the liver. Indomethacin, a prostaglandin synthetase inhibitor, promptly reversed gallbladder fluid "secretion" into absorption and reduced the increased bile flow to a normal level. These results are discussed in relation to clinical findings in man. A mechanism by which prostaglandins are responsible for the inflammatory gallbladder "secretion" and the increased bile flow from the liver is proposed.

The secretion of cholecystokinin in the gallstone patient before and after removal of a functioning gallbladder.

Cholecystectomy will not always relieve the abdominal symptoms of the patient with gallstones. The functional effects of gallbladder removal in a patient with a patent cystic duct are not known in detail. Studies of the function of the gallbladder and pancreas have suggested feedback mechanisms for the release of cholecystokinin (CCK). A disturbed regulation of CCK release after cholecystectomy might induce pancreaticobiliary and gastrointestinal dysfunctions. In our study the concentrations of CCK in plasma were measured in 17 patients with gallstones. The measurements were taken with gallbladders opacified at cholecystography and with patent cystic ducts at the operation, in the fasting state, and during stimulation before and 17 weeks after the cholecystectomy. The CCK assay used measures sulfated CCK-8, CCK-22, and CCK-33 with equimolar potency but neither nonsulfated CCK nor any gastrins. Emtobil (containing peanut oil and sorbitol) was used for peroral stimulation of the CCK release. The basal concentration of CCK was 4 pmol/L and rose five times during a "test meal." No significant differences were seen in fasting or stimulated concentrations of plasma CCK before and after the cholecystectomy. Thus cholecystectomy in gallstone patients with functioning gallbladders does not seem to influence the regulation of CCK release.

Vasoactive intestinal peptide in the normal and inflamed feline gallbladder.

Intravenous infusion of vasoactive intestinal peptide (VIP) causes gallbladder mucosal fluid secretion by an action on epithelial cell receptors in the cat. Gallbladder fluid secretion is observed also in experimental cholecystitis and this secretion is abolished when the intramural gallbladder nerves are blocked. In the present study, immunoreactive VIP was detected in the gallbladder contents (29 +/- 5 (S.E.M.) pM) in the obstructed lumen of the gallbladder in cats with experimental cholecystitis and gallbladder mucosal fluid secretion, but not in the normal feline gallbladder. During luminal perfusion of the gallbladder in vivo, the calculated secretion of VIP into the gallbladder lumen in animals with experimental cholecystitis was significantly higher (0.31 +/- 0.08 (S.E.M.), pmol/h) than in controls (0.11 +/- 0.02 (S.E.M.), pmol/h) while plasma levels of VIP were similar. Recovery of exogenously administered VIP was similar in normal and inflamed gallbladders. The present results support the hypothesis that intramural VIP-releasing nerve fibers may be activated in cholecystitis.

Cholecystokinin octapeptide induces both proliferation and apoptosis in the rat pancreas.

Cholecystokinin-8 (CCK-8) causes exocrine pancreatic hypertrophy and hyperplasia. High doses of the CCK analogue cerulein causes necrosis and an inflammatory response in the pancreas. We have studied the pancreatic growth response in rats after administration of CCK-8 for 3 days, given either intermittently (20-80 microg/kg) twice a day, or continuously (2.4-48 microg/kg per 24 h). Plasma CCK-8 levels, pancreatic wet weight, water, protein and DNA contents and the pancreatic caspase-3 activity were measured. Cell proliferation was visualized by [3H]thymidine incorporation and apoptosis by TUNEL reaction. Continuous administration of CCK-8 dose-dependently increased the plasma CCK levels, the pancreatic wet weight, protein and DNA contents as well as thymidine labeling index, apoptotic index and caspase-3 activity. Intermittent injections of CCK-8 caused transient raises in plasma CCK, increased apoptotic index and caspase-3 activity, a dose-dependent increase in thymidine labeling but caused a dose-dependent reduction of pancreatic wet weight, protein, and DNA contents. It is concluded that CCK-8 causes both increased proliferation and apoptosis in the pancreas. In case of continuous administration of CCK-8, the proliferation outweighs the apoptosis causing hyperplasia but in the case of intermittent administration the opposite effect is seen.

VIP-antiserum inhibits fluid secretion by the inflamed gallbladder mucosa.

