Learning of flexible endoscopy, particularly endoscopic vacuum therapy (EVT).

BACKGROUND: Anastomotic insufficiency and perforations in the gastrointestinal tract are severe complications associated with a high complication rate and mortality. Conventional treatment options (particularly re-operations) are often unsatisfactory. Endoscopic vacuum therapy (EVT) is increasingly being used as a promising alternative. PROBLEM: The use of EVT requires a high level of competence in interventional flexible endoscopy, which is primarily not available to every surgeon. Special training programs are required here. METHODS: Based on this need the long-proven Tuebingen training system for flexible endoscopy was modified to meet the special requirements of surgeons and is currently being extended by a special training module for EVT. RESULTS: In addition to the theoretical principles, the training is focused on learning the manual skills for flexible endoscopy. A 2-stage process was developed for this purpose: 1) to become familiar with handling of the flexible endoscope and to learn spatial orientation by means of a didactically optimized abstract phantom ("Tuebingen Orientophant") and 2) learning and training of EVT using a newly developed patient-analogous training model with various insufficiencies and abscess cavities in the upper and lower gastrointestinal tract ("Tuebinger Spongiophant"). The procedure can be trained hands-on step by step exactly as with the patient, whereby the sponge can be applied using different methods, such as overtube and dragging procedures. The consequences of mistakes and complication management can also ideally be trained hands-on using the phantom. DISCUSSION: Evaluations of the first course series show that surgeons achieve endoscopic competence very quickly and learn to master the new procedure. The structure of such a course must, however, be designed according to long-term experience in an optimal didactic manner. Decision-makers in healthcare policy should give much more support to such courses in order to improve patient care and to increase patient safety.

[Treatment of nonvariceal upper gastrointestinal bleeding: endoluminal-endovascular-surgical]. / Therapie der nichtvarikösen oberen gastrointestinalen Blutung: endoluminal ­ endovaskulär ­ chirurgisch.

BACKGROUND: Nonvariceal upper gastrointestinal bleeding (UGIB) has a high mortality. Hematemesis sometimes with melena are the leading clinical symptoms. Peptic ulcers and (erosive) inflammation are common, whereas Mallory-Weiss syndrome, neoplasms, angiodysplasia and diffuse UGIB are less common. PROBLEM: A risk stratification is based on the medical history, clinical presentation and laboratory tests, which are considered in the Glasgow-Blatchford score; however, which treatment approach is optimal? RESULTS: After stabilisation under restricted transfusion indications, temporary stoppage of anticoagulants and optimized coagulation is beneficial and proton pump inhibitors (PPI) should be started. Prokinetics improve the endoscopic conditions in UGIB. The use of an endoscopic Doppler probe optimizes localization of the bleeding site. The use of the Forrest classification and Helicobacter pylori diagnostics are recommended. Mechanical (clips, injection), thermal (argon plasma coagulation, APC) and topical (hemostatic powder) endoscopic treatment procedures are available. Endoluminal hemostasis is very effective. Only clip application is suitable as monotherapy whereas all other endoscopic options should be combined. Angiography followed by transarterial embolization (TAE) can be used for therapy. Despite the high primary success rate, the risk of rebleeding is high. Surgery as the primary treatment is rarely necessary, although effective. Compared to TAE complications are higher, but there is no difference regarding mortality. CONCLUSION: Endoscopy remains the gold standard for the initial diagnostics and treatment of UGIB. In cases of rebleeding repeated endoscopy is recommended. With persistent UGIB an endovascular procedure should be evaluated. Surgery remains an important salvage option.

[Learning of flexible endoscopy, particularly endoscopic vacuum therapy (EVT)]. / Erlernen der flexiblen Endoskopie, insbesondere der endoskopischen Vakuumtherapie (EVT).

