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Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6–3.79) for all evaluable patients and 8.4 months (95% CI: 0–18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08–9.31) and 9.4 months (95% CI: 4.82–13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24–15.35) versus 2.7 months (95% CI: 1.03–4.36; P = 0.002), and 9.8 months (95% CI: 3.23–16.37) versus 4.4 months (95% CI: 3.14–5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of

Nonadherence may cause severe health problems in heart transplant (HTx) recipients.The present study aimed to investigate adherence to prescribed medication and recommended lifestyle habits in post-HTx patients and to assess associations between adherence, quality of life (QOL), and psychological well-being.A questionnaire package was sent to all HTx patients from our clinic (n = 858) to answer questions anonymously on medication adherence, dietary recommendations (avoidance of raw animal products and ice cream), pet keeping (risk of zoonosis), anxiety and depression, QOL, and posttraumatic stress disorders.Of the contacted patients, 524 (61%) responded and 505 fulfilled the inclusion criteria (age ≥18 years and ability to understand German). Of the study participants, 72.4% reported taking their medications very correctly, 72.2% stated consuming alcohol less often than once a week, 58.3% performed physical exercise at least once a week, one-third reported eating nonrecommended foods, 22.1% stated pet keeping, and 4.3% reported smoking. Adherence to prescribed medication was positively associated with age ( P.001) and mental QOL ( P = .015) but was unrelated to eating nonrecommended foods ( P.05). Depressiveness correlated inversely with physical QOL ( r = -0.232; P.01) and mental QOL ( r = -0.411; P.01). Stress disorders and minor stressful events were reported by 7.8% and 46.6%, respectively. Stress disorders correlated inversely with mental QOL ( r = -0.282; P.01) and physical QOL ( r = -0.422; P.01).Many HTx patients adhere to prescribed medications and health advice. Nevertheless, nonadherence is a problem, especially in younger HTx patients, indicating the need for a nonadherence crisis intervention program for long-term HTx patients.

Purpose: The purpose of this study was to find out whether pneumothorax detection and exclusion is superior in expiratory digital chest radiography. Materials and Methods: 131 patients with pneumothorax with paired inspiratory and expiratory chest radiographs were analyzed regarding localization and size of pneumothorax. Sensitivity, specificity, negative (npv) and positive predictive value (ppv) as well as the positive (LR+) and negative likelihood ratio (LR-) were determined in a blinded randomized interobserver study with 116 patients. The evaluation was performed by three board-certified radiologists. Results: In 131 patients, there were 139 pneumothoraces, 135 (97.1 %) were located apical, 88 (63.3 %) lateral and 33 (23.7 %) basal. Sensitivity was 99 % for inspiratory and 97 % for expiratory radiographs. The interobserver study yielded a mean sensitivity of 86.1 %/86.1 %, specificity of 97.3 %/93.4 %, npv of 88.7 %/88.5 % and ppv of 96.7 %/92.1 % for inspiration/expiration. For inspiratory radiographs the LR+/LR- were 40.2/0.14 and for expiration 13.9 and 0.15. McNemar-Test showed no significant difference for the detection of pneumothoraces in in-/exspiration. Conclusion: Inspiratory and expiratory digital radiographs are equally suitable for pneumothorax detection. Inspiratory radiographs are recommended as the initial examination of choice for pneumothorax detection, an additional expiratory radiograph is only recommended in doubtful cases. Key Points: • Basal pneumothoraces during inspiration demonstrate a greater width than during expiration. • There is statistically no difference between inspiration/expiration for the diagnosis of pneumothorax. • An image taken during inspiration is recommended to confirm or rule out a pneumothorax. Citation Format: • Thomsen L, Natho O, Feigen U et al. Value of Digital Radiography in Expiration in Detection of Pneumothorax. Fortschr Rontgenstr 2014; 186: 267 – 273

Lymphoid hyperplasia of the intestine has been associated with multiple diseases and symptoms. This study was undertaken to analyze the number and topographical distribution of the lymphoid follicles. A total of 302 adult consecutive patients were enrolled when they underwent elective colonoscopy. Standardized pictures from terminal ileum and colon were taken using video colonoscopes. In each picture, the number, size, and mucosal elevation of lymphoid follicles were analyzed in relation to histological and immunological findings and medical history. Lymphoid hyperplasia was found to be most extensive in the terminal ileum and cecum. Patients with untreated gastrointestinally mediated allergy (GMA) showed the highest number of lymphoid follicles per visible field in the terminal ileum ( P < 0.001) and cecum ( P = 0.003) vs. the control group. Patients with infectious colitis also showed a high number of lymphoid follicles per endoscopic visible field in the transverse colon ( P = 0.020). The presence of lymphoid hyperplasia is a frequent finding during colonoscopy. It may indicate an enhanced immunological mucosal response to antigenic stimulation such as GMA or infection.

To investigate the relationship of strictures of the common bile duct (CBD) with pain in patients with chronic pancreatitis (CP) and jaundice.A total of 61 patients with CBD strictures caused by CP of alcoholic etiology were treated by endoscopic stent insertion for 1 year with scheduled stent exchanges. Pain was assessed using a visual analogue scale, and analgesic medication was recorded prior to and after endoscopic treatment.Endoscopic drainage was successful in all cases, with complete resolution of jaundice during the 1-year follow-up period. Prior to the endoscopic stent insertion, pain scores were 6.8 +/- 6.3. Following stent therapy pain scores were 7.7 +/- 7.7. Pain scores, the number of patients requiring analgesics, the required amount of analgesics, and the type of analgesic medication did not change following treatment of CBD stricture.Successful endoscopic drainage of biliary obstruction has no influence on pain pattern in patients with CP. CBD obstruction does not cause pain in patients with CP.

Reduced pulmonary diffusion capacity is a hallmark of COPD, although the relative contribution of the subcomponents of pulmonary diffusion--membranous component (Dm) and capillary volume (Vc)--is unknown. These components can be measured with the method of NO single-breath diffusion (DLNO). In a prospective study, pulmonary function tests including spirometry, body plethysmography and single-breath measurements of diffusion capacity with CO and NO were performed in 183 patients with COPD of varying severity. There was a severity-dependent decrease in DLCO. Furthermore, Dm as well as Vc was positively correlated with the severity of COPD measured by FEV1. In all stages of COPD, reduction of Vc was more pronounced than constriction of Dm. In patients with most severe COPD, the preponderance of the reduction of Vc was significantly more marked than in milder stages.We conclude that Dm as well as Vc contributes to the reduction of DLCO in COPD, with a predominance of Vc at all stages of COPD. This confirms the idea that the loss of pulmonary capillaries in COPD is functionally relevant.