The inflammatory fluid secretion by the gallbladder mucosa in experimental cholecystitis is induced by an increased prostaglandin formation and is mediated by intramural nerves. In the present study the effect of VIP-antiserum on the inflammatory fluid secretion in the gallbladder was tested in a validated experimental model in cats. The animals were studied in acute experiments 6 weeks after a procedure when the cystic duct was tied and gallstones were implanted in the gallbladder. During basal conditions there was a continuous secretion of fluid into the lumen of the inflamed gallbladder averaging 0.43 +/- 0.18 ml/h. Injection of VIP antiserum, obtained from immunized rabbits and diluted with saline 1:10 in a bolus of 4 ml into the coeliac artery reversed this secretion into an absorption of 1.72 +/- 0.44 ml h-1 (P < 0.001). VIP-antiserum did not affect the fluid adsorption in control animals with an intact gallbladder and injection of control serum from rabbits not immunized to VIP did not affect fluid secretion in the inflamed gallbladders. The results support the idea that the inflammatory fluid secretion in the gallbladder mucosa is mediated by VIP-ergic nerve fibres.

Loperamide inhibits gallbladder inflammatory fluid secretion in experimental cholecystitis.

Fluid secretion by the gallbladder mucosa is suggested to have a key pathophysiological role in acute cholecystitis, since it causes distension of the obstructed gallbladder. The present study investigates the actions of loperamide on the gallbladder function in experimental cholecystitis. Gallbladder fluid transport and motility were studied in vivo with a continuous perfusion technique. A net fluid secretion by the gallbladder mucosa was seen in cats in which cholecystitis was induced whereas there was a net fluid absorption from the gallbladder lumen in the control animals. The net fluid secretion in experimental cholecystitis was inhibited by loperamide (1 mg/kg), an effect that was blocked by naloxone (1 mg/kg), suggesting an involvement of specific opiate receptors. Loperamide (1 mg/kg) relaxed the normal gallbladder but had no significant effects on its fluid absorption. Since loperamide reduces mucosal fluid secretion in experimental cholecystitis without contracting the gallbladder wall, it is suggested that this peripherally acting opiate agonist could be useful in the treatment of patients with acute cholecystitis.

Role of cyclooxygenase-2 for fluid secretion by the inflamed gallbladder mucosa.

Inflammatory fluid secretion by the gallbladder mucosa in experimental cholecystitis is induced by activation of cyclooxygenase, which leads to an increase in prostaglandin formation. Cyclooxygenase exists as a constitutive (cyclooxygenase-l) and an inducible (cyclooxygenase-2) isoform. The aim of this study was to demonstrate the role of cyclooxygenase-2 in inflammatory fluid secretion of the feline gallbladder. Experiments were performed 10 weeks after a surgical procedure in which chronic cholecystitis was induced in cats by ligation of the cystic duct and implantation of a gallstone in the gallbladder. Gallbladder fluid transport was continuously monitored via a perfusion system. In inflammed gallbladders the continuous fluid secretion was reversed to absorption by intravenous injection of the selective cyclooxygenase-2 blocker, NS 398 (P <0.001). Increased levels of the inducible cyclooxygenase-2 were shown by immunoblotting in inflamed gallbladders. Selective pharmacologic blockage of cyclooxygenase-2 reduced the prostaglandin E2 release to the inflamed gallbladder lumen (P <0.01). These data suggest that cyclooxygenase-2 is involved in the inflammatory response during chronic cholecystitis. Selective cyclooxygenase-2 blockers may offer an alternative to traditional nonsterodial anti-inflammatory drugs with fewer side effects in patients with cholecystitis who are awaiting operation.

Sludge is calcium bilirubinate associated with bile stasis.

Biliary sludge is a frequent finding on abdominal sonography. It is most often found after prolonged stasis of gallbladder bile associated with other illness or mechanical obstruction of the common duct, and seldom indicates primary gallbladder disease. In most cases, sludge is a suspension of pigment precipitates in bile, and is at least in part calcium bilirubinate. Sludge may disappear with the return of normal gallbladder contractility. The ease with which this precipitate forms during stasis of gallbladder bile suggests a role for this process in the pathogenesis of cholelithiasis.

Hydatid disease of the spine: case report.

A rare case of spinal hydatid disease presenting with paraparesis and sensory loss is reported. The patient was treated with albendazole resulting in significant improvement within eight weeks. Investigations and treatment modalities are discussed.

[The incidence of gallbladder cancer in Sweden has decreased. The poor prognosis can possibly be improved by radical surgery]. / Incidensen av gallblåsecancer i Sverige har minskat. Den dåliga prognosen kan möjligen förbättras genom radikal kirurgi.