BACKGROUND: Anastomotic insufficiency and perforations in the gastrointestinal tract are severe complications associated with a high complication rate and mortality. Conventional treatment options (particularly re-operations) are often unsatisfactory. Endoscopic vacuum therapy (EVT) is increasingly being used as a promising alternative. PROBLEM: The use of EVT requires a high level of competence in interventional flexible endoscopy, which is primarily not available to every surgeon. Special training programs are required here. METHODS: Based on this need the long-proven Tübingen training system for flexible endoscopy was modified to meet the special requirements of surgeons and is currently being extended by a special training module for EVT. RESULTS: In addition to the theoretical principles, the training is focused on learning the manual skills for flexible endoscopy. A 2-stage process was developed for this purpose: 1) to become familiar with handling of the flexible endoscope and to learn spatial orientation by means of a didactically optimized abstract phantom (Tübingen Orientophant) and 2) learning and training of EVT using a newly developed patient-analogous training model with various insufficiencies and abscess cavities in the upper and lower gastrointestinal tract. The procedure can be trained hands-on step by step exactly as with the patient, whereby the sponge can be applied using different methods, such as overtube and dragging procedures. The consequences of mistakes and complication management can also ideally be trained hands-on using the phantom. DISCUSSION: Evaluations of the first course series show that surgeons achieve endoscopic competence very quickly and learn to master the new procedure. The structure of such a course must, however, be designed according to long-term experience in an optimal didactic manner. Decision-makers in healthcare policy should give much more support to such courses in order to improve patient care and to increase patient safety.

Neuronal and ependymal expression of selenoprotein P in the human brain.

Selenoprotein P (SePP) is central to selenium (Se) metabolism in the mammalian organism. Human SePP contains 10 Se atoms that are covalent constituents of the polypeptide chain incorporated as the rare amino acid selenocysteine (Sec). Since hepatocytes secrete SePP into plasma, SePP is commonly regarded as a Se transport protein, although SePP mRNA is expressed in many organs. Gene targeting of SePP in mice leads to neurological dysfunction resulting from Se deficiency and associated reduction of selenoenzyme activities in the brain. However, more recent data revealed that isolated hepatic SePP deficiency does not alter brain Se levels, suggesting a role for SePP locally expressed in the brain. Some of the best characterized and most abundant selenoenzymes, glutathione peroxidases, thioredoxin reductases, and methionine sulfoxide reductase B, play major roles in the cellular defense against reactive oxygen species. Therefore, it was hypothesized that reduced brain Se bioavailability may be involved in the pathogenesis of neurodegenerative disease and normal ageing. We present evidence that human CSF contains SePP and that the human brain expresses SePP mRNA. Moreover, SePP-like immunoreactivity localizes to neurons and ependymal cells and thus appears strategically situated for maintenance and control of Se-dependent anti-oxidative defense systems.

Photocrosslinking locates a binding site for the large subunit of human replication protein A to the damaged strand of cisplatin-modified DNA.

The repair proteins XPA, XPC and replication protein A (RPA) have been implicated in the primary recognition of damaged DNA sites during nucleotide excision repair. Detailed structural information on the binding of these proteins to DNA lesions is however lacking. We have studied the binding of human RPA (hRPA) and hRPA-XPA-complexes to model oligonucleo-tides containing a single 1, 3-d(GTG)-cisplatin-modification by photocrosslinking and electrophoretic mobility shift experiments. The 70 kDa subunit of hRPA can be crosslinked with high efficiency to cisplatin-modified DNA probes carrying 5-iodo-2"-deoxyuridin (5-IdU) as crosslinking chromophore. High efficiency crosslinking is dependent on the presence of the DNA lesion and occurs preferentially at its 5"-side. Examination of the crosslinking efficiency in dependence on the position of the 5-IdU chromophore indicates a specific positioning of hRPA with respect to the platination site. When hRPA and XPA are both present mainly hRPA is crosslinked to the DNA. Our mobility shift experiments directly show the formation of a stable ternary complex of hRPA, XPA and the damaged DNA. The affinity of the XPA-hRPA complex to the damaged DNA is increased by more than one order of magnitude as compared to hRPA alone.

Cell volume is a major determinant of proteolysis control in liver.

Hepatic proteolysis is inhibited by insulin, amino acids and hypoosmotic cell swelling and is stimulated by glucagon. These effectors simultaneously modulate cell volume in the intact liver, as shown by measurements of the intracellular water space. A close relationship exists between the effect on proteolysis and the accompanying cell volume change, regardless of whether hepatic proteolysis was modified by insulin, glucagon, cyