[Prevention of road accidents involving non-motorized traffic participants (pedestrians and cyclists) in Germany]. / Prävention von Verkehrsunfällen äußerer Verkehrsteilnehmer (Fußgänger und Fahrradfahrer) in Deutschland.

During a 1-day workshop organized by the German Society of Orthopaedics and Traumatology (DGOU) 15 German accident researchers used different approaches to improve the effectiveness of accident prevention for pedestrians and bicyclists on German roads. The main results of this analysis show: Fatal injuries of pedestrians have been significantly reduced by 82% between 1970 (n=6.056) and 2007 (n=695). Similarly, fatalities of bicyclists have been reduced during the same time period from 1,835 to 425 which amount to almost 80%. However, the total number of injured cyclists increased almost twice, i.e. from 40,531 (in 1979) to 78,579 (in 2007) a fact that needs to be analyzed in more detail. Although scientifically proven to provide protection against severe head injuries, helmets are worn less frequently by adolescents and women as compared to younger children and men. Fatalities of bicyclists might be reduced by using Dobli mirrors which allow the truck driver to see the bicyclist when turning right. Recently developed sensors are able to detect pedestrians walking closely (<2.5 m) and warn the truck driver acoustically. Bicycle lanes should be planned for one direction only, separated from the pedestrian way and large enough (2.0 m are safer than 1.6 m). Traffic education for school beginners and younger children should be repeated to be effective. Training for elderly bicyclists in cities with heavy traffic would also be reasonable. Active security systems in cars like ESP (electronic stability program), BAS (brake assist system), special light systems for curves, and night vision utilities are most effective to prevent collision with pedestrians and bicyclists. TV spots for bicyclists could help to point out dangerous situations and the proven benefits of wearing a helmet in the same way as previous campaigns, e.g."The 7th Sense" for car drivers.

Differential processing of proenkephalin-A by human peripheral blood monocytes and T lymphocytes.

Human peripheral blood mononuclear cells are analyzed for preproenkephalin gene expression and peptide processing. Met-enkephalin immunoreactivity as detected with a specific antiserum is found in the cytoplasm of monocytes but not in T lymphocytes. Secretion of met-enkephalin was analyzed with an RIA that is specific for the met-enkephalin pentapeptide. Unfractionated PBMC spontaneously released 40 pg/ml met-enkephalin and this increased two- to fourfold after stimulation with PHA. Lower levels (less than 100 pg/ml) of met-enkephalin were detected in supernatants from purified T cells that were activated with PHA and IL-2. In contrast, stimulation of purified monocytes with LPS or PMA resulted in the release of up to 600 pg/ml of the processed peptide. To examine whether T cells can produce met-enkephalin precursor peptides, T cell conditioned media were treated with trypsin and carboxypeptidase-B, which is known to release met-enkephalin from the propeptide. This increased levels of met-enkephalin to 400 pg/ml, indicating that lymphocytes secrete the propeptide but do not process it to met-enkephalin. The 1.4-kb preproenkephalin mRNA is detected in activated blood mononuclear cells and in purified monocytes and T cells. To determine whether monocytes or lymphocytes express met-enkephalin in vivo, lymphoid tissues were analyzed by immunohistochemistry. In human spleen tissue, positive cells were found in the red pulp but not in the follicles, which is also consistent with met-enkephalin expression in monocytes. In summary, these results show that human peripheral blood mononuclear cells express preproenkephalin mRNA and that monocytes, but not T cells, process the propeptide to metenkephalin.

Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy.

Cells of the macrophage lineage are considered to be of special importance in the defense of the host against tumor development and spread. Immunotherapeutic strategies to stimulate macrophage (MAC) tumor cytotoxicity make use of activating compounds such as gamma-interferon which are given systemically. However, there are several lines of evidence that in malignant disease the generation of cytotoxic effector MACs is impaired. Both defective cell maturation and loss of responsiveness to activation are described. Here, a first clinical phase I trial of adoptive immunotherapy in cancer patients using autologous MACs generated in vitro from blood monocytes (MOs) is reported. Mononuclear cells were isolated by cytapheresis and density centrifugation and cultured in hydrophobic Teflon bags for 7 days with 2% autologous serum and recombinant human gamma-interferon being present for the last 18 h. Cytotoxic MO-derived MACs were then purified by countercurrent elutriation and reinfused into the patient. A total of 72 therapies have been performed with patients being treated i.v. (n = 8) and i.p. (n = 7). In vitro generated MACs proved to be mature as judged by the expression of maturation-associated surface molecules (MAX antigens, CD16, CD51, CD71), were cytotoxic to U937 tumor cells, and were efficient secretory cells. Cell dose escalation was performed in the first patients beginning with 10(8) MACs to finally infuse the total number of cells recovered from one single cycle of isolation and culture. MAC yield varied from 1 to 17 x 10(8) representing 13-79% of MOs initially seeded. Adoptive MAc transfer was well tolerated. Side effects observed were low-grade fever (less than 38.5 degrees C), induction of the coagulation cascade, and abdominal discomfort after i.p. application. The procoagulant activity of MAC autografts was cell dose dependent and demonstrated by detection of circulating fibrin monomers and thrombin-antithrombin complexes. Biological responses observed included elevated serum neopterin levels and the appearance of interleukin-6 in sera and ascitic fluids. Indication of a possible therapeutic effect was only observed in i.p.-treated patients and consisted of disappearance of malignant ascites in 2 of 7 patients.