Gallbladder cancer is a rare disease with poor prognosis and short survival time. The condition is usually associated with gallstones and predominantly affects women. We have taken data from the National Cancer Register and the Cause of Death Register in Sweden and studied the annual incidence of and mortality due to gallbladder cancer from 1988 to 1997. Incidence has declined during this period, which may be explained by a high rate of cholecystectomies in Sweden between 1950 and 1970. Prognosis has traditionally been poor, with a median survival time of 3.5 months, which might be explained by the fact that the disease usually is diagnosed at an advanced stage. Epidemiological figures show that prognosis may have improved during the past decade. In several retrospective studies, mainly from Japan, better results with longer survival times are reported after extended surgery. In a small group of 11 patients with gallbladder cancer, Nevin grade II-V, who underwent extended surgery at The University Hospital in Linköping, there are no signs of recurrent disease in 10 patients after a follow-up of 1-8 years.

[Guidelines for management of patients with acute pancreatitis]. / Riktlinjer för handläggning av patienter med akut pankreatit.

During recent years new concepts and methods have been introduced in the management of acute pancreatitis. Severity and risk of complications show wide variation. Outcome is also dependent on the physician's experience and on his local resources. In this light the Swedish Society of Upper Abdominal Surgery has elaborated national guidelines for management. Attention is paid to diagnosis, severity assessment and etiology. Furthermore, guidelines are offered for treatment of mild and severe pancreatitis, as well as for the management of pseudocysts. The role of multidisciplinary intensive care specialist teams in the management of severe disease is emphasized. The guidelines are supported by the Swedish Society of Gastroenterology, the Swedish Society of Gastroenterology, the Swedish Society of Anesthesiology and Intensive Care and by experts from other Nordic countries.

A possible role of ursodeoxycholic acid in liver transplantation.

There are many different causes of graft dysfunction and cholestasis after liver transplantation. These include non-primary function, preservation and reperfusion injury, acute rejection, artery thrombosis, drug toxicity, bile leakage, and bile duct stenosis. Medication with ursodeoxycholic acid (UDCA) has beneficial effects in different cholestatic conditions. The initial rationale for its use after liver transplantation was to alter the bile acid pool to a more atoxic composition, as liver transplantation can be associated with cholestasis and can stimulate the initial bile production. We have consecutively treated 41 patients with primary graft function with UDCA. During the first postoperative month, 17% of the UDCA treated patients had an episode of acute rejection compared with 75% of a historical control group of 8 patients. The results suggest that adjuvant treatment with UDCA reduces acute liver graft rejection. This has to be confirmed by controlled prospective trials; one is presently being carried out in the Nordic countries. Several studies have indicated an immunomodulating capacity of this bile acid and we have recently reported our results from a heart transplant model in the rat, where treatment with UDCA prolonged graft survival. Improvement in surgical technique and postoperative care as well as immunosuppressive treatment has improved the results of liver transplantation. Acute rejection is nowadays a dominating problem after liver transplantation and the inclusion of UDCA may reduce morbidity.

Enzyme substitution in chronic pancreatitis: effects on clinical and functional parameters and on the hydrogen (H2) breath test.

Ten patients with chronic pancreatitis (with abdominal pain and/or diarrhoea) were treated in a double-blind multiple cross-over trial with Pankreon granules 20 g per day or placebo during three periods of one month each. Pain and bowel habits were recorded. Faecal fat and breath hydrogen (H2) excretion were analyzed during the last days of each treatment period. The pain score was initially low in all patients and was not affected by enzymes. The number of daily bowel movements was reduced from 3.16 to 2.32 (n.s.). Faecal fat excretion per 72 hrs was reduced from 357 +/- 158 mmol free fatty acid to 226 +/- 98 mmol (p less than 0.05). With placebo treatment H2 excretion (from 60 and 180 min after a standard breakfast) was significantly increased compared with 19 healthy volunteers (p less than 0.05). It was not significantly reduced by enzymes. In 28 comparisons the H2 output between 60 and 180 min was correlated to faecal fat. In eight patients the oro-coecal transit-time could be determined by the H2 breath test. The transit-time did not differ from that of ten healthy volunteers and remained unchanged by enzymes. Carbohydrate maldigestion occurs parallel to fat maldigestion in chronic pancreatitis, and is not sufficiently reduced by 20 g of pancreatic enzymes.