Effects of different proton pump inhibitors on cardiac contractility in isolated human failing myocardium.

AIM: Proton pump inhibitors (PPI), e.g. pantoprazole (PP), esomeprazole (EP) and omeprazole (OP), work as anti-ulcer/gastrointestinal reflux drugs. Also, they are widely used in postoperative care of patients in cardiac surgery to prevent upper gastrointestinal bleeding. Therefore, in western industrial countries they play a major economic role, representing one of the most important drugs in open heart cardiac surgery. METHODS: Intact muscle strips (n=32) were isolated from the right ventricle wall of failing human hearts. In four different groups (PP, EP, OP, control group, each n=8), force amplitudes were recorded at a frequency of 60 beats per minute (bpm) with increasing PPI concentrations (0 to 320 µm/mL). RESULTS: In isometrically contracting muscle strips, significant negative inotropic effects were observed in the presence of all three PPI-groups (PP, EP and OP) with doses of 2.5 µg/mL and higher compared to the control group (p < 0.05 each). With high doses (320 µm/mL), force amplitudes could be almost completely depressed. The half maximal inhibitory concentration (IC50) for EP was 35.7 (confidence interval: 17.3-73.6) vs. OP 29.3 (6.8-126.6) vs. PP 25.1 (14.6-43.1) µg/mL (n.s.). No significant differences were found between the different proton pump inhibitors (PP, EP, OP) throughout the range of all concentrations. Relaxation was impaired in all PPI subgroups with prolonged time to 90% relaxation (RT90%) and maximum relaxation velocity (­df/dt) was reduced, too. These effects were partially reversible after wash-out of the drugs. CONCLUSION: We conclude that proton pump inhibitors show significant negative inotropic effects on isolated human failing myocardium. There is no apparent difference seen in the magnitude of the effects of each PPI-group. Further, in-vivo investigations are necessary to reveal the clinical evidence of PPI's negative inotropic effects, e.g. in cardio-surgical patients with heart failure.

Infliximab as therapeutic option in steroid-refractory ulcerative colitis after kidney transplantation: case report.

In inflammatory bowel disease refractory to established therapies, treatment with biological agents such as monoclonal tumor necrosis factor-α antibodies is an established therapeutic option. However, application in renal allograft recipients is either not licensed or has not yet been systematically examined. Herein, we present 2 case reports of renal allograft recipients who had steroid-refractory ulcerative colitis who demonstrated improvement of symptoms after treatment with infliximab, without signs of effect on transplant function. In both patients, stool frequency decreased significantly. Colonoscopy controls and histologic examination after initiation of treatment revealed a state of remission. Renal function parameters and drug concentrations remained constant.

Exocrine pancreatic function in patients with end-stage renal disease.

AIM: malnutrition is a common problem in patients with end-stage renal disease (ESRD). Several studies showed 30 years ago that more than half of patients with ESRD suffered from exocrine pancreatic insufficiency. However, the studies never investigated whether the functional impairments led to morphological changes of the pancreas or to steatorrhea and thus indicating the need for lifelong pancreatic enzyme substitution. Our goal was therefore not only to establish the frequency but also the severity of exocrine pancreatic insufficiency in hemodialysis patients. METHODS: the study included 50 hemodialysis patients with no history of acute or chronic pancreatitis or upper abdominal symptoms of uncertain origin. All patients with hyperthyroidism, status post-gastrectomy or (partial) small bowel resection, or chronic inflammatory bowel disease were excluded. In all 50 patients, fecal elastase-1 was determined using two different methods (Bioserv Diagnostics and ScheBo Biotech) and fecal fat content and fecal weight were measured. RESULTS: mild to moderate exocrine pancreatic insufficiency (elastase-1 100 - 200 microg/g stool) was found in 10% of patients. It was not correlated with age, sex, and underlying renal disease, duration of hemodialysis, or diarrhea and steatorrhea. In no patient was the enzyme content < 100 microg/g stool, i.e., it never sank to a level at which pancreatic enzyme substitution would have been recommended. Nine patients (18%) had mild diarrhea (200 - 300 g stool/ day), and 10 (20%) had mild steatorrhea (7 - 15 g fat/day in the stool). Five patients had both diarrhea and steatorrhea. CONCLUSIONS: mild to moderate but not severe exocrine pancreatic insufficiency is not infrequent in patients on hemodialysis but unlikely to be responsible for malnutrition in ESRD. Non-pancreas-related steatorrhea is also not uncommon. This finding requires further analysis because steatorrhea might influence nutrition, thus potentially opening the way to new therapeutic approaches.

[Successful management of malaria tropica with 50% parasitaemia]. / Erfolgreiche Therapie einer Malaria tropica mit 50%-iger Parasitämie.

HISTORY: A 52-year-old woman was hospitalized with fever after a 3-week stay in tropical Kenya. Prophylaxis against malaria had been carried out with chloroquine. DIAGNOSIS: Falciparum malaria with 28% parasitaemia at first examination, rising to 50% after 3 hours. TREATMENT AND COURSE: Treatment with quinine dihydrochloride i.v. was initiated immediately after diagnosis. In addition, in view of increasing parasitemia of up to 50%, a partial exchange blood transfusion was carried out. No clinical signs of organ damage caused by malaria were observed. Because of a drop in blood pressure the patient needed catecholamine treatment for a short time. After decrease of the parasitemia the patient rapidly recovered and complete cure was achieved. CONCLUSION: Despite extremely high parasitemia the clinical signs were unusually mild. Standard treatment for severe malaria is intravenous administration of quinine. However, this drug is no longer sold in Germany, so that difficulty in obtaining it must be expected. A stockpiling of quinine is recommended for hospitals treating patients with malaria. Transfusion may improve outcome and must be considered if parasite counts are high or if there are clinical signs of malaria complications.

Glucocorticoid receptor expression in inflammatory bowel disease: evidence for a mucosal down-regulation in steroid-unresponsive ulcerative colitis.

BACKGROUND: Glucocorticoids (GC) play a major role in the attenuation of inflammation. Glucocorticoid receptor (GR) expression is an important determinant of steroid sensitivity. AIMS: To investigate whether GR mRNA expression is altered in inflammatory bowel disease, and whether GR mRNA expression correlates with disease activity and may predict response to GC therapy. METHODS: Mucosal biopsies were taken from 33 patients with ulcerative colitis, 21 with Crohn's disease and 11 controls. Peripheral blood mononuclear cells were isolated from 24 ulcerative colitis and 18 Crohn's disease patients and 11 controls. GR mRNA was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and correlated to endoscopic findings, clinical activity and outcome of GC therapy. In a subset of subjects GR localisation was shown by immunohistochemistry. RESULTS: In patients with inflammatory bowel disease GR expression was not different from controls. However, GR was decreased in biopsies from ulcerative colitis patients with impaired GC response. The inhibitory subtype GRbeta was expressed 100-1000 times lower than GRalpha. GR immunoreactivity was identified in immune and epithelial cells except for colonic crypts. CONCLUSION: In inflammatory bowel disease systemic and mucosal GR mRNA expression is not altered. However, in ulcerative colitis patients, low mucosal GR expression may predict the outcome of GC therapy. The low expression of GRbeta challenges its role in steroid refractoriness in inflammatory bowel disease.

[HCV, HBV and HIV infections: risk for surgeon and staff. Results and consequences of routine screening in emergency patients]. / HCV-, HBV- und HIV-Infektionen -- Gefahren für Arzt und Pflegepersonal. Konsequenzen aus dem Routinescreening von unfallchirurgischen Notfallpatienten.

BACKGROUND: Trauma and emergency surgeons (S) are in contact with high-risk patients (P) infected with HBV, HCV, and HIV without knowing which P is and which is not infected. The aim of this paper was to analyze routine screening (SCR) in trauma care. METHOD: Microparticle enzyme immunoassays (MEIA) (Abbott Axym system) were analyzed from routine blood samples: HBsAg (V2), HCV version 3.0, HIV 1/2gO. All positive or uncertain samples were confirmed with ELISA/PCR. RESULTS: From January 2002 to October 2002 a total of 1074 emergency P were examined. The results were available within 50 min after admittance to the emergency room. In 53 of 1074 (4.9%) the MEIA was positive or in threshold margins (LV): HBV 15 P plus 3 LV (9 secured by ELISA/PCR), prevalence (PV) 0.84%. HCV 34 P plus 1 LV (31 secured with ELISA/PCR), PV 2.9%. HIV 2 P, PV 1.86 per thousand, 1 in co-infection with HCV, 1 with HBV. Of 42 infections, 21 were unknown before screening, and in 5 P the S suspected an infection. After screening, nine surgical procedures were changed to safer procedures. CONCLUSION: MEIA is a good tool for quick SCR of HCV, HBV, and HIV in emergency surgery (ES). When the infection is known the S is more aware to perform only safe procedures during surgery (no touch technique) or to use more protective devices (e.g., fluid shield, double gloves). Our results indicate that surgeons and nurses in ES are exposed four to six times more often to infection with HCV, HBV, and HIV than represented by officially published data. We recommend routine SCR of HBV, HCV, and HIV for all P in ES. Prevention procedures are discussed.

