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Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC). Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity. In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively. In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.

Gastric outlet obstruction as a result of gallstone (Bouveret syndrome) is a rare but serious complication of cholelithiasis. In many cases, surgery has been conducted for treatment. In recent years, minimal invasive treatment modalities (e.g. shockwave lithotripsy) have been shown to be effective in some of those patients. Laserlithotripsy has so far been described in two cases with a Rhodamine-6G dye laser. We present the case of a 90-year-old woman with duodenal obstruction due to a huge gallstone. The patient was referred to our hospital because attempts at endoscopic extraction and extracorporeal shockwave lithotripsy had failed. The man was treated successfully in just one session with a new cost-efficient frequency doubled doublepulse Nd:YAG laser (FREDDY) using a total of 5726 laser pulses (120 mJ pulse energy, 10 Hz pulse repetition rate) and recovered rapidly. Laserlithotripsy can be considered an effective non-invasive therapeutic alternative to surgical treatment in Bouveret's syndrome, especially in old or high-risk patients.

In patients with diarrhoea, faecal elastase-1 is used to detect exocrine pancreatic insufficiency. Diarrhoea is defined as85% stool water content.We analysed elastase-1 in 519 stool samples from 310 patients unprocessed as well as after lyophilization in a standard laboratory lyophilizator. Stool water content was calculated by weight difference before and after lyophilization.151 stool samples were classified as 'diarrhoea' (mean stool water content 88.8%); all others had a mean water content of 75.4%. In the 'diarrhoea' samples, elastase-1 levels were considerably higher after lyophilization--with a calculated normal water content of 75% (606 +/- 359 microg/g, mean +/- s)--compared to measurement when unprocessed (279 +/- 151 microg/g; P0.0001). In 16 of the 151 cases (11%), the abnormally low elastase-1 level below 200 microg/g found in unprocessed stools proved normal (200 microg/g) after lyophilization and correction for stool water content.Diarrhoea can result in falsely decreased elastase-1 levels in a number of patients with non-pancreatogenic diarrhoea. Lyophilization is a simple measure by which to determine elastase-1 independently of stool water content. Lyophilization of stool samples can therefore help to prevent wrong positive elastase-1 test results.

Mast cell hyperplasia in the gut is a feature of inflammatory bowel disease (IBD), but the role of mast cells in this disease is still unclear. Since mast cell-nerve interactions might have some impact on intestinal inflammation, the present study investigated whether the neuropeptide substance P causes histamine secretion from human gut mucosal mast cells.Four hundred and eighteen colorectal endoscopic samples from 20 patients with IBD and 10 controls were studied. Colorectal biopsy samples were cultured in an oxygenated medium for spontaneous histamine release or were stimulated with substance P, anti-human immunoglobulin E, and a combination of substance P and anti-human immunoglobulin E. Histamine release was measured using a highly sensitive and specific radioimmunoassay.Substance P failed to induce mast cell activation in histologically normal mucosa from controls. In contrast, mucosal specimens taken from inflamed IBD tissue or from uninvolved Crohn disease tissue showed a considerably enhanced rate of histamine secretion towards substance P, alone or in combination with anti-IgE. Unaffected mucosa with ulcerative colitis appeared insensitive towards substance P.The neuropeptide substance P was shown to preferentially enhance mucosal mast cell mediator secretion in active IBD. Thus, it appears likely that mast cell-nerve interactions are involved in as yet uninvestigated neurovegetative histamine-releasing processes of the gut in IBD.

Risperidone, a widely used atypical and potent neuroleptic drug, is assumed to induce fewer hepatic side-effects than phenothiazine anti-psychotics. Recently, we observed a case of risperidone-induced cholestatic hepatotoxicity. A 37-year-old male developed a rapid increase in liver enzymes and cholestatic parameters after starting treatment with risperidone for paranoid psychosis. Work-up for other potential aetiologies was negative. The results of a percutaneous liver biopsy were consistent with drug-induced liver injury and cholestasis. Over the course of one month after the discontinuance of all anti-psychotic agents, the liver function test results returned to near-normal values. This observation supports the need to monitor cholestatic parameters in addition to liver function enzymes during initiation and the first weeks of risperidone intake.

Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.

Tree-based methods can be used to generate rules for prognostic classification of patients that are expressed as logical combinations of covariate values. Several splitting algorithms have been proposed for generating trees from survival data. However, the choice of an appropriate algorithm is difficult and may also depend on clinical considerations. By means of a prognostic study of patients with gallbladder stones and of a simulation study, we compare the following splitting algorithms: log-rank statistic adjusted for measurement scale with (AP) and without (AU) pruning, exponential log-likelihood loss (EP), Kaplan-Meier (KP) distance of survival curves, unadjusted log-rank statistic (LP), martingale residuals (MP), and node impurity (ZP). With the exception of the AU algorithm (based on a Bonferroni-adjusted p-value driven stopping rule), trees are pruned using the measure of split-complexity, and optimally-sized trees are selected using cross-validation. The integrated Brier score is used for the evaluation of predictive models. According to the results of our simulation study and of the clinical example, we conclude that the AU, AP, EP, and LP algorithm may yield superior predictive accuracy. The choice among these four algorithms may be based on the required parsimonity and on medical considerations.

Many patients with chronic pancreatitis (CP) complain of several types of food intolerance despite elimination of fat and alcohol. Since there are no data on serum immunoglobulin E (IgE) concentrations in CP, IgE concentrations in serum were detected in 97 persons with CP and 50 controls. IgE was analyzed by the use of a highly sensitive fluoro-enzyme-immunoassay. In CP, a significantly raised IgE level (mean +/- SEM; 286.1 +/- 49 KU/L; p0.0001) was detected compared with controls (65.2 +/- 13 KU/L). CP-patients without alcohol consumption and normal exocrine pancreatic function were found to have only slightly elevated serum IgE values (120.2 +/- 54 KU/L), whereas patients with exocrine insufficiency treated with enzyme supplementation showed an IgE level of 153.7 +/- 51 and exocrine insufficient patients without treatment of 261.0 +/- 173 KU/L (p = 0.01). IgE levels were far more elevated in the corresponding groups with continued alcohol consumption (25 g/day). Alcohol consuming patients with CP and normal pancreatic function had a mean serum IgE of 295.0 +/- 114 KU/L, while patients with alcohol consumption and sufficiently treated exocrine pancreatic insufficiency showed a serum IgE of 393.7 +/- 147 KU/L (p = 0.03). Non-enzyme supplemented patients with CP and exocrine pancreatic insufficiency were characterized by approximately 10-fold increased serum IgE (1080.0 +/- 313 KU/L; p = 0.001). Non-allergic, alcohol consuming patients with CP have significantly increased serum IgE values. Since patients without alcohol consumption and normal pancreatic function or sufficiently treated exocrine insufficiency showed clearly lower IgE values than non-compliant patients with manifest exocrine pancreatic insufficiency, these results are compatible with the assumption that a reduced rate of antigen digestion in exocrine pancreatic insufficiency may lead to an increased intestinal antigen load, stimulating an abnormal humoral immune response with IgE production. Alcohol may further contribute to this by damaging the mucosal barrier.

Our aim was to compare color-coded Doppler sonography (CCDS) and quantitative testing of liver function (QTLF) in patients with chronic hepatitis C. In all, 74 patients with chronic hepatitis C and mild fibrosis underwent QTLF, which included aminopyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol clearance (SC), and indocyanine green clearance (ICG). Hepatic artery velocity and resistance index (HA-V, HA-RI) as well as portal vein velocity (PV-V) were measured by CCDS. ABT, GEC, and PV-V were significantly reduced, whereas SC1, ICG, HA-V, and HA-RI showed normal levels. There was a significant correlation between reduction in PV-V only with GEC and ABT. QTLF did not correlate with HA-V and HA-RI. In conclusion, in hepatitis C patients with liver fibrosis, ABT and GEC are decreased significantly, which was paralleled by a reduction of PV-V. Unexpectedly SC1 and ICG, the classical hepatic perfusion parameters, do not correlate with the parameters measured by CCDS.

Quantitative testing of liver function (QTLF) may allow a prognostic assessment of patients with various liver diseases. However, there are insufficient data about patients with liver cirrhosis due to hepatitis C.86 consecutive patients (58 males, 28 females, age: 48.3 +/- 11.7 years) with chronic hepatitis C (HCV RNA pos.) underwent sonographically guided liver biopsy to confirm the diagnosis of cirrhosis. QTLF included aminopyrine breath test (microsomal liver function), galactose elimination capacity (cytosolic liver function), sorbitol clearance (liver plasma flow) and indocyanine green clearance (liver perfusion). Values were correlated with the Child-Pugh classification.55% of the patients (n=47) had cirrhosis of Child-Pugh grade A, 28% of grade B (n=24) and 17% of grade C (n=15). QTLF showed a steady decrease from Child-Pugh grade A to grade B and to grade C. Contrary to markedly reduced tests of metabolic liver function in Child-Pugh grade patients, surrogate tests of hepatic perfusion were at the lower normal limit. All QTLF were significantly reduced in Child-Pugh grade B and C patients compared to healthy controls. Differences between the three Child grades were significant.In patients with cirrhosis due to hepatitis C, QTLF correlated inversely with Child-Pugh grades. Since in cirrhosis of grade A, surrogate tests of hepatic perfusion remained at the lower normal limit, whereas those of metabolic function were decreased, QTLF may be a tool to predict prognosis or complications in early cirrhosis due to chronic hepatitis C.

Liver perfusion has an influence on therapy results in patients undergoing orthotopic liver transplantation (OLT). The objective of the present study was to investigate changes in hepatic hemodynamics in patients after OLT with color-coded Doppler sonography (CCDS).Forty-five consecutive patients were included. The examinations were done before, on postoperative day 1, and then weekly until the patients were discharged. Mean velocity of the portal (PV-V) and splenic (SV-V) veins and the maximum velocity and resistance index of the hepatic artery were determined.After OLT a significant increase in PV-V and SV-V was observed. Twenty-five patients had normal perfusion of the hepatic artery, whereas 16 patients had abnormal flow patterns. In these patients prostaglandin I(2) was used until flow rates normalized. In four patients, CCDS could not detect perfusion of the hepatic artery.CCDS is a suitable method for evaluating hepatic hemodynamics before and after OLT. Changes in blood flow velocities in the liver-supplying vessels are detectable, but perfusion of the hepatic artery is seldom detectable. These observations are of special interest after OLT, where liver circulation has an influence on therapy results.

Is "pulverization" or "fragmentation" the best endpoint of extracorporeal shock wave application in ESWL of gallbladder stones? Has gallbladder motility a potential for the prevention of stone recurrence?Prospective, monocentric study with randomization between the conventional treatment strategy (endpoint of shock wave application: fragmentsor = 4 mm, concomitant oral chemolitholysis) and an intensified treatment strategy (endpoint of shock wave application: Pulverization, no chemolitholysis). Prevention of stone recurrence: At least once per month for one hour after a meal standardized position (back position, lowered chest).34 patients, age 46 +/- 14 years (27 women, seven men) were included (F-ESWL: n = 18; P-ESWL: n = 16). Gallbladder motility, number, size and CT-measured calcifications of stones were comparable for both groups. P-ESWL patients received more shock wave pulses than F-ESWL patients and more treatment sessions. P-ESWL resulted in a better fragmentation and pulverization of stones was reached significantly more often (p0.05). The time period for stone clearance was significantly depending on the fragmentation result (pulverization: 0.7 months vs. fragmentsor = 4 mm: 6.6 months vs. fragmentsor = 4 mm: 8.0 months; p0.01). The stone free rate after twelve months was 87.5% for P-ESWL and 72.2% for F-ESWL (n.s.) and correlated significantly with the fragmentation result (p0.01). Pain sensations during stone clearance were significantly reduced by P-ESWL. Stonefree patients were followed up for 30 +/- 13 months, the total recurrence rate was 7.1%.Aiming for pulverization of gallbladder stones by means of intensified extracorporeal shock wave application is at least equal or in tendency superior compared to disintegration to fragementsor = 4 mm. Gallbladder motility might be useful to prevent gallstone recurrence after successful ESWL.

If non-surgical methods are to be taken into account in the therapeutic decision-making process in cholecystolithiasis, an expanded diagnostic work-up including not only stone parameters but also gallbladder function, is needed. In 2270 patients (1649 women, 621 men; age: 47.2 +/- 14 years) with (suspected) "cholecystolithiasis" attending the special gallstone outpatient clinic at a university medical department within a period of 5 years the diagnostic procedures most commonly used in both the doctor's office and hospital were abdominal ultrasonography (52%/78%), laboratory investigations (28%/39%) and plain films of the biliary tract (27%/39%). In the doctor's office gallbladder function testing took the form of an cholecystogram (17% of the patients); in the hospital ultrasonography to determine gallbladder contractility (38%). With decreasing frequency, the following additional procedures were carried out (office/hospital): CT 3%/19%, esophagogastroduodenoscopy 7%/3%, intravenous cholegram 6%/0.6%, abdominal X-ray 1%/0.4%, ERCP 1%/0.4%, chest X-ray 0.8%/1.6%. Duplicated examinations showed a relevant frequency only for ultrasonography (39% of the cases), laboratory investigations (18%) and plain films of the gallbladder (4%). Pathologic secondary findings were established in 22% of the cases.

The treatment of cholecystolithiasis has changed fundamentally in recent years due to the development of non-surgical techniques (extracorporeal shockwave lithotripsy [ESWL], oral litholysis) and the implementation of laparoscopic cholecystectomy.Retrospective analysis of 2270 patients (1649 women, 621 men; age: 47.2 +/- 14 years) presenting with gallstone disorders in a university medical outpatients department between 1988 and 1992 in order to be instructed as to the most suitable therapy method bear witness to the rapid change in therapeutic procedure. Laparoscopic removal of the gallbladder has virtually supplanted conventional cholecystectomy, and within 5 years the proportionate role of ESWL has declined from 21 to 12%. Over the years, the proportion of patients requiring no therapeutic intervention remained constant (at about 20%). The therapeutic recommendations of the "experts" were implemented in almost 80% of cases. The majority of patients were satisfied with the chosen therapeutic approach (surgery: 93.0%, ESWL: 77.6%), although 44% of ESWL-patients and 36% of surgically managed patients reported complaints which persisted even after completion of therapy. Despite unsuccessful ESWL (residual fragments or recurrent stones) 58/95 (61%) of interviewed patients would again give preference to this non-invasive modality in the event of a renewed therapeutic decision.Only a few years after its introduction, laparoscopic cholecystectomy has asserted itself as the predominant treatment option. But as far as acceptance and preference by the patient are concerned extracorporeal shockwave lithotripsy--as a non-invasive treatment modality--also enjoys high popularity and can be recommended as an alternative to surgery in suitable patients chosen according to the currently established stringent selection criteria.

To investigate the presence of extracellular matrix (ECM) proteins in human bile and gallstones and to determine whether they play a role in gallstone formation.ECM components [procollagen-III-peptide (P-III-P), laminin, and hyaluronic acid] in bile from patients with (n = 22) and without (n = 6) gallstone disease were investigated by immunoassay. Bile, gallstones, and serum were assayed for extracellular matrix components in an additional 19 patients with gallstone disease and gallstones were analysed in a third set of 26 patients. The expression of hyaluronic acid synthetase in bile duct and gall bladder epithelia was investigated by immunocytochemistry.Hyaluronic acid levels were significantly elevated in hepatic and gall bladder bile, but not in the serum of patients with compared with those without gallstone disease (137 versus 81 micrograms/l, respectively; P0.05). No differences were found between hepatic and gall bladder bile. Procollagen-III-peptide and laminin were detected in the hepatic bile of patients in both groups. Laminin levels were higher in gall bladder bile than in serum in all patients and measurable amounts of hyaluronic acid were found in gallstones. The amount of hyaluronic acid was inversely correlated to the volume of the gallstone, i.e., the smallest gallstones contained the highest levels of hyaluronic acid. No procollagen-III-peptide or laminin was found in the gallstones. Immunocytochemistry of the epithelial cells of bile duct and gall bladder mucosa stained strongly for hyaluronic acid synthetase.Hyaluronic acid as a progenitor of ECM can be detected in bile and is significantly elevated in patients with gallstone disease. Small gallstones contain more hyaluronic acid than large stones, suggesting that hyaluronic acid may play a role in gallstone formation, particularly since it is produced by the epithelial lining of bile ducts and is found in gall bladder mucosa.