Surface phenotype analysis of human monocyte to macrophage maturation.

Cells of the mononuclear phagocyte system arise from circulating blood monocytes. Upon emigration from the vasculature, monocytes differentiate into macrophages, a process that monocytes similarly undergo in vitro. We have established primary cultures from elutriated or adherence-purified blood monocytes and analyzed the antigenic modulation during monocyte to macrophage transformation, which could be followed by the expression of specific antigens and which required as yet unknown inducer signals present in the serum. It is shown that in the absence of serum monocytes only survive in vitro when cultured adherent to plastic but rapidly die in suspension culture. Starting at 0.5%, serum induced maturation dose-dependently, with the optimal concentration being 2 to 5%. Of those antigens not present on monocyte, the low-affinity Fc receptor (CD16), the alpha-chain of the vitronectin receptor (CD51), gp65-MAX.1, and gp68-MAX.3 were expressed only upon serum-induced macrophage differentiation, whereas the transferrin receptor (CD71), MAX.26, and to some degree also gp65-MAX.11 appeared to be independent of maturation and were also found on primary cultures of adherent monocytes under serum-free conditions. In addition, the rapid induction of HLA class II antigens (within 24 hr) was similar with and without serum, as was the continued high-density expression in long-term culture. The monocyte-specific CD14 antigen was down-regulated in the absence of serum but kept its level of expression on differentiated macrophages. In comparison, alveolar and peritoneal macrophages, respectively, differed in their antigenic phenotype: Alveolar macrophages expressed high HLA class II antigens but low CD14, whereas for peritoneal macrophages the opposite was found. Both interferon-gamma and -alpha suppressed macrophage maturation in vitro but had contrary effects on HLA class II and CD16 expression: Interferon-gamma up-regulated the two types of antigens, which, in contrast, were down-regulated by interferon-alpha.

Increased prostaglandin E release and tumor cytostasis by resident Kupffer cells during Listeria monocytogenes infection.

Liver macrophages isolated from Listeria monocytogenes-infected mice were studied for their functional capacities in vitro. Spontaneous release of prostaglandin E and tumor cytostatic activity by liver macrophages of infected mice were markedly enhanced when compared to controls. Irradiated mice showing no increase in the number of their liver macrophages after Listeria monocytogenes infection, in contrast to solely infected mice, nevertheless demonstrated comparable activities. Our data suggest that radioresistant liver macrophages, most probably resident Kupffer cells, can be activated during in vivo infection to express enhanced effector functions.

Suppression of T lymphocyte proliferation during lymphoma growth in mice: role of PGE2-producing suppressor macrophages.

The suppressed T lymphocyte response occurring during lymphoma growth in mice was largely due to the generation of suppressor macrophages which released high amounts of prostaglandin E2 (PGE2). Based on these findings, the role of macrophage-derived PGE2 as a regulating and potentially immunosuppressive agent of the immune response is discussed.

Interleukins and their antagonists but not TNF and its receptors are released in post-ERP pancreatitis.

