Current concepts on pathophysiology, diagnosis and treatment of diffuse oesophageal spasm.

Diffuse oesophageal spasm is a functional oesophageal motility disorder of unknown aetiology, which appears to be due to a disturbance of the normal pharmacological timing of propulsive contraction occurring in the oesophageal body after swallowing. The lack of pathophysiological understanding may be due to the fact that there is more than one pathophysiological pathway causing symptoms of diffuse oesophageal spasm. Barium studies, oesophageal scintigraphy and fiberoptic examination can be helpful in finding the correct diagnosis, but manometry is still the gold standard of diagnostic procedures. Similar to other spastic oesophageal motility disorders, pharmacological treatment of diffuse oesophageal spasm includes nitrates, calcium antagonists, anticholinergics and antidepressants with varying beneficial effects. Botulinum toxin, which provides sufficient treatment as measured by symptom score and manometric patterns in patients with achalasia, was recently evaluated for the treatment of diffuse oesophageal spasm in small patient selections with promising results.

Endohyperthermia--experimental evaluation of a new therapeutic approach for treatment of biliary carcinoma.

BACKGROUND AND STUDY AIMS: To improve the prognosis of patients with unresectable, locally advanced bile duct carcinoma, new treatment strategies need to be evaluated. Hyperthermia has been successfully applied as part of multimodal therapy in esophageal and rectal carcinoma. We performed in-vitro and in-vivo experiments with a new intraluminal hyperthermia system in the biliary tract. METHODS: A radiofrequency system (13.56 MHz, Endoradiotherm XERT-200A; Olympus Optical Co., Tokyo, Japan) was used with a special intraluminal microelectrode (diameter 4.5 mm, length 40 mm) covered by a silicone balloon with cooling water and a large counter electrode for focusing the electromagnetic field around the electrode. The heating capacity of the endohyperthermia unit was examined in vitro in a muscle-equivalent phantom (agar 4 %), in isolated livers of pigs and cows, as well as in vivo in anesthetized sheep. Continuous thermometry was done with thermosensors at the applicator surface, and with multichannel thermocouple probes in the environment of the applicator. RESULTS: Endohyperthermia induced a homogeneous heating of the phantom and the isolated liver bile duct preparation to a temperature > or = 40 degrees C in an area at least 10 mm in depth. After placement of the applicator into the common bile duct of anesthetized sheep, endohyperthermia led to a consistent and repeatable heating of the surrounding tissue to 40.5 +/- 0.5 degrees C at 1 cm distance, and 39.9 +/- 0.7 degrees C at 2 cm distance. Blood pressure, heart rate, and systemic temperature did not change in vivo. Histological examination of the bile duct showed superficial mucosal necrosis (depth 100-200 microm), microvascular damage with petechiae, congestion and edema of the bile duct wall and adventitia after hyperthermia treatment in vivo. CONCLUSIONS: The intraluminal endohyperthermia system produces consistent and repeatable heating of the surrounding tissue. Since effective thermal power can reach a depth of up to 2 cm, tumors may also be heated adequately.

Microbiological examinations and in-vitro testing of different antibiotics in therapeutic endoscopy of the biliary system.