The efficacy of extracorporeal piezoelectric shock wave lithotripsy in patients with obstructing pancreatic duct stones was investigated.Fifty patients suffering from chronic pancreatitis and obstructing pancreatolithiasis were treated by ESWL (Piezolith 2500). Shock wave treatment was administered, inasmuch as the stones were not extractable by initially applied endoscopic measures.A total of 119 (2.4 +/- 1.4, range 1-7) lithotripsy sessions were conducted; only mild sedation/analgesia was used. Optimum targeting of the concrements in the shock wave focus was achieved in 17 (14%) treatment sessions with ultrasonography only; it was achieved in 65 (55%) cases by fluoroscopy and, in further 37 (31%) sessions by using both localization systems. Stone fragmentation was successful in 43 (86%) patients. Nineteen (38%) patients achieved spontaneous stone discharge after shock wave lithotripsy. In 11 (22%) cases, it was possible to remove all fragments endoscopically; residual fragments remained in 20 (40%) patients. Severe complications attributable to shock wave application did not occur. During follow-up, six patients had to be referred to surgery; two male patients died of specific diabetic complications and pleural mesothelioma, respectively. Thirty-five (90%) of 39 patients whose conditions were followed for 2-50 (20 +/- 14) months reported improvement of their pain sensations. Six (15%) patients required endoscopic treatment, including ESWL in five of those patients, to be repeated due to recurrent formation of calculi in the main pancreatic duct, which was again successful in five of the six patients.Piezoelectric shock wave lithotripsy offers a basis for safe and effective fragmentation of pancreatic stones and facilitates endoscopic procedures. Most of the patients with obstructing pancreatic stones became stonefree and showed a significant reduction of pain.

Gallstone recurrence was evaluated in 184 patients exhibiting complete stone disappearance after successful extracorporeal shock-wave lithotripsy (ESWL) and concomitant oral bile acid therapy. Follow-up examinations conducted 6-43 months after termination of adjuvant bile acid therapy revealed recurrent calculi in 40/184 (21.7%) patients (27 females, 13 males, p0.01; 13 patients with solitary, 27 patients with multiple stones) after a median stone-free period of 11 months (range 1-33 months; mean +/- SD, 13 +/- 8 months). Therefore, an overall probability of stone recurrence of 11.8% was observed 12 months after complete stone disappearance had been confirmed sonographically and bile salt therapy terminated, and a probability of 25.5% after 24 months. Gallstone reformation occurred in 30/146 (20.5%) patients with initially solitary and 10/38 (26.3%) patients with multiple calculi [not significant (NS)]. Only 3/40 (8%) patients with recurrent calculi reported biliary colic. Sonographic gallbladder contractility values acquired at the time recurrent stones were detected did not show any significant differences, compared with the data obtained in the pretreatment examinations; neither were any differences noted between the patients with gallstone reformation and those who remained stone-free. In 20/33 (61%) patients with recurrent stones who opted for further conservative retreatment (ESWL and/or oral litholysis), complete stone disappearance was achieved a second time. The recurrence rates achieved within the first 3 yr after successful shock-wave lithotripsy of biliary calculi cover a range similar to the rates noted after dissolution therapy.

This study assesses the feasibility of pen-based remote data entry and measures the acceptance of such systems by patients and physicians. Three clinical investigators participated in a phase-I/II clinical trial of escalated doses of chemotherapy followed by Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). The study included 20 patients with testicular cancer who were treated at three university hospitals. The patients' data obtained in this trial were recorded and stored on a pen-based computer system. A total of 798 data points were recorded for each patient using 33 electronic forms resembling the paper forms used during an earlier phase of the study. The data recorded include the past medical history, inclusion/exclusion criteria, disease staging, therapy documentation, laboratory values and side effects. Both physicians and patients were interviewed directly after using the pen-based remote data entry system. Patients accepted that their physician was taking notes on an electronic form rather than on paper. All patients noted that a pen-based system is superior to a desktop computer when used during an interview. For the investigators electronic data entry takes additional effort, but time savings are realized later with less data clearing and increased data quality. These benefits are important for the study sponsor as well. In conclusion, pen-based remote data entry is a feasible new mode of recording clinical data with concrete benefits to both investigators and sponsors.