OBJECTIVE: Usually it is not possible to study the initial systemic response in patients with acute pancreatitis in the first hours after onset of the disease. We used postendoscopic retrograde pancreatography (ERP) pancreatitis as a model to study cytokine and anticytokine release in the early phase of human acute pancreatitis. METHODS: Post-ERP pancreatitis was defined as a threefold increase in serum amylase and at least two of the following clinical symptoms: abdominal pain, nausea, vomiting or peritonism 24 h after ERP. Serum levels of pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF), as well as endogenous antagonistic mediators of the systemic inflammatory response such as soluble tumour necrosis factor alpha receptors p55 (TNFR p55) and p75 (TNFR p75), and IL-1-receptor antagonist (IL-1-RA) and interleukin-2-receptor (IL-2R) as indicators of lymphocyte activation were measured before and 0, 1, 4, 12, 24 and 48 h after ERP. In nine patients with acute post-ERP pancreatitis, these parameters were monitored daily until C-reactive protein (CRP) was within normal ranges and were compared to patients without pancreatitis after ERP. RESULTS: IL-1beta was not detectable in five patients with and four patients without post-ERP pancreatitis. The values of the remaining patients in both groups were lower than 3.9 pg/ml. IL-8 and IL-1-RA serum concentrations peaked 12 h after ERP (132.9 and 3245.0 pg/ml respectively) compared to patients without post-ERP pancreatitis (25.8 and 389.9 pg/ml respectively). The IL-6 concentration increased to 81.6 pg/ml (8.0 pg/ml in control patients) 24 h after ERP, while the peak values for CRP were measured 72 h after ERP (164.0 versus 7.7 mg/l). IL-2R content was maximally elevated 144 h after ERP (688.8 versus 255.9 U/ml), while concentrations of TNF and its receptors showed no significant change over time. CONCLUSION: The initial response of the cytokine network to damage of the human pancreas leading to acute pancreatitis includes the release of IL-8 and the IL-1 antagonist IL-1-RA, while IL-1beta is not found in the systemic circulation. The TNF system does not seem to be involved as indicated by the lack of detectable changes in TNF and the soluble TNFR p55 and p75 serum concentrations. Lymphocyte activation as indicated by elevated IL-2R levels occurred days after the initial trauma. Even mild post-ERP pancreatitis leads to significant systemic release of cytokines and their biological counterparts.

Diagnostic approach to acute pancreatitis: diagnosis, assessment of etiology and prognosis.

The aims of initial diagnostic procedures leading to early treatment in an appropriate setting in acute pancreatitis are: initial diagnosis and differential diagnosis, assessment of etiology and assessment of prognosis. Etiology can be assessed with certainty only by endoscopic retrograde cholangiopancreaticography. This method allows us to differentiate between pancreatic duct abnormalities as seen in so-called alcoholic pancreatitis as an exacerbation of chronic pancreatitis and biliary causes of the disease. Contrast-guided computed tomography is useful for detecting necroses and their infection. As in other inflammatory diseases, the prognosis in acute pancreatitis seems to be determined by mediators leading to "whole body inflammation", confirmed by high concentrations of interleukin-8 as a major attractant of neutrophils, by interleukin-6 preceding high levels of CRP, as well as by leukocyte immigration into the pancreas. Besides these determinants of the course of acute pancreatitis the prognosis can be assessed by simple clinical means. A clinical score based on physical examination seems to be the best standard for assessing prognosis. Measurement of PMN-elastases and CRP may be additionally helpful.

Inflammatory mediators and cytokines--new aspects of the pathophysiology and assessment of severity of acute pancreatitis?

Most attacks of acute pancreatitis are mild and self-limiting. In 10-20% of the cases, however, severe disease with multiple systemic complications develops. During the last few years it has been recognized that activated leukocytes have an important role in the multisystem involvement during acute pancreatitis. Activated leukocytes are thus a pathogenetic factor in the severity of the disease. Activation of polymorphonuclear granulocytes (PMNs) and of monocytes/macrophages is an early event during severe acute pancreatitis. Factors released by activated leukocytes therefore reflect the severity of the disease. Three independent studies have shown that released PMN-elastase is a reliable early prognostic marker that permits correct classification of 80-95% of the patients within the first 24-48 hours. Interleukin-6 (IL-6), mainly secreted by activated monocytes/macrophages, is also an early prognostic parameter (shown in one study), but is not superior to PMN-elastase. Leukocyte activation markers are more reliable than multiple scoring systems in the assessment of the severity of acute pancreatitis. Compared with PMN-elastase or IL-6, increased plasma concentrations of such acute-phase proteins as alpha-1-antitrypsin or CRP, and consumption of the protease inhibitor alpha-2-macroglobulin, are later events that can be detected only 1 to 4 days later. Comparison of the various inflammatory parameters suggests that PMN-elastase is the best early and reliable prognostic marker in acute pancreatitis. The reviewed data underscore the role of activated leukocytes in the pathogenesis of complicated acute pancreatitis.

Prospective, randomised, double blind trial of prophylaxis with single dose of co-amoxiclav before percutaneous endoscopic gastrostomy.