The present study evaluates the effect of free radicals generated by xanthine oxidase-catalyzed oxidation of hypoxanthine on cellular function of isolated rat pancreatic acinar cells. The results show that a rapid and sustained increase in intracellular Ca 2+ concentration ([Ca 2 +] i ) preceded all other morphological and functional alterations investigated. Radical-induced [Ca 2+ ] i increase was largely inhibited by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, which prevents Ca 2+ release from intracellular stores, but not by Ca 2+ -depleted medium. Radicals released Ca 2+ from thapsigargin-insensitive, ryanodine-sensitive intracellular stores, whereas the secretagogue caerulein at physiological concentrations mainly released Ca 2+ from thapsigargin-sensitive stores. In contrast to effects of the secretagogue, radical-induced Ca 2+ changes did not cause luminal protein secretion but cell death. In single-cell measurements, both secretagogue and radicals induced oscillations of [Ca 2+ ] i . Radical-induced oscillations had a lower frequency but similar amplitude when compared with caerulein-induced oscillations. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and ryanodine, which prevented the radical-induced Ca 2+ increase without altering the generation of radicals, markedly reduced the radical-induced cell damage. These results suggest that the Ca 2+ increase mediates the radical-induced cell injury. The studies also indicate that not only the extent and duration but also the origin of [Ca 2+ ] i release as well as the frequency of Ca 2+ oscillations may determine whether a pancreatic acinar cell will secrete or die.

The square of ultrasound transmission velocity in a material is related to the modulus of elasticity, which is known to be an indicator of stability in bone. The aim of our study was to use ultrasound transmission velocity to obtain information about the material properties of bone tissue, keeping other factors possibly influencing ultrasound transmission as constant as possible. Apparent phalangeal ultrasound transmission velocity (APU) measured in 54 isolated, fresh pig phalanges was shown to be independent of bone mineral density (BMD) measured by SPA. Fastest sound transmission led exclusively through cortical bone so that intertrabecular connectivity in spongious bone could not influence the result. In humans APU was measured in the mediolateral direction at the midphalanx of the middle finger. In 53 healthy subjects (15–81 years old; 27 women, 26 men), there was a decrease of APU with age (r=−0.30, p

Obstruction of bile flow following pancreatoduodenectomy can be caused by stenosis of the hepaticojejunostomy created at the time of surgery, obstruction of the bile-draining jejunal loop, stones or, very rarely, ingested foreign bodies in the common hepatic duct. In analogy with endoscopic sphincterotomy or the once popular side-to-side-choledochduodenostomy, the creation of a hepaticojejunostomy eliminates the barrier of the sphincter Oddi, enabling intestinal content such as ingested foreign bodies or food fibers to migrate into the bile duct. We report on the case of a patient developing biliary tract obstruction due to fibrous material in the common hepatic duct 15 years after pancreatoduodenectomy. In addition, an overview of the literature on the rare phenomenon of foreign body-associated obstructive jaundice is given.

This study was a pre-planned country-specific secondary analysis of results in Germany from a multinational multicenter observational study to retrospectively evaluate clinical outcomes with caspofungin in patients with probable and proven invasive fungal infection following solid organ transplantation (SOT).Data were retrospectively collected on a single episode of invasive fungal infection (IFI) in patients who had a SOT between January 2004 and June 2007. Effectiveness was reported as the proportion of patients who received at least five doses of caspofungin with a favorable (complete or partial) response. Safety was assessed for patients who received at least one dose of caspofungin. Descriptive statistics were employed for all evaluations.A total of 41 SOT patients (27 male, 14 female; median age 56 years, median APACHE II score at start of caspofungin therapy 23) were enrolled from 5 sites in Germany. Organs transplanted were mainly heart (51%) and liver (46%). Prevalent risk factors for IFI at baseline were use of central venous catheter (37 out of 41 patients, 90%), steroid use (37 out of 41 patients, 90%), recent stay in intensive care (36 out of 41 patients, 88%),and duration of SOT procedure5 hours (21 out of 41 patients, 51%). Candidiasis was diagnosed in 34 patients (83%) and aspergillosis in 10 patients (24%). The lungs were the most common site of IFI (21 out of 41, 51%). Caspofungin as monotherapy was received by 28 patients (68%); 6 patients (15%) received caspofungin as salvage therapy for IFI, in most cases because they were refractory to prior antifungal drugs. Immunosuppressants were administered with caspofungin in 39 out of 41 patients (95%). In subjects with at least 5 doses of caspofungin (modified intention to treat population) the favorable response rate at the end of caspofungin therapy was 88% overall, 29 out of 33 patients; 95% confidence interval (95%-CI) 72-97%), 86% (19 out of 22 patients) with monotherapy and 91% (10 out of 11 patients) with combination therapy. No (serious) adverse events or drug interactions related to treatment with caspofungin were reported. The overall survival rate was 79% (26 out of 33 patients; 95%-CI 61-91%) at 7 days after completion of caspofungin treatment.Caspofungin was found to be an effective treatment of probable and proven invasive fungal infections in patients following SOT in Germany.

M. Winkler, J. Pratschke, U. Schulz, S. Zheng, M. Zhang, W. Li, M. Lu, D. Sgarabotto, G. Sganga, P. Kaskel, S. Chandwani, L. Ma, J. Petrovic, M. Shivaprakash. Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study. Transpl Infect Dis 2010: 12: 230–237. All rights reserved Objective This study was designed to determine clinical outcomes with caspofungin in patients with proven or probable invasive fungal infection (IFI) after a solid organ transplant (SOT) procedure. Methods In this retrospective observational study, data were collected for a single episode of IFI in patients with an SOT between January 2004 and June 2007. Response was determined by the investigator as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). The primary effectiveness population was the proportion of patients who received ≥5 doses of caspofungin (modified all-patients-treated population). Safety was assessed for patients who received ≥1 dose of caspofungin. Results A total 81 of patients from 13 sites in China, Germany, Italy, and the United Kingdom were enrolled, including 49 (60%) liver, 22 (27%) heart, 5 (6%) lung, 2 (2%) kidney, 2 (2%) liver and kidney, and 1 (1%) pancreas and kidney recipients. Candidiasis was diagnosed in 64/81 patients (79%) and aspergillosis in 22/81 patients (27%). Most patients received caspofungin monotherapy (75%). Caspofungin was given as first-line therapy to 59 (73%) patients. The overall favorable response at EOCT was 87% (58/67; 95% confidence interval [CI]: 76%, 94%), with favorable responses in 88% (43/49; 95% CI: 75%, 95%) of patients receiving caspofungin monotherapy and 83% (15/18; 95% CI: 59%, 96%) of patients receiving combination therapy with caspofungin (modified all-patients-treated population). Response by type of SOT was as follows: liver 87% (39/45), heart 93% (14/15), kidney 100% (5/5), and lung 50% (2/4). An overall survival rate (all-patients-treated) of 69% (56/81; 95% CI: 59%, 79%) was observed at 7 days post EOCT. No serious drug-related adverse events were reported. Conclusion In this study, caspofungin was effective and well tolerated in the treatment of IFIs involving SOT recipients.

Corynebacterium pseudotuberculosis is the causative organisms of caseous lymphadenitis (pseudotuberculosis) in sheep and goats (Lloyd et al. 1990; Lindsay and Lloyd 1991). This condition is characterized by abscessation of one or more lymph nodes, but sometimes presents as pneumonia, hepatitis, mastitis, arthritis, orchitis and subcutaneous abscesses. Corynebacterium pseudotuberculosis is associated with lymphadenitis in horses and ulcerative lymphangitis in cattle (Sutherland et al. 1993; Aleman et al. 1996; Miers and Ley 1980) and affects rarely in human beings (Peel et al. 1997). Pseudotuberculosis occurs worldwide and it has also been described in camels in several countries (Wernery and Kaaden 2002). Two biotypes of C. pseudotuberculosis, based on nitrate-reducing ability, have been reported and these biotypes can be correlated with different genotype patterns (Songer et al. 1988; Sutherland et al. 1996). Isolates from sheep and goats were nitrate negative whereas those from horses were nitrate positive. Reactions from cattle isolates were variable. Strains that reduce nitrate are referred as biotype equi and strains that fail to do so are referred as biotype ovis. Barakat et al. (1984) found two serotypes referred as type I and type II which corresponded with nitrate reductase negative and positive strains, respectively. In camels, only the serotype I (biotype ovis) has been described in the available literature (Wernery and Kaaden 2002). A study on pseudotuberculosis in camels was carried out in the Canary Islands, using 13 affected dromedaries, and isolating C. pseudotuberculosis biotype ovis in all cases (Tejedor et al. 2004). This communication presents the isolation of Corynebacterium pseudotuberculosis nitrate reductase positive from two camels belonging to the same herd and located in Canaries.

Metacarpophalangeal flexion of the thumb is known to be highly variable. To obtain normative values, active metacarpophalangeal flexion of the thumb was measured bilaterally in healthy Caucasian adults (female n = 403; male n = 366) in a standardized manner. Independent of gender, inter-individual variation was high, ranging between 16 degrees and 90 degrees and showing a continuous decrease with increasing age. Women showed a bigger range of motion than men but in both range of motion was higher on the left thumb (mean 1.4 degrees in women and mean 1.1 degrees in men). No influence of hand dominance was observed. Thus, the healthy contralateral side should be used as parameter of comparison.

Based on hypothesis that calcific tendonitis of the supraspinatus tendon (CTSSP) could be associated with glenohumeral imbalance, glenohumeral stress distribution was analyzed.26 patient shoulders with CTSSP, unsuccessfully treated by non-operative measures, were examined. A group of 26 macroscopically normal shoulder specimens served as controls. Analysis of glenohumeral stress distribution was indirect evaluating glenoid subchondral bone mineralization by computed tomography osteoabsorptiometry. Density distribution of glenoid subchondral bone mineralization and the position of the two most frequent density maxima were analyzed.Patterns of subchondral mineralization and position of the anterior density maximum were significantly different between both groups. CTSSP mostly presented with a monocentric, anteriorly increased mineralization indicative for a regional increase of stress. The inferior shift of the anterior density maximum demonstrates a parallel shift of glenohumeral stress distribution.Mineralization patterns indicate that glenohumeral stress distribution is not physiologic in CTSSP. Moreover, it is comparable with glenohumeral stress distribution as observed in atraumatic antero-inferior glenohumeral instability. Relevance of this observation should be proven for etiology of CTSSP.

The aim of this investigation was the quantification of leukocyte/lymphocyte populations in the peripheral blood of ENT-carcinoma patients before and long after therapy. PROBANDS AND METHOD: PBL T-lymphocytes and NK-cells were examined in 346 patients and 31 controls using flow cytometry. In 248 participants additional populations of leukocytes, monocytes, granulocytes, lymphocytes in toto, CD4+- and CD8+-lymphocytes, CD4+8+-lymphocytes, B-lymphocytes, activated T-lymphocytes, NK-cells and CD3+56+-T-lymphocytes were studied.We demonstrated a long-term reduction in T-lymphocytes (CD4+-lymphocytes) in patients more than 10 years after receiving therapy, caused mainly, but not solely, by radio/chemotherapy. We also showed a long-term, significant increase in NK-cells after more than 10 years in patients following therapy without renewed carcinoma in comparison to controls, patients prior to therapy or patients with a recurrence of carcinoma.Due to long-term deficits in CD4+-lymphocytes, and considering the possible protective effect of NK-cells in treated patients, an immune-supportive therapy is recommended.

Spontaneous or postoperative hemorrhage into the abdominal cavity due to inflammatory vessel arrosion represents an uncommon but menacing situation. According to the literature, such hemorrhage is associated with a lethality of nearly 2%. Therapeutical options include reoperation and interventional radiological techniques such as endovascular catheter techniques with stent graft implantation or the embolization of vessels. We report on the management of seven cases with hemorrhage either from the gastroduodenal artery ( n=5) following pancreatic surgery for pancreatic carcinoma, liposarcoma, and chronic pancreatitis or from the common hepatic artery ( n=1) and the superior mesenteric artery ( n=1) following chronic pancreatitis. The present article describes our experiences with stent graft implantation (hemobahn prosthesis) in four cases. Based on these experiences, we see the advantages of stent grafts in primary hemostasis without any contact to infected tissue and the preservation of regular perfusion. However, further clinical data are required focussing on indication, technical success rates, stent-related complications, and long-term outcome.

The most frequently reported adverse events associated with acetylsalicylic acid intake are minor gastrointestinal complaints. Galenic modifications, such as buffered formulations with or without ascorbic acid, may improve the benefit-risk ratio by decreasing the local mucosal side-effects of acetylsalicylic acid.To assess endoscopically-proven gastrointestinal lesions and the amount of gastric microbleeding of four different buffered and plain acetylsalicylic acid formulations, one containing paracetamol.A randomized, four-fold cross-over study was performed in 17 healthy subjects who underwent serial oesophago-gastro-duodenoscopy before and after each course of 4-day dosing. Gastric aspirates were collected for the determination of haemoglobin concentrations to detect microbleeding.Buffered acetylsalicylic acid plus ascorbic acid yielded the lowest Lanza score, the lowest increase in the number of mucosal petechiae and the lowest increase in the amount of gastric microbleeding. Subjects receiving acetylsalicylic acid plus paracetamol plus caffeine showed the highest Lanza score of all treatments, and a considerably greater sum of petechiae in the oesophagus, stomach and duodenum compared with those receiving buffered acetylsalicylic acid plus ascorbic acid.The trial confirms that buffering of acetylsalicylic acid improves local gastric tolerability. Acetylsalicylic acid in combination with ascorbic acid shows significantly fewer gastric lesions and the lowest increase in gastric microbleeding compared with the other tested formulations.