BACKGROUND AND STUDY AIMS: Prior to endoscopic therapeutic procedures, no antibiotic prophylaxis is administered routinely. Because of the reported incidence of infectious complications, which may reach up to 10%, a prospective study was undertaken to investigate the effects of a prophylactic dose of cefuroxime on the incidence of bacteremia and clinical signs of infection, but no significant effects could be demonstrated. In addition to this published work, blood and bile cultures obtained in this trial were also investigated, and the in-vitro susceptibility to several antibiotics was tested in order to recommend the appropriate substances. PATIENTS AND METHODS: Ninety-nine consecutive patients (51 men, 48 women; mean age 61.4 +/- 17 years) with biliary obstruction who underwent an endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography with drainage (PTCD) were included. Sequential blood cultures were taken before and up to 60 minutes after the endoscopic intervention. Bile cultures were obtained in 56 patients with biliary drainage. Aerobic and anaerobic cultures were prepared from all obtained specimens and the isolated organisms were identified. In the case of positive cultures, an in-vitro resistance test for 15 different antibiotics was performed. RESULTS: The incidence of bacteremia was 11.1% (n = 11), and 16 bacteria were isolated. Twelve different microorganisms were detected, with Escherichia coli found in four cases. From 41 positive out of 56 prepared bile cultures (73.2%), 91 isolates were found with 25 different species. A single agent was detected in eight cases (19.5%), while a mixed growth, with pathogens ranging from two to six species, was found in 33 cases (80.5%). The seven most frequently isolated germs were E. coli and Enterococcus (each n = 19), Klebsiella (n = 10), Streptococcus viridans (n = 9), Staphylococcus epidermidis (n = 5), Morganella morganii (n = 4), and Bacteroides fragilis (n = 3), representing 76% of all agents. Examination for fungal infection revealed positive cultures of Candida albicans in 16.1% of bile cultures (nine of 56). Interestingly, the use of proton-pump inhibitors (PPIs), with a consequent rise in the gastric pH value, led to an increase in the rate of bacteremia to 26.2% (five of 19) compared to the other patients not on PPIs (n = 80), who developed bacteremia in only six cases (7.5%; p = 0.02). In-vitro testing of different antibiotics was carried out in 73 isolates. Imipenem showed the best antimicrobial activity (98.4%), followed by trimethoprim and sulfamethoxazole (90%), amoxicillin plus clavulanic acid (87.3%), vancomycin (82.4%), and ofloxacin (76.9%). CONCLUSIONS: Escherichia coli was found to be the pathogen most frequently detected in blood and bile following endoscopic interventions in the biliary tract. Enterococci, Klebsiella and Streptococcus viridans were found in bile cultures with an incidence exceeding 10%. In view of the in-vitro test results, possible side effects, and contraindications, amoxicillin plus beta-lactamase inhibitors or quinolones are considered to be suitable antibiotics for the prophylaxis of biliary infections.

Functional impairment of rat enterochromaffin-like cells by interleukin 1 beta.

BACKGROUND & AIMS: Histamine-producing enterochromaffin-like (ECL) cells play an integrative role in the regulation of acid secretion. Decreased mucosal histamine concentrations and increased levels of interleukin (IL) 1 beta, IL-6, and IL-8 have been detected in the gastric mucosa inflamed with Helicobacter pylori. The aim of this study was to investigate the response of isolated ECL cells to these cytokines. METHODS: Enriched rat gastric ECL cells (85%-95%) were cultured for 2-4 days. RESULTS: Polymerase chain reaction showed IL-1 and IL-6, but not IL-8 receptors, in ECL cell complementary DNA. Positive receptor staining with biotinylated IL-1 beta corresponded to ECL cell enrichment (92%). IL-6 and IL-8 had no effect on histamine secretion. IL-1 beta (2 U/mL) stimulated basal histamine secretion and nitric oxide production within 60 minutes and cyclic guanosine monophosphate production within 20 minutes. Pretreatment for 20 minutes with IL-1 beta (2 U/mL) attenuated gastrin-stimulated histamine secretion by 40%-50%, reversed by the IL-1 receptor antagonist (10 U/ mL). Pretreatment for 20 minutes with IL-1 beta (2 U/mL) completely inhibited gastrin-stimulated (1 nmol/L) histidine decarboxylase activity. IL-1 beta (2 U/mL, 60 minutes) increased lactate dehydrogenase release to 25% of cell content. Cells pretreated with IL-1 beta did not respond to gastrin after a further 48-hour culture and showed decreased histamine content. CONCLUSIONS: ECL cells appear to express IL-1 receptors. IL-1 beta causes sustained functional impairment of ECL cells in vitro.

Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (echinacin) in patients with far advanced colorectal cancers: preliminary results.

Outpatients (n = 15) with metastasizing far advanced colorectal cancers received immunotherapy consisting of low-dose cyclophosphamide (LDCY) 300 mg/m2 every 28 days i.v., thymostimulin 30 mg/m2, days 3-10 after low-dose cyclophosphamide i.m. once daily, then twice a week, and echinacin 60 mg/m2 together with thymostimulin i.m. All patients had had previous surgery and/or chemotherapy and had progressive disease upon entering the study. Two months after onset of therapy a partial tumor regression was documented in one and a stable disease in 6 other patients by abdominal ultrasonography, decrease of the tumor markers carcinoembryonic antigen (CEA), CA 19-9, CA 15-3, and/or chest roentgenography, which may also be attributed to the natural course of disease. Mean survival time was 4 months, 2 patients survived for more than 8 months. Immunotherapy was well tolerated by all patients without side effects.

Neuropeptide Y and food intake in fasted rats: effect of naloxone and site of action.