The aim of this prospective, randomized study was to compare two second-generation lithotripters based on different physical principles in patients with gallbladder stones at a single lithotripsy center under the same clinical conditions. Sixty patients with one to three symptomatic gallbladder stones were selected for lithotripsy, either with an electrohydraulic or a piezoelectric device. With both lithotripters, treatment was performed under standard conditions (prone position, sonographic monitoring, sedoanalgesia if necessary, up to 3000 pulses/session, retreatments (maximum, two) if fragments4 mm, concomitant oral chemolitholysis). If no fragmentation could be obtained in the first session, the other lithotripter was used for the following treatments. The two groups did not differ significantly with regard to the anthropometric data or number and size of stones. In contrast to piezoelectric lithotripsy (0%), with the electrohydraulic lithotripter, iv analgesics and sedatives were necessary in all treatments (100%); however, in 11/53 treatments (21%), patients did not tolerate the full session despite maximum medication. The treatment time was nearly twice as long with electrohydraulic (56 +/- 22 min) than with piezoelectric lithotripsy (31 +/- 8 min) (p0.001). With the electrohydraulic lithotripter, used in 20% of the patients, no fragmentation was seen after the first session, and therapeutically adequate fragmentation (or = 4 mm) occurred in only 33%. In contrast, with the piezoelectric lithotripter, the stones were disintegrated in all patients (p0.05); in 50% a maximum fragment sizeor = 4 mm was measured after the first treatment. Whereas in the first months after lithotripsy, stone-free rates were higher with piezoelectric lithotripsy (43% vs. 25% after 1 month; 47% vs. 38% after 2 months; 60% vs. 48% after 4 months; NS), rates of complete stone disappearance were equally high in both groups after 12 months (82%).

Five patients suffering from various diseases were investigated for biliary elimination of aspirin given i.v. (500 mg, n = 3; 1500 mg, n = 1) or orally (500 mg, n = 2). Two bile draining systems, t-tube and naso-biliary tube, were used to collect the bile fluid. The analysis of biliary secretion of salicylates revealed only small amounts of salicylic acid and its conjugates undergoing biliary elimination and subsequent enterohepatic circulation ranging between 0.02 and 1.89% of the given dose (median 0.18%). Urinary recovery was calculated between 22.4 and 101.78% (median 92.27%). From these data it is concluded that biliary elimination and subsequent enterohepatic circulation plays no (aspirin) or only a minor role (salicylic acid) in the excretion of aspirin in man.

Extracorporeal piezoelectric lithotripsy (PEL) with oral lysis (about 7.5 mg/kg urso- and chenodeoxycholic acid as single dose in the evening) was performed, according to a standardized treatment and follow-up protocol, in 219 patients (177 women, 42 men; aged 47 +/- 14 years) with symptoms of gallbladder stones. The average number of treatment sessions per patient was 2.0 +/- 0.8. Significantly fewer sessions with fewer shockwave charges were required in solitary gallstones of less than or equal to 20 mm diameter than in those of greater than 20 mm diameter and in multiple concrements (P less than 0.01). Fragmentation was successful in 99% of patients. Sedation and/or analgesia during PEL were required in only 2% of patients. There were no marked side effects during the treatment. The stone-free rate 12 months after the start of treatment was 76% in the group with solitary stones less than or equal to 20 mm, 75% with solitary stones greater than 20 mm and 64% for multiple stones. During the follow-up period 36% of patients had biliary colics and 3% had fragments impacted in the common bile duct. Biliary pancreatitis occurred in 1% of patients. PEL is an effective and sparing procedure in the treatment of selected patients with gallbladder stones.