Presence of melatonin in the human hepatobiliary-gastrointestinal tract.

A variety of speculations about the possible origin and physiological role of the neurohormone melatonin in the gastrointestinal tract exist. However, the experimental evidence supporting any of these theories is not substantial and are missing for humans. We studied the distribution of melatonin which was measured with radioimmunoassay in the following compartments and organs of the human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic retrograde cholangiopancreaticography), peripheral venous and portal venous blood (obtained from patients undergoing liver transplantation), endoscopically derived biopsies (mainly consisting of mucosa and submucosa) of stomach, duodenum, large intestine as well as in resected liver tissue. Melatonin concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg (stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the bile duct. Melatonin concentrations were slightly higher in portal than in peripheral venous blood and also the liver contained higher concentrations of melatonin than the blood. In conclusion the presence and distribution of melatonin in human gut, bile, liver and portal blood and the various reports on modulatory actions of melatonin on gut and liver functions suggest that melatonin may act as a mediator of inter-organ communication between gut and liver.

Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2: evidence of inhibition by interleukin-1beta.

BACKGROUND AND AIMS: Glucocorticoids are potent anti-inflammatory drugs widely used in the treatment of inflammatory bowel disease, but many patients do not benefit from glucocorticoid therapy (glucocorticoid resistance) or need inappropriately high doses to retain remission (glucocorticoid dependency). Because of the role of intestinal epithelial cells in inflammatory bowel disease we examined glucocorticoid receptor signaling and the effect of interleukin-1beta as one of the main proinflammatory cytokines in the intestinal epithelial cell lines IEC-6 and Caco-2. METHODS: Dexamethasone effects on transcriptional activation was measured by reporter gene assay using a construct containing glucocorticoid-responsive elements. The transrepressive effect was monitored by a nuclear factor (NF) kappaB inducible reporter construct. In addition in IEC-6 cells immuncytochemistry was used to monitor glucocorticoid receptor translocation. RESULTS: Dexamethasone induced receptor-mediated reporter gene transcription and receptor translocation, while interleukin-1beta significantly inhibited dexamethasone effects. Dexamethasone inhibited interleukin-1beta induced, NF-kappaB driven gene transcription only in IEC-6 and not in Caco-2 cells. However, in Caco-2 cells glucocorticoid receptor overexpression resulted in a marked decrease in NF-kappaB activity even in absence of dexamethasone. CONCLUSIONS: These studies demonstrate that glucocorticoid receptor driven gene regulation in intestinal epithelial cells may contribute to the anti-inflammatory effects of glucocorticoids in inflammatory bowel disease. Our data are consistent with the notion that interleukin-1beta produced during inflammatory response induces steroid resistance, which is a common clinical problem in treating patients with inflammatory bowel disease.

[Acute pancreatitis--adverse effect of 5-aminosalicylic acid (mesalazine) in various galenic dosage forms]. / Akute Pankreatitis--unerwünschte Wirkung von 5-Aminosalicylsäure (Mesalazin) in verschiedenen galenischen Applikationsformen.

HISTORY AND ADMISSION FINDINGS: A 34-year-old woman, being treated with oral mesalazine for colitis, developed upper abdominal pain radiating to the back one week after the drug was started, but the symptoms quickly regressed after mesalazine had been discontinued. The patient was admitted about 15 months later because of watery diarrhoea and lower abdominal pain. Physical examination revealed dehydration and pain on pressure over the lower abdomen. INVESTIGATIONS: Coloscopy demonstrated Crohn's disease of the colon, more marked on the left. Laboratory tests indicated inflammatory disease. TREATMENT AND COURSE: During treatment with oral prednisone and mesalazine enema the diarrhoea and laboratory parameters of inflammatory disease regressed. But 10 days after the start of treatment the patient complained of upper abdominal pain radiating to the back. Amylase and lipase levels were, respectively, four and twelve times normal. Ultrasound demonstrated an enlarged head of the pancreas, while endoscopy of the oesophagus, stomach and duodenum was unremarkable. 3 days after prednisone and mesalazine had been discontinued the symptoms had regressed and laboratory tests were normal. The symptoms did not recur when prednisone was administered again. CONCLUSION: Mesalazine may cause an acute pancreatitis when given either orally or by rectal infusion.