Obstructive jaundice is a common clinical sign in patients with pancreatic cancer. 52% of all patients with a potentially resectable pancreatic cancer suffer from painless obstructive jaundice. There are no prospective studies showing a beneficial effect of preoperative drainage in patients with resectable pancreatic cancer. Morbidity (53%) and mortality (15%) in patients without preoperative biliary drainage are not significantly different from those who had endoscopic drainage preoperatively (morbidity 41%; mortality 15%). However, there are some logistic reasons for preoperative drainage, especially if surgery is delayed. In cases of nonresectable pancreatic cancer endoscopic drainage for palliation of obstructive jaundice is the method of choice. The decision between metallic and plastic stents for palliation is based on expected survival time and quality of life. Implantation of metal stents is the method of choice in patients with life expectancy exceeding six months. Scheduled three months exchange of plastic stents is recommended to avoid complications. After a six months interval about 70% of patients with scheduled exchange are without symptoms, compared to about 40% of patients who had exchange of plastic stents on demand. Scheduled three months exchange of plastic stents leeds to a patency rate of plastic stents comparable to those of metallic stents.

To determine the intraobserver reproducibility and interobserver reliability of DePalma and Kruper's classification of calcific tendinitis of the rotator cuff. The result of this classification influences the choice of therapeutic procedures in patients with symptomatic calcific tendinitis.Plain anteroposterior radiographs of shoulders from 100 patients with symptomatic calcified deposits of the rotator cuff were classified according to the criteria of DePalma and Kruper by 6 independent observers at 2 different time points within 4 months. The kappa values of intraobserver reproducibility and interobserver reliability were calculated.Kappa values of intraobserver reproducibility had a mean of 0.487 (SD 0.094); kappa values of interobserver reliability were 0.234 for the first test and 0.273 for the second test.Determination of intraobserver reproducibility gave satisfactory to sufficient results and interobserver reliability was satisfactory for both tests indicating that studies based on the classification of DePalma and Kruper should be interpreted cautiously.

The roentgenologic morphology of symptomatic calcified deposits of the rotator cuff can be classified according Gärtner. This classification influences therapeutic procedures and prognosis of clinical outcome in these patients. In the present study intraoberserver-reproducibility and interobserver-reliability of Gärtner's classification were tested.Plane radiographs of 100 patients with calcifications of the supraspinatus tendon were classified according the criteria of Gärtner by 6 independent observers twice within 4 months. Intraoberserver-reproducibility and interobserver-reliability were calculated by means of Cohen's kappa-index.kappa-values of intraoberserver-reproducibility had a mean of 0.4208 (SD 0.1299), kappa-values of interobserver-reliability were 0.490 for the first and 0.474 for the second classification.Determination of intraoberserver-reproducibility gave insufficient to satisfactory results, interobserver-reliability was sufficient. The clinical use of Gärtner's classification to plan therapeutic procedures or to determine clinical prognosis in patients with calcifying tendinitis can be recommended only with limitations.

The sublabral foramen is considered to be a clinically asymptomatic, isolated variant of the anterior-superior capsulo-labral-complex. It may be observed during shoulder arthroscopy and may implicate problems in differential diagnosis of traumatic lesions. In an anatomic study on 89 macroscopically healthy shoulder specimens the age distribution and the incidence in relation to the varying shape of the glenoid as feasible factors of influence for a sublabral foramen (SF) were analyzed in order to elucidate the unknown pathogenesis of SF. In addition histologic sections of three SF samples were obtained. Mean age of the specimens with a sublabral foramen [n=20; 69 (37-84) years] was significantly higher (p=0.04) compared to samples without a sublabral foramen [n=69; 59 (18-94) years]. An increased incidence of a sublabral foramen in relation to a distinct shape of the glenoid could not be established although a prevalence of a glenoid with anterior notch was observed. The results indicate an age-related development of the sublabral foramen,thus in younger patients with an anterior-superior capsulolabral displacement local signs of trauma and involvement of the biceps anchor should be controlled before definitive diagnosis.

Open surgical removal of calcifications in chronic courses of calcifying tendinitis of the shoulder can be combined with acromioplasty. Independent of the surgical procedure not all patients achieve satisfactory surgical results. The aim of the study was to investigate whether preoperatively known epidemiologic, social, clinical and radiologic factors or intraoperative findings might influence the therapeutic outcome.Following diagnostic arthroscopy, open removal of the calcifications was done as an isolated procedure (group A, n = 12) or combined with open acromioplasty (group/B, n = 24). Follow-up was 33 months for both groups.Clinical outcomes were comparable in both groups (Group A, 74.9 points; Group B 73.4 points, Constant-Murley score) and independent of gender, age, profession, duration of anamnesis, hospital-stay period, follow-up period, dominance of arm, preoperative Constant-Murley score, calcification morphology and size and acromial type. 20 patients in total achieved a clinical outcome of/= 75 points (Constant-Murley score). 12 of these demonstrated lesions of the rotator cuff and joint cartilage combined with synovialitis. In 6 patients an adverse preoperative Constant-Murley score or the wish to receive a pension was recorded.Both surgical procedures lead to overall good and satisfactory clinical results. Below average clinical outcomes are associated with pathologic findings of the glenohumeral joints, adverse preoperative clinical situation or the wish to receive a pension.

Extracorporeal shockwave application (ESWA) is in clinical use to promote disintegration of symptomatic calcifications of the rotator cuff of the shoulder. However, disintegration of roentgenologically comparable calcifications of the rotator cuff is not always successfull. It is known from urologic stone lithotripsy that the susceptibility for disintegration of stone-like concrements depends on their mineral content. Therefore, in the present investigation the relative contents of calcium and phosphorus in rotator cuff calcifications were determined.39 surgically removed rotator cuff calcifications were analyzed by means of atomic emission spectrometry.The relative content of calcium of the rotator cuff calcifications was found to be 22.3 % +/- 5.7 % (mean +/- SD; 6.8 % - 32.4 %), that of phosphorus as 10.5 % +/- 2.4 % (2.7 % - 14.4 %). The data neither depend on the gender of the patients nor on their age at the time point of surgical removal of the rotator cuff calcifications.Roentgenologically comparable calcifications of the rotator cuff demonstrated distinct individual differences concerning the relative contents of calcium and phosphorus. The present results may serve as the first indication that the susceptibility of rotator cuff calcifications for disintegration may depend on their relative contents of calcium and phosphorus.

The pancreas of 24 male Wistar rats was perfused extracoporally by modified Krebs-Ringer-buffer for 80 minutes (including a 20 minutes equilibration period). To verify any organ damage we measured the activity of pancreatic enzymes like amylase, lipase and lactatdehydrogenase in the portal effluent. Furthermore histological changes were analysed after perfusion. Organ damage was induced by adding cerulein in a physiological dose (10(-10) M, n = 6) and in a supramaximal dose (10(-8) M, n = 6) and by intraductal injection of taurocholate (3.5 %, n = 6).Already 10 minutes after stimulation with cerulein (10(-8) M) and after intraductal injection of taurocholate increased activities (p0.01) of amylase and lipase were measured in the portal effluent compared to the group without any treatment. Lactatdehydrogenase levels did not changed. Apart from marked oedema in both groups considerable zones of necrosis could be noticed especially in the taurocholate group.Our data suggest that the isolated perfused rat pancreas (IPRP) is a valuable experimental tool to verify pathophysiological changes in the early phase of acute pancreatitis (AP). Various established models of AP such as by cerulein hyperstimulation or intraductal injection of taurocholate, could be applied to the IPRP. We conclude that this method enlarges the spectrum of established experimental models of acute pancreatitis.