Central administration of neuropeptide Y (NPY) induces food intake in freely feeding animals and this effect is mediated by hypothalamic sites. Little is known, however, about the effect of NPY on food intake and site of action in food-deprived animals. To examine this further, 24-h fasted rats received injections of saline or NPY into the lateral cerebral ventricle (10 micrograms/10 microliters; n = 8) or into the lateral (LH) or ventromedial hypothalamus (VMH) (1 microgram/0.5 microliters; n = 44). In addition, intracerebroventricular (i.c.v.) injections of NPY were carried out with or without i.c.v. naloxone (25 micrograms), a specific opioid receptor antagonist. During the first 40 min food intake was not different with or without NPY. After 60 and 120 min, food intake was 5.9 +/- 0.4 g and 8.3 +/- 0.6 g with i.c.v. saline which was significantly augmented by i.c.v. NPY to 8.7 +/- 0.9 g and 14.4 +/- 1.5 g, respectively (P less than 0.05). This increase in food consumption was due to a prolongation of feeding time. The opioid receptor antagonist naloxone significantly augmented latency to feed, both in the absence and presence of NPY (8.0 vs 1.7 min or 14.7 vs 2.8 min, respectively) and abolished the NPY-induced increase in food intake. Following intrahypothalamic injection of NPY, an increase in food intake (greater than 20%) was observed in 50% of the histologically identified LH and VMH sites, but only in 15% of the injection sites outside the LH/VMH.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil reduces ethanol-induced damage of the duodenal mucosa in humans.

Eight healthy volunteers were studied before and after 3 weeks of dietary supplementation with fish oil (10.5 g day-1, 18% (1.9 g) eicosapentaenoic acid). Duodenal mucosal lesions were induced by instillation of 40 ml ethanol (40%). Mean endoscopic lesion score was lower after fish oil treatment (1.62 +/- 0.32; mean +/- SEM) than before (3.25 +/- 0.31; P less than 0.01). Histologic lesion score fell from 22.75 +/- 1.98 before treatment to 13.50 +/- 1.51 after fish oil (P less than 0.01). Basal and pentagastrin-stimulated gastric acid output remained unaffected. Release of prostaglandin E2, 6-keto-prostaglandin F1 alpha, and thromboxane B2 from biopsy specimens of the duodenal mucosa in vitro was not significantly altered after fish oil ingestion. In the same in vitro system calcium ionophore A23187-induced release of total leukotriene C (LTC) increased from 10.6 +/- 1.5 ng g-1 mucosa 20 min before treatment to 30.4 +/- 3.2 ng after fish oil. High pressure liquid chromatography analysis showed that this increase was partly due to formation of LTC5 as after fish oil 28% of total LTC were identified as LTC5 whereas 72% were LTC4. We conclude that in humans fish oil reduces ethanol-induced damage of the duodenal mucosa without inhibiting gastric acid secretion or stimulating prostaglandin formation. It remains to be clarified if the changes in leukotriene formation are relevant for the mucosaprotective fish oil effect.

Effect of CCK on food intake in man: physiological or pharmacological effect?

The present study was designed to determine in humans the dose of CCK which suppresses food intake. 18 male subjects received in randomized order either i.v. saline or Thr28 Nle31 CCK 25-33 (CCK-9) at 100 or 500 pmol/kgh, respectively. In addition, 7 subjects received CCK together with the opiate receptor antagonist naloxone to examine if activation of endogenous opioids might interfere with the potential satiating effect of CCK. Food intake during saline was 32 +/- 2 sandwiches (mean +/- SEM), during CCK-9 100 pmol/kgh 28 +/- 2 (n.s.) and only 12 +/- 3 during CCK-9 500 pmol/kgh (p less than 0.01). The respective water intake was 730 +/- 70 ml, 590 +/- 60 ml (n.s.) and 320 +/- 50 ml (p less than 0.01). Naloxone further reduced food and water intake during high but not low dose CCK or saline. During saline postprandial insulin levels rose by 49 +/- 6 microU/ml within 45 min which was attenuated during low dose (23 +/- 6 microU/ml; p less than 0.01) and high dose CCK-9 (1 +/- 1 microU/ml; p less than 0.001). Plasma glucagon did not change in control or CCK experiments. The postprandial rise of pancreatic polypeptide was attenuated during high dose CCK. Naloxone had no effect on the hormonal response except for a prolonged reduction of insulin and glucose levels following high dose CCK + naloxone. Plasma CCK levels rose by 5.4 pmol/l in controls but by 55 and 255 pmol/l during the low and high dose CCK infusion, respectively. These data demonstrate that suppression of food intake in man by i.v. CCK is a pharmacological rather than a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of the immune response in outpatients with hepatocellular carcinomas by low doses of cyclophosphamide (LDCY), echinacea purpurea extracts (Echinacin) and thymostimulin.

Outpatients with inoperable far advanced hepato-cellular carcinomas (n = 5) were treated with LDCY--300 mg/m2 i.v. every 28 days-, echinacin--60 mg/m2 i.m.--and thymostimulin--30 mg/m2 i.m., day 3-10 after LDCY, then twice a week. Therapy was well tolerated by all patients. Their Karnofsky' index increased for 10% in the mean. A stable disease for more than 8 weeks was documented by abdominal ultrasonography in one patient. Serum levels of Alpha-Fetoprotein (AFP), Carcinoembryonic Antigen (CEA) and Tissue Polypeptide Antigen (TPA) did not increase in 2 patients. Median survival time was 2.5 months. One patient is still alive after 8 months. Absolute numbers of CD8+ cells significantly (p less than 0.02) decreased for 7% 1 day after LDCY, whereas CD4+ cells increased (p less than 0.02) from day 1-7. Numbers of natural killer (NK-) cells increased for 17% (p less than 0.05), their activity for 90% (p less than 0.05). Activities of peripheral polymorphs (p less than 0.05) increased for 27% and of Lymphokine Activated Killer (LAK-) cells for 180% (p less than 0.05).

Modulation of rat gastric mucosal prostaglandin E2 release by dietary linoleic acid: effects on gastric acid secretion and stress-induced mucosal damage.

We studied chronic intake of diets deficient in or supplemented with linoleic acid to determine whether it affects gastric acid secretion, release of prostaglandin E2, and stress-induced lesions. For 8-10 wk rats were fed three dietary regimens supplying 3.5% (control group), 0.3%, and 10% of total calories as linoleic acid. We found that diets deficient in linoleic acid (0.3%) reduced release of prostaglandin E2 into the gastric lumen (-77%) and increased basal (+133%) and pentagastrin-stimulated acid secretion (+93%) and the area of cold restraint-induced gastric mucosal lesions (+280%), when compared with the control group. Diets supplemented with linoleic acid (10%) increased prostaglandin E2 release into the gastric lumen (+106%) and reduced basal (-44%) and pentagastrin-stimulated acid secretion (-78%) and the area of cold restraint-induced mucosal.lesions (-80%). Prevention of these lesions by the 10% linoleic acid diet was confirmed by quantitative histology. Pretreatment with indomethacin (8 mg/kg intraperitoneally) abolished the effects of the 10% linoleic acid diet on prostaglandin formation, acid secretion, and mucosal injury. We conclude that in rats chronic intake of dietary linoleic acid reduces acid secretion and prevents cold restraint-induced mucosal lesions, possibly because of augmented synthesis of endogenous prostaglandins in the gastric mucosa.

A rare source of occult gastrointestinal bleeding: jejunal filiae secondary to metastatic lung carcinoma.

A case of occult gastrointestinal bleeding due to jejunal metastases of a primary lung carcinoma in a 53-year-old man is reported. When after healing of a large gastric ulcer melena persisted, a subsequently performed double contrast enema of the small bowel revealed evidence of several jejunal tumors. This was confirmed by angiography of the superior mesenteric artery and computed tomography of the abdomen. After resection of the tumor-bearing jejunal loop, histological evaluation revealed metastases secondary to a large-cell bronchogenic carcinoma which had been resected 1 year previously.

Alternating treatment of common bile duct stones with a modified glyceryl-1-monooctanoate preparation and a bile acid-EDTA solution by nasobiliary tube.

Twenty patients with bile duct stones were treated via an indwelling nasobiliary tube with a modified Capmul 8210 preparation (GMOC) and alternating with a bile salt-EDTA (BA-EDTA) solution for an average of 12 days. In vitro the dissolution capacity of GMOC and BA-EDTA for cholesterol stones was higher than that of Capmul 8210. The nasobiliary tube was tolerated well for a maximum of 84 days; this renders us independent of the T-tube. The therapeutic success rate of GMOC was 64%, even though we treated mostly old and large concrements. Side effects occurred markedly less than with Capmul 8210. In patients with acute cholecystitis or cholangitis the clinical course improved under therapy, and there was no deterioration of a chronic condition.