[Surgical treatment of cholangiocellular carcinoma and proximal bile duct tumors]. / Operative Therapie der cholangiozellulären Karzinome und der proximalen Gallengangstumore.

According to its different location, clinical features, treatment modalities and prognosis, intrahepatic cholangiocarcinoma should be well differentiated from proximal bile duct carcinoma. There is no therapeutic measure with curative potential apart from surgical treatment. Partial or extended hepatectomy is the treatment of choice in cholangiocarcinoma. Thereby, hilar resection in combination with hepatectomy is increasingly performed in proximal bile duct carcinomas. In most centers liver transplantation is not considered as a therapeutic option for irresectable cholangiocarcinomas.

Pantoprazole does not affect cyclosporin A blood concentration in kidney-transplant patients.

OBJECTIVE: Renal-transplant patients who are immunosuppressed with cyclosporin A (CyA) are often treated with proton-pump inhibitors to prevent ulcer disease. No data are available on the effect of the novel proton-pump inhibitor pantoprazole on CyA levels. METHODS: In a controlled treatment, we investigated the effect of pantoprazole, which was administered in a pragmatic schedule for acid suppression (40 mg as single oral dose at 2200 hours) in six renal-transplant patients who received CyA (Sandimmun optoral, 50-175 mg twice daily) and prednisolone (5-7.5 mg/24 h). CyA trough levels (0730-0800 hours) were measured by immunoassay. RESULTS: In the absence of pantoprazole, mean CyA trough levels measured on three consecutive days were between 164 ng/ml and 173 ng/ml (therapeutic range 120-200 ng/ml). Pantoprazole did not affect CyA trough levels during an observation period up to 3 months long. CONCLUSIONS: Pantoprazole seems to be a safe drug in combination with CyA.

Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.

Serous adenoma of the pancreas with multiple microcysts communicating with the pancreatic duct.

The rare neoplastic cystic adenomas of the pancreas form two groups of tumors: macrocystic mucinous and microcystic serous adenomas. Both entities show specific radiologic and histologic features. Several recent case reports, however, suggest some diversity within the group of microcystic serous adenomas. We present the case of a young man operated because of epigastric pain for 12 months and a palpable microcystic tumor of the pancreatic head. Multiple cysts communicating with branches of the pancreatic duct in an alveolar-like pattern were demonstrated on endoscopic retrograde cholangiopancreatography. Histologic examination of the specimen confirmed the diagnosis of a serous adenoma of the pancreas. The tumor morphology in this case may suggest a ductal origin of microcystic serous adenomas.

[Pathologic fundus changes in advanced liver cirrhosis. Reduction of symptoms after portosystemic shunt]. / Pathologische Fundusveränderungen bei fortgeschrittener Leberzirrhose. Reduzierung des Befundes nach Anlage eines portosystemischen Shunts.

BACKGROUND: In patients with advanced cirrhosis and portal hypertension a portosystemic shunting procedure is often necessary. This induces haemodynamic changes in the systemic circulation. The aim of this study was to find out whether there were changes in the retinal perfusion as well. METHODS AND PATIENTS: 17 patients with mainly ethyl-toxic cirrhosis (13 male, 4 female; mean age 54 years, range 34-72 years) underwent ophthalmologic examination before and 3 months after TIPS (transjugular intrahepatic portosystemic stent shunt). RESULTS: Before TIPS there were pathological findings in 11 patients: In five cases cotton-wool spots, in three cases discrete vessel abnormalities, in two cases small intraretinal haemorrhages and in one case papilloedema. In all cases these pathological findings were similar in both eyes. Three months after TIPS all these changes had completely disappeared or were at least considerably declining. CONCLUSIONS: The pathological findings in patients with advanced cirrhosis were interpreted as signs of reduced retinal perfusion. After a portosystemic shunting procedure signs of recovery were seen.