External perfusions of the pancreatic glands of Wistar-rats were done, using a modified Krebs-Ringer-Buffer (KRB). We looked for an elevation of amylase, lipase and lactate-dehydrogenase in the effusion fluid (portal outflow fluid). We investigated a normal perfusion (KRB, 60 minutes), a long term perfusion (KRB, 240 minutes) and a perfusion (60 minutes) including an additive of the detergents triton x-100 or the cholecystokinin analogue ceruletid (10(-8) M).An isolated external perfusion of a rat pancreas is possible without inducing any increase of parameters of damage such as amylase, lipase or lactate-dehydrogenase in the outflow medium. The perfusion time should be limited to 80 minutes including a 20 minutes equilibration period. A damage of pancreatic parenchyma is indicated by increased levels of pancreatic enzymes in the perfusion medium. Such damage can be induced by various noxious substances like detergents or cerulein, which has a significance in the pathophysiology of experimental acute pancreatitis. A significant increase (p0.01) of lactate-dehydrogenase, lipase and amylase was found 10, 20 and 30 minutes after an application of triton x-100. During a perfusion with the cholecystokinin analogue ceruletid (10(-8) M) we found an increase of lipase (p0.05) after 30 minutes and an increase of amylase (p0.05) after 50 minutes perfusion.The isolated perfused rat pancreas is a valuable experimental model to investigate the early phase of pathophysiology in acute pancreatitis.

Stromal tumors of the gut (GISTs) have rarely been analyzed for genetic alterations. This study aimed at determining telomerase activity and the expression of the telomerase subunits human telomerase reverse transcriptase (hTRT) and human telomerase RNA (hTR) in GISTs and extragastrointestinal neurogenic or myogenic sarcomas. Telomerase activity was investigated using the telomeric repeat amplification protocol assay in 21 GISTs, recurrences and liver metastases from 16 patients, and in 22 leiomyosarcomas and 21 malignant peripheral nerve sheath tumors (MPNSTs), which served as reference tumors. Expression of hTRT and hTR mRNA was investigated using reverse transcription-PCR. Thirteen GISTs were localized in the stomach and three in the small intestine. Two tumors were benign. In one case, the biological behavior was uncertain. In 67% of GISTs, high telomerase activity was found, whereas high activity was noted in only 18% of leiomyosarcomas and in 48% of MPNSTs. There was no activity in two benign and two malignant GISTs. In one malignant tumor of the small intestine, the primary tumor showed no activity at first but a marked activity in its recurrence. In the tumor with uncertain behavior, telomerase activity and hTRT expression were only weak. In all GISTs showing telomerase activity, the catalytic subunit hTRT was expressed. All GISTs and extragastrointestinal sarcomas expressed hTR. In comparison with leiomyosarcomas and MPNSTs, malignant GISTs showed a higher telomerase activity, which, however, was not seen in benign GISTs. It is possible that telomerase activity occurs during the progression of malignant GISTs. There was a correlation between telomerase activity and the expression of hTRT.

Differential display is a valuable tool for the identification of differentially expressed genes in human carcinogenesis and development. The search for differentially expressed genes in gastric cancer and its premalignant lesions may help to define molecular alterations in the gastric mucosa that may precede the development of gastric cancer. Using the differential display technique, we identified a cDNA fragment, encoding metallothionein (MT) IIa mRNA. We performed immunohistochemical analysis using a monoclonal antibody directed against human MT and tissues obtained from 34 patients with gastric cancer and 20 healthy individuals to determine the expression and localization of MT in gastric cancer and its associated premalignant lesions and to correlate our findings with histomorphological features and Helicobacter pylori status. In addition, MT expression was assessed in gastric tissues obtained from patients with gastric cancer and first-degree relatives of patients with gastric cancers and healthy individuals using reverse transcription-PCR analysis. Northern blot analysis confirmed the overexpression of MT IIa in gastric cancer. In the normal gastric tissues, no MT immunoreactivity was observed at the superficial gastric epithelium toward the top of gastric glands. However, MT immunoreactivity was detected at the foveolar neck of the gastric glands. Immunohistochemical analysis revealed an intense MT immunoreactivity in gastric cancer cells, independent of tumor stage, grade of differentiation, or tumor type. Furthermore, areas of dysplasia and intestinal metaplasia also exhibited intense MT immunoreactivity. Reverse transcription-PCR analysis of gastric biopsies obtained from first-degree relatives of patients with gastric cancer revealed the frequent expression of MT Ia in this high-risk group as compared with healthy subjects (P0.01). The overexpression of MT in gastric cancer and the expression of MT in intestinal metaplasia and dysplasia, as well as the expression of MT in the gastric mucosa of first-degree relatives of patients with gastric cancer, point to a role for MT in the early process of malignant transformation of the gastric mucosa.

Hepatic metastases after a Wilms' tumor in adult patients are seen extremely rarely. A 21 year-old male patient developed liver metastases 13 years after resection of a primary left extrarenal Wilms' tumor. In this case, without any other metastases, extended right curative hepatic lobectomy was performed. The patient was re-admitted 4 months after the hepatic lobectomy for a resection of a new Wilms' tumor metastatic mass in the area of the pancreatic tail. The patient received adjuvant high dose systemic chemotherapy with ordinary bone marrow cell rescue after the 2nd operation. He is alive and well with no signs of new metastases 18 months after surgery and adjuvant chemotherapy.

Oral drug treatment of detrusor overactivity often causes undesirable side effects in other organs. For some patients, in particular those with neurogenically induced detrusor overactivity (detrusor hyperreflexia), the tolerance level for adverse effects is low and oral treatment may become ineffective. Intravesical administration of the drug can diminish the side effects or increase treatment effectivity in patients who are (partially) refractory to oral treatment because the relative concentration of the drug is increased in the target organ and decreased in the circulation. Six men (19-34 years old) with traumatic spinal cord lesions between C2 and Th11 were randomized to intravesical instillation with 15 or 30 mg trospium chloride in 40 ml saline into the empty bladder. Catheterization was postponed until at least 3 h after instillation, and fluid intake was not allowed during the first 4 h. Blood samples were taken before and 11 times after instillation; the last sample 12 h post instillation. Four positive samples were found in three patients: 0.10 ng/ml after 1 h and 0.13 ng/ml after 2(1/2) h in two patients with 15 mg, and 0.24 ng/ml after 30 min and 0.70 ng/ml after 6 h in one patient with 30 mg instilled trospium chloride. Three adverse effects were reported and were rated as probably not related to the drug. It is concluded that intravesically instilled trospium chloride is not absorbed into the circulation in significant amounts and, thus, it may be expected that this mode of administration will improve the efficacy of trospium chloride therapy by reducing the side effects. Neurourol. Urodynam. 18:447-453, 1999.

With ongoing development of minimally invasive surgery the laparoscopic techniques are increasingly used also in patients with intra-abdominal inflammatory diseases. The systemic sequelae of laparoscopy are not yet clear. In this study, we investigated three experimental models of peritonitis in rats (cecal ligation and puncture n = 14, cecal stent peritonitis n = 14, implantation of a standardized fecal inoculum n = 18) concerning the therapeutic potential of laparoscopy, reproducibility of the results and clinical relevance (elimination of the inflammatory focus, intraperitoneal modulation of inflammation). The peritonitis model of implantation of a standardized fecal inoculum was shown to be the experimental model with the closest clinical relevance. In this technically simple, reproducible model, the primary inflammatory focus can be eliminated by laparoscopic lavage. A significant difference (p0.002) of survival between the groups with and without laparoscopic lavage was found. In addition, the intraperitoneal application of drugs is possible in order to modulate peritoneal and systemic inflammation.

Gastrointestinal stromal tumors (GIST), which form a rare group of neoplasias of the gastrointestinal tract, have not yet been fully investigated. Although good progress has been made in their diagnosis, classification of these lesions with regard to their histogenesis and biological behavior remains problematic. Between 1994 and 1998, 18 GIST patients underwere operation in the Department of Surgery. Twelve of these patients (67%) had stromal tumors in the stomach, and six (33%) had intestinal stromal tumors. The primary tumor could be removed in all patients with R0 resection. Six patients developed hematogenous liver metastasis, with the size of their primary tumor exceeding 10 cm. Extrahepatic distant metastases were not found in any case. Lymphadenectomy showed that lymph node metastases did not occur. Histological evaluation was made according to the guidelines of Lewin, Weinstein and Riddell. Currently established therapy is limited to complete surgical resection of the primary tumor and its metastases. Adjuvant or neoadjuvant chemotherapy approaches have failed.

In an open, randomized four-period crossover study in 24 healthy male volunteers a newly developed tramadol (CAS 27203-92-5) sustained release capsule with and without concomitant food intake and an instant release formulation were administered. Additionally, a sustained release tablet was applied as further reference substance. Statistical analysis of AUC(0-infinity) and Cmax after logarithmic transformation yielded bioequivalence of tramadol sustained release capsules with and without concomitant food intake. Therefore, lack of food interaction could be concluded. The investigation also showed an only slightly diminished bioavailability of the tramadol sustained release capsules compared to the instant release formulation. Furthermore, the sustained release capsules investigated showed enhanced retardation at almost identical bioavailability compared with the sustained release competitor drug.

The relationship between the dose and the pharmacokinetic characteristics. AUC(0-infinity) and Cmax was investigated with respect to linearity in 12 healthy male volunteers. Single doses of 50 mg, 100 mg and 200 mg tramadol (CAS 27203-92-5) hydrochloride were administered as sustained release capsules in an open, randomized three-period crossover study. Tramadol plasma concentrations were determined by a validated gas chromatography method. Statistical analysis after logarithmic transformation of the dose-adjusted characteristics mentioned above yielded bioequivalence for all doses applied. Therefore, dose linearity for the range investigated could be concluded.

In an open, randomized two-period crossover study in 24 healthy male volunteers multiple doses of tramadol (CAS 27203-92-5) test and reference medication were administered as follows: Test: sustained release capsules containing 100 mg tramadol hydrochloride, a total of 6 capsules at intervals of 12 h; Reference: instant release capsules containing 50 mg tramadol hydrochloride, a total of 12 capsules at intervals of 6 h. As a result of the statistical analysis of AUCss(48-72 h) after logarithmic transformation a bioavailability of 100% for the sustained release capsules compared with the instant release capsules was obtained. As expected statistical analysis of the peak trough fluctuation at steady state PTFss(48-72 h) yielded a distinct diminution of the fluctuation.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis has been suggested as a model for acute pancreatitis (AP), which allows evaluation of early alterations in the time course of the disease. The influence of the clinical course on procalcitonin (PCT), serum amyloid A (SAA), and several proinflammatory and inhibitory cytokines was evaluated in patients with AP following ERCP. Blood samples were prospectively collected from patients undergoing ERCP. The incidence of ERCP-induced pancreatic damage, defined as abdominal complaints, a threefold increase of serum lipase, and elevation of CRP from10 to20 mg/liter was 12.8% (12/94). Only mild clinical courses of acute pancreatitis were observed. PCT significantly increased in subjects with post-ERCP pancreatitis after 24 hr. However, PCT levels did not exceed 0.5 ng/ml in any patient. Interleukin-1 receptor antagonist (IL-1RA) began to differ from baseline 2 hr after ERCP, followed by interleukin-6 (IL-6, 6 hr), solubilized tumor necrosis factor-alpha receptor II (sTNF-alphaRII, 24 hr) and SAA (24 hr). Interleukin 10 (IL-10) showed marked interindividual variations with no obvious peak. Among all parameters evaluated, only peak values of IL-6 and IL-10 showed significant correlations with the reported pain score (r2 = 0.62/0.78), degree of ampullar irritation (r2 = NS/0.87), and the duration of ERCP (r2 = 0.58/0.76). No correlation was found with the volume of the injected contrast agent. We conclude that IL-10 and IL-6 appear to be useful to monitor patients after ERCP. The absence of any PCT elevation in the present study is in accordance with the clinical course of the patients who suffered from mild pancreatic damage without systemic or infectious complications.