In order to determine whether cholecystography and computed tomography (CT) are capable of better gallstone characterization than conventional radiography alone, 91 patients (76 females, 15 males; mean age 47 +/- 12 years) with symptomatic single gallstones were studied prospectively prior to extracorporeal shock-wave lithotripsy with concomitant oral stone dissolution therapy. In addition, the value of oral cholecystography in demonstrating patency of the cystic duct was compared with ultrasound assessment of gallbladder function. Despite "negative" plain gallbladder radiographs in all patients, oral cholecystography showed significant stone calcification in 8 of the 91 patients and CT showed stone calcifications in 52 of the 91 patients. In 12 patients the maximum stone density was between 50 and 90 Hounsfield units, and in 40 patients it was more than 90 Hounsfield units. CT revealed ring-like calcification in the majority (79%) of these stones. Oral cholecystography showed satisfactory concentration of contrast medium in all patients, while ultrasonography of the gallbladder following a chemically defined test meal demonstrated contractility of more than 50% of initial volume in 69 patients and of less than 30% in 9 patients. Although oral cholecystography is a simple, readily available complication-free method, ultrasound assessment of gallbladder contraction is better for selecting patients for extracorporeal shock-wave lithotripsy. CT allows significantly better characterization of gallstones than oral cholecystography and conventional plain gallbladder radiography.

Aspirin shows a high incidence of gastric side effects. These are thought to result from both systemic and local effects during drug absorption. In contrast, a lipophilic derivative of salicylic acid, diflunisal, causes significantly fewer adverse gastric effects. This is thought to be due to a lack of gastric absorption. To test this hypothesis, three types of experiments were performed with diflunisal: 1. Transgastric permeation was quantified under different pH conditions, using an isolated mouse stomach model. 2. Ulcerogenic potencies of buffered and unbuffered drug solutions were determined in rats. 3. The time course of its anti-inflammatory effect and the serum concentrations of diflunisal, given alone and with neutralizing buffer, were measured in rats with carrageenan-induced paw edema. Corresponding to the low gastric ulcerogenicity, absorption of diflunisal in the isolated stomach preparations was very small. However, absorption was pH-dependent and ranged between 0.69 and 8.73% with a maximum at pH 4.5. Gastric lesions were found to be more evident 24 hr after drug administration than after 5 hr. Comparing buffered vs. unbuffered diflunisal preparations, no difference in ulcerogenicity was detectable. However, using a buffered preparation, the anti-inflammatory effect of diflunisal was enhanced significantly (p less than 0.01), and elevated serum concentrations were found (p less than 0.05). The results show that raising the solubility of diflunisal does not influence gastric absorption or gastric toxicity considerably. However, its serum concentrations and systemic anti-inflammatory effects were significantly enhanced.

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.

The present review focuses on some aspects of the function of catechol-O-methyl-transferase (COMT) in the hypothalamic control of gonadotrophin release by the pituitary gland. The in situ influence of a catecholestrogen (2 OH.E2) on the amount of COMT in the hypothalamic nuclei involved in such control as well as on the process of sexual differentiation of the brain is also discussed. Catecholestrogens do not play a significant role in the induction of sexual differentiation and the observed action is probably a pharmacological one. It is difficult to understand why a substance whose structure is so closely related to that of estrogen is so much less active. Most probably the estrogen receptor in the cytosol at this stage of development is not able to recognize the catecholestrogen. Since catecholestrogens are not true virilizing substances they may be used to assess the critical levels of enzymes which are required to determine the sexual pattern of hypothalamic activity. The fact that the extent of the changes in COMT content of the hypothalamus is related to the amount of hormone used to induce virilization strengthens the view that sexual differentiation is the consequence of a genomic change during the critical period, which will induce an enzymatic pattern characteristic of the male acyclic pattern of gonadotrophin control. The finding that the COMT content of the hippocampus also changes in parallel to sexual differentiation leads us to speculate that perhaps sexual behavior may also be differentiated in the same way.

1. An assay using [14C-methyl]-S-adenosyl-L-methionine was used to measure catecholamine-O-methyl-transferase (COMT) activity in the hypothalamus of newborn male and female rats from day 1 to day 12 and in adult animals after day 60. 2. There was no difference in COMT activity between sexes until day 8, when it became significantly higher in females. 3. Administration of 200 micrograms testosterone propionate to female rats at birth reduced the hypothalamic COMT level of the adult to that observed for male littermates. The response was dose-dependent in the range 50 to 200 micrograms. The hypothalamic content of COMT after puberty of male rats castrated at birth was comparable to that of post-pubertal females. 4. These results show that COMT, one of the enzymes involved in the control of brain biogenic amines, is also affected by the process of sexual differentiation of the brain.