OBJECTIVE: To determine the efficacy of antibacterial prophylaxis in preventing infectious complications after percutaneous endoscopic gastrostomy. DESIGN: Prospective, randomised, placebo controlled, double blind, multicentre study. SETTING: Departments of internal medicine at six German hospitals. SUBJECTS: Of 106 randomised adult patients with dysphagia, 97 received study medication, and 84 completed the study. The median age of the patients was 65 years. Most had dysphagia due to malignant disease (65%), and many (76%) had serious comorbidity. INTERVENTIONS: A single intravenous 2.2 g dose of co-amoxiclav or identical appearing saline was given 30 min before percutaneous endoscopic gastrostomy performed by the thread pull method. MAIN OUTCOME MEASURES: Occurrence of peristomal wound infections and other infections within one week after percutaneous endoscopic gastrostomy. RESULTS: The incidence of peristomal and other infections within one week after percutaneous endoscopic gastrostomy was significantly reduced in the antibiotic group (8/41 (20%) v 28/43 (65%), P<0.001). Similar results were obtained in an intention to treat analysis. Several peristomal wound infections were of minor clinical significance. After wound infections that required no or only local treatment were excluded from the analysis, antibiotic prophylaxis remained highly effective in reducing clinically important wound infections (1/41 (2%) v 11/43 (26%), P<0.01) and non-wound infections (2 (5%) v 9 (21%), P<0.05). CONCLUSIONS: Antibiotic prophylaxis with a single dose of co-amoxiclav significantly reduces the risk of infectious complications after percutaneous endoscopic gastrostomy and should be recommended.

[Papillotomy in acute pancreatitis: more benefits than risks]. / Papillotomie bei akuter Pankreatitis: Mehr Nutzen als Risiken.

The pathogenesis of acute pancreatitis is still unclear. OPIE's theory that obstruction of the Ampulla of Vater can be an important etiological factor in acute pancreatitis is still relevant for the ongoing discussion whether endoscopic papillotomy can improve acute pancreatitis. Patients with severe acute pancreatitis have to undergo an early ERCP for the detection of the biliary origin of the disease. In case of the detection of choledocholithiasis endoscopic papillotomy should be performed. The rate of complications and the duration of hospitalization can be significantly reduced in contrast to conservative treatment. Controlled clinical studies are necessary to answer the question if endoscopic papillotomy should be carried out in all patients with severe acute pancreatitis.

[Percutaneous transhepatic cholangioscopy. A new approach to the diagnosis of bile duct tumors]. / Die perkutan-transhepatische Cholangioskopie. Ein neuer Zugang zur Diagnostik von Tumoren der Gallenwege.

New surgical and radiotherapeutic regimens for the treatment of carcinoma of the bile ducts require histologic diagnosis as well as diagnostic delineation of the tumor. Percutaneous transhepatic cholangioscopy fulfils these requirements. This technique combines the advantages of radiological and endoscopic diagnostic procedures in the biliary tract. Cholangioscopy has been performed successfully in four patients with malignant tumors of the bile ducts and we did not observe any complications.

Depressed mediator release by inflammatory exudate cells in immunized rats following antigen challenge.

The aim of the present study was to characterize leukocytes present in a local inflammatory reaction with respect to production of prostaglandin E (PGE) and the release of factors affecting lymphocyte function, which are produced by macrophages (interleukin-1) or stimulated lymphocytes (interleukin-2). Lewis rats immunized against bovine serum albumin (BSA) were challenged by intraperitoneal injection of antigen. The PGE release by peritoneal cells (PEC) was tested in vitro and found to be enhanced in immunized rats before BSA challenge. However, PEC harvested after the injection of antigen showed a marked reduction in prostaglandin production during the first 24 hr. When these cells were tested for the secretion of lymphokines (IL-1, IL-2) the same depression was found.

Uridine catabolism in Kupffer cells, endothelial cells, and hepatocytes.