Two open, randomized cross-over trials were performed in 18 healthy volunteers each to evaluate the relative bioavailability and the pharmacokinetics of chloral hydrate (CAS 302-17-0), the active ingredient of Chloraldurat 500 (immediate release capsules, CH), Chloraldurat rot (immediate release capsules, CR) and Chloraldurat blau (enteric-coated modified release capsules, CB). In the first study the male subjects, aged 21 to 31 years, were randomly given one capsule of CH or 500 mg of chloral hydrate as drinking solution. In the second study the volunteers, aged 20 to 28 years, received either one capsule of CR or one capsule of CB or 250 mg of chloral hydrate as drinking solution. The time of administration was between 6:30 and 7:30 a.m. and the capsules had to be swallowed with 150 ml water. The reference medication consisted of 150 ml drinking solution. The wash out time in both studies was 4 weeks. Prior to the administration and (2, 4, 6, only for CH) 8, 10, 15, 20, 40, 60 min and 1.5, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, 192, 240 (and 408 only for CR/CB) h afterwards blood samples of 4.5 ml were taken from the antecubital vein. Additional 4.5 ml were drawn before and 10, 20, 40 and 60 min after administration to detect unchanged chloral hydrate. In the second study times of blood sampling were modified up to 4 h after administration due to the estimated later onset of release from CB in comparison to CR. Blood samples were centrifuged within 20 min, the plasma was separated and immediately frozen at -20 degrees C. Due to the extremely short terminal half-life of chloral hydrate its active metabolite trichloroethanol is regarded as the pharmacokinetically relevant parameter for the assessment of the bioavailability of the parent substance. Compared to the reference formulation (drinking solution) the bioavailability of trichloroethanol was 94.8% (CH), 100.7% (CR) and 101.6 (CB), respectively. The maximum plasma concentrations (Cmax) of trichloroethanol were 5176 ng/ml after intake of CH (reference 6131 ng/ml), after intake of CR 3241 ng/ml and CB 3279 ng/ml (reference 2993 ng/ml). Maximum plasma concentrations (tmax) of trichloroethanol were reached after 0.67 h (reference) and after 0.98 (CH), 0.76 (CR) and 2.38 h (CB), respectively. The terminal half-life for trichloroethanol was calculated to be 9.3 to 10.2 h, for the inactive metabolite trichloracetic acid the half-life ranged from 89 to 94 h. Chloral hydrate itself could be detected only 8 to 60 min after application at very low concentrations in some of the plasma samples. It is justified to characterize its bioavailability by the active metabolite trichloroethanol due to the extremely short terminal half-life and high variability of the parent substance.

Chloral hydrate (CAS 302-17-0) is a widely used hypnotic and sedative agent. It was recently reported in the literature that a neurotoxin, TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), may be formed in vitro from tryptamine (Ta) and chloral (Clo). Intraperitoneal administration of TaClo led to parkinson-like symptoms in the rat. Hence, the plasma levels of TaClo were determined at various time-points in 18 healthy volunteers in two periods each during a bioavailability study of several chloral hydrate preparations. The limit of quantitation for TaClo was 5 ng/ml. No TaClo could be determined in the plasma of the various volunteers following administration of human therapeutic doses of chloral hydrate. Hence, it is unlikely that TaClo will be formed in man after application of therapeutic doses of chloral hydrate to patients.

The pharmacokinetics of a multiple-unit carbamazepine slow-release preparation were studied after a 12-hour fast and after a standardized breakfast in 24 healthy male volunteers. There was a small increase in mean values of AUC0-infinity and Cmax when the drug was given with food. The rate of absorption of slow-release carbamazepine, as reflected by HVD, appeared to be unchanged in the presence of food. Bioequivalence was concluded for the AUC0-infinity and HVD ratios applying the inclusion rule, thus demonstrating the lack of food interaction. The results indicate that administration of the investigated carbamazepine slow-release formulation to patients in the fasting or nonfasting state seems not to be a major consideration when deciding on the regimen.

Free radical-mediated injury is believed to play a key role in the pathogenesis of acute pancreatitis (AP). Therefore, oxidative damage of proteins may be an important event in the development of AP. The present study was performed to investigate oxidative protein modification, quantified as 2,4-dinitrophenylhydrazine-reactive protein-carbonyls, during the time course of taurocholate-induced pancreatitis of the rat and to analyze oxidatively modified proteins by Western blotting. Protein modification in pancreatic homogenates was found as early as 30 min after induction of severe AP with 3% taurocholate preceding the elevation of serum amylase activity and the increase of malondialdehyde in the tissue. A correlation of protein-carbonyl contents to a score of pancreatic macroscopic alterations (r = .69) and to the wet weight/dry weight ratio (r = .65) was found. Infusion of 5% taurocholate resulted in fulminant AP with high lethality during the 24 h of the experiment. However, rats surviving showed significantly lower level of protein-carbonyls than animals that died between 20-24 h after AP induction. The quantitative data were confirmed by the intensity of immunostained protein-carbonyls. The present data show a rather uniform increase in the staining pattern not revealing single, selectively damaged proteins. The aldehydic product of lipid peroxidation 4-hydroxynonenal (HNE) is known for its reactivity towards proteins. Interestingly, an antibody raised against protein-bound HNE did not indicate an increased protein modification by this aldehyde. In conclusion, experimental AP is characterized by an early oxidative protein modification, possibly contributing to functional impairment of the pancreas. This protein alteration may not be mediated by HNE.

A prospective multicenter trial was performed to evaluate survival, patterns of relapse, and toxicity for clinically staged patients with lymph node centroblastic-centrocytic (cb/cc) lymphomas in Stages I-IIIA after large extended field irradiation (EFI) or total central lymphatic irradiation (TCLI).Between January 1986 and August 1993, 117 adults with clinical Stage I-IIIA lymph node cb/cc lymphoma (Kiel classification) were recruited. Patients in Stages I or II with mediastinal, hilar, periaortic, iliac, or mesenteric involvement and in Stage IIIA received TCLI, whereas patients with more peripherally located cb/cc lymphomas were treated with EFI. TCLI and EFI were administered to a total dose of 26 gray (Gy) with 2 Gy per daily fraction, with the exception of the whole abdomen, which was irradiated to a total dose of 25.5 Gy with 1.5 Gy per fraction. A boost of 10 Gy with 2 Gy per fraction was administered to enlarged and involved lymph nodes at the start of radiotherapy.Sixty, 40, and 17 patients had Stage I, II, and limited IIIA disease (no bulk and less than 6 involved lymph node regions), respectively. Overall survival was 86% at 5 and 7 years; median follow-up was 68 months. The probabilities of relapse at any site, recurrences in lymph nodes, and in-field lymph node recurrences after TCLI were 17% in Stage I; 56%, 43%, and 40% in Stage II, respectively; and 44%, 35%, and 35% in Stage IIIA, respectively. The risk of disseminated extralymphatic relapses was 9% at 7 years. The most important adverse prognostic factor for in-field lymph node recurrences was a deviation of20% from the assigned total radiation dose. After EFI, patients in Stage I had a significantly lower risk of recurrences in adjuvant irradiated lymph node regions than in unirradiated lymph node regions. Acute toxicity of EFI and TCLI was moderate.In-field lymph node recurrences remained the main risk after TCLI, and a deviation of20% from the assigned radiation dose was the major risk factor for in-field recurrences. From these data, a total dose of 40-44 Gy in conventional fractionation for the treatment of macroscopic cb/cc lymphomas and 30 Gy for the treatment of subclinical disease is recommended. A randomized study comparing TCLI with EFI is now being organized by this group.

We studied the stress hormone response to surgery in 42 infants and children. Plasma levels of the stress hormones ACTH, cortisol, beta-endorphin and arginine-vasopressin (AVP) were determined on three occasions, i.e., one day before surgery, 60 to 90 minutes after skin closure and on the day after surgery (anesthesia by halothane and nitrous oxide). We observed an increase in the levels of both ACTH and cortisol in most patients after surgery, although there was no correlation between them. Beta-endorphin levels, on the other hand, rose after surgery and correlated significantly with ACTH in 30 patients. A steep rise in AVP levels was found in 84% of the subjects, a phenomenon that could not have been due only to osmotic or cardiovascular stimuli. The values of all the stress hormones declined and normalized on the day after surgery. We conclude that routine surgery in infancy or childhood induces a dramatic, albeit transient, stimulation of neuroendocrine stress hormones.

In central precocious puberty (CPP), characterised by premature but otherwise normal puberty, the early onset of the pubertal growth spurt with increased height velocity results in premature epiphyseal closure with reduced final height. We examined the growth pattern in 11 patients (9 girls and 2 boys) with CPP treated with a long-acting gonadotropin-releasing hormone analogue (GNRHa). Every 28 days 75 micrograms of the GNRHa Triptorelin (Decapeptyl CR, Fa. Ferring) per kg body weight are given intramuscularly. We observed body height, height velocity, bone maturation (dBA/dCA) and predicted adult height in these patients for up to 4 years. Before treatment body height was markedly elevated (2.5 +/- 4.4 SD above the age appropriate mean); after two years of therapy it reached the normal range. Height velocity decreased significantly within the first six months of treatment and remained subsequently low (F = 7.59; p0.0001). In the first year on treatment bone maturation (dBA/dCA) dropped from 1.8 +/- 0.42 to 0.7 +/ 0.27 and in the second year to its lowest value of 0.3 +/- 0.13 (F = 2.35; p0.05). The predicted adult height increased from 154.5 +/- 4.0 cm at the beginning of treatment to 160.3 +/- 3.9 cm at the most recent follow-up examination. The present data indicate that treatment with a long-acting GNRHa markedly affects body growth in CPP by reducing height velocity and delaying bone maturation. The predicted adult height appears to increase, consequently.

In an open, randomized change-over study the steady state profile of two theophylline (CAS 58-55-9) sustained-release preparations (Theophyllard resp. reference preparation) in 24 healthy volunteers was evaluated with respect to AUC, Cmax, Cmin, and tmax. Cmax of the test preparation is higher than that of the reference. During the daytime the adjusted Cmax-values are about 25% higher than the Cmax-values of the reference, during the night they are 10% higher. Tmax of the test preparation is 6 h; tmax of the reference is 5 h.

Based on a standardized technic and reliable attachment of the presented structures the suitability of spinal sonography as a screening-method in newborns and infants should be estimated.Enabled by the comparison of sonographic transverse and sagittal plains with identical anatomic sections of an infant corpse the anatomic structures of an healthy spine were associated, which was verified in the clinical use later on.Exemplary photographs of a collective of 50 newborns and infants reproduce the presentation of the spine found in the preparation of the corpse. The technical practicability of such an examination in clinical use was confirmed herein and it became clear that the application of this method is limited from the 6.-8. months of living on because of the increasing ossification which involves a reduction of the image quality. The deviations from the spine presentation in normal relations were shown by some ultrasound examples of malformed spines (spinal dysraphism, hemivertebrae).Reproducible attachment of the structures obviously seen with ultrasound and the clear demarcation of deformations as well as the simply practicable examination make evident the suitability of spinal sonography in newborns and infants as a noninvasive screening for the exclusion of spine malformations.

A bioavailability study of two commercial carbamazepine sustained-release formulations was carried out in 14 healthy male subjects in order to compare plasma concentration/time profiles and to determine the relative bioavailability of carbamazepine (CBZ). This randomized study had a single-dose, crossover design and consisted of two trial periods separated by a three-week wash-out period. A sensitive, validated HPLC method was used to analyze plasma carbamazepine levels. Bioequivalence was only accepted for the test (Timonil 600 retard from Desitin Arzneimittel GmbH) and reference preparations (T and R) if the 90% confidence interval (parametric or non-parametric) for the ratios of the median values of the target variables was completely within the bioequivalence range. The following values were found for relative bioavailability: T/R: AUC = 109.6 (101.5-116.5)%, MRT = 96.4 (92.0-100.4)%, HVD = 92.4 (85.0-97.8)%. Applied to these pharmacokinetic data, the requirements for bioequivalence are met when the inclusion rule is used.

Based on general guidelines and requirements for the design and analysis of bioequivalence studies, specific recommendations are made for the presentation of results, both in tabular and graphical form. This is done by means of two examples, one of a single-dose study and one of a multiple-dose study. The recommendations in this paper are twofold. Firstly, a complete and rather detailed presentation of results is given, which practically corresponds to the standard of research reports. Secondly, a subset of this is suggested for publication. It gives the essential results for bioequivalence assessment in a standardized form. From an editorial point of view, it would be highly appreciated if the papers submitted for publication were always accompanied by a complete presentation including the individual concentration/time data and the various steps of calculation. This would speed up peer review and ultimately improve and harmonize the standard of bioequivalence publications.

The extent to which bismuth is absorbed following single and multiple oral administration of basic bismuth nitrate was investigated in healthy male subjects. The blood concentration of bismuth and the amounts excreted in urine and feces were determined. The results show that only a small fraction of the administered bismuth dose given in this form is absorbed. Existing differences in the absorption kinetics between this relatively insoluble bismuth salt and colloidal bismuth citrate are discussed.

The potential influence of pantoprazole (BY1023/SKF96022), a newly developed selective inhibitor of the gastric H+,K(+)-ATPase, on therapeutic serum theophylline concentrations was investigated in a crossover study in 8 healthy male volunteers (age 25-30 [median 27] years, body weight 63-80 [median 68] kg). Steady-state serum theophylline concentrations were obtained by a two-step intravenous infusion scheme of approximately 350 mg theophylline each over 0.5 h and subsequently over approximately 10 h, respectively. In the test period, 30 mg pantoprazole were injected over 2 min on 5 consecutive days and theophylline was infused on day 4. In the reference period, placebo was administered i.v. on 2 consecutive days and theophylline on day 1. Serum pantoprazole concentrations were measured up to 12 h, serum theophylline concentrations up to 36 h. Pantoprazole was well tolerated with and without theophylline. There were no clinically relevant changes in blood pressure, heart rate, ECG and routine clinical laboratory parameters. Primary characteristic for confirmative assessment of no interaction was the area under the concentration/time curve (AUC). Lack of interaction in the sense of equivalence was concluded both for theophylline (with and without pantoprazole) and pantoprazole (with and without theophylline), as the 90%-confidence intervals of the AUC-ratio test/reference were within the equivalence range of 0.8 to 1.25. Further explorative analysis of theophylline disposition kinetics revealed this inclusion also for clearance and volume of distribution, but not for the half-life. In the case of pantoprazole, the corresponding 90%-confidence intervals for any of the secondary characteristics clearance, volume of distribution and half-life were within the above mentioned range. In conclusion, repeated once-daily i.v. injections of 30 mg pantoprazole have no clinically relevant influence on steady-state theophylline serum concentrations, nor does theophylline at therapeutic serum concentrations influence the pantoprazole disposition kinetics. Hence, in clinical practice theophylline and pantoprazole can be administered concomitantly without dose adjustment.