Kupffer cells, endothelial cells, and hepatocytes were separated by centrifugal elutriation. The rate of uracil formation from [2-14C]uridine, the first step in uridine catabolism, was monitored in suspensions of the three different liver cell types. Kupffer cells demonstrated the highest rate of uridine phosphorolysis. 15 min after the addition of the nucleoside the label in uracil amounted to 51%, 13%, and 19% of total radioactivity in the medium of Kupffer cells, endothelial cells, and hepatocytes, respectively. If corrected for Kupffer cell contamination, hepatocyte suspensions demonstrated similar activities as endothelial cells. In contrast to non-parenchymal cells, hepatocytes continuously cleared uracil from the incubation medium. The lack of uracil consumption by Kupffer cells and endothelial cells points to uracil as the end-product of uridine catabolism in these cells. Kupffer cells and endothelial cells did not produce radioactive CO2 upon incubation in the presence of [2-14C]uridine. Hepatocytes, however, were able to degrade uridine into CO2, beta-alanine, and ammonia as demonstrated by active formation of volatile radioactivity from the labeled nucleoside. There was almost no detectable formation of thymine from thymidine or of cytosine, uracil, or uridine from cytidine by any of the different cell types tested. These results are in line with low thymidine phosphorolysis and cytidine deamination in rat liver. Our studies suggest a co-operation of Kupffer cells, endothelial cells, and hepatocytes in the breakdown of uridine from portal vein blood with uridine phosphorolysis predominantly occurring in Kupffer cells and with uracil catabolism restricted to parenchymal liver cells.

[Diagnostic imaging in acute pancreatitis]. / Bildgebende Verfahren bei akuter Pankreatitis.

With a sensitivity of 90% in the diagnosis of necrotic pancreatic tissue contrast-enhanced computed tomography is the most reliable imaging tool for classifying acute pancreatitis. ERCP is essential for the diagnosis of stones in the common bile duct and in the pancreatic ducts and of tumors of the duodenal papilla and the pancreatic head and thus for clarifying the etiology of acute pancreatitis. Sonography as the only imaging tool would not be sufficient, because its sensitivity for necrotizing pancreatitis is only 33% and stones in the common bile duct are often missed.

[Time requirements of medical and non-medical personnel for ultrasound studies]. / Zeitaufwand von ärztlichen und nichtärztlichen Mitarbeitern für Ultraschalluntersuchungen.

To assess the time needed for ultrasound examinations for physicians and assistants we carried out a survey among members of the German Association of Ultrasound in Medicine (DEGUM) in hospitals and practices. The physician's examination time for the investigation of the upper abdomen and kidneys was 12.3 min with additional time for preparation (2.9 min), for work up (2.3 min) and written documentation (3.6 min), together 21.3 min. The examination times in practices (18.9 min) are shorter than in ultrasound labs in hospitals. Assistants in ultrasound laboratories need for organisation, upkeep of equipment, to filing the images in archives etc. medium 15.2 min per patient. Assistants with exclusive employment in the ultrasound laboratory need 17.6 min (4-57 min), whereas assistants employed in the ultrasound laboratory and other departments need 12.7 min (1.6-31 min). In internal practices the desired time is 7.9 min (3.5-20 min). Because of the different organisation in the ultrasound laboratories in several hospitals and in practices a comparison of times needed by assistant personnel (or, in many cases, by the physicians who perform such work themselves) is very difficult. The examination time really needed by physicians and the time for assistant personnel are shorter than presumed earlier, but are longer than estimated in the recent discussion about money saving in medicine.

The role of nonparenchymal and parenchymal liver cells in the catabolism of extracellular purines.

Adenosine-degrading enzymes within the liver lobule can modulate both vascular and metabolic effects of circulating adenosine in the liver. Since it has not been fully established whether nonparenchymal cells participate in the elimination of sinusoidal purines, isolated Kupffer cells and endothelial cells were tested for their capacity to degrade extracellular purines. After perfusion and digestion of rat livers by collagenase, the resulting mixed cell population was separated by centrifugal elutriation. The isolated parenchymal and nonparenchymal cells were incubated for up to 2 hr in the presence of [8(-14)C]adenosine, [8(-14)C]guanosine and [8(-14)C]hypoxanthine (50 mumoles per liter). In the deproteinized medium, adenosine, guanosine, inosine, adenine, guanine, xanthine, hypoxanthine, uric acid and allantoin were separated by reversed-phase high-performance liquid chromatography. Radioactive peaks were collected and counted. Nonparenchymal cells catalyzed the degradation of adenosine into inosine and hypoxanthine. However, the formation of xanthine, uric acid or allantoin from adenosine could only be detected in hepatocyte suspensions. Within 15 min, adenosine was completely eliminated from the medium by Kupffer cells, whereas endothelial cells catabolized only less than half of the initial amount of the adenine nucleoside during this time period. Accordingly, incubation of nonparenchymal cells in the presence of hypoxanthine did not result in the formation of further breakdown products of the purine, whereas its catabolites slowly accumulated in the medium of hepatocytes. Guanosine conversion into guanine and xanthine was much slower in endothelial cells as compared to Kupffer cells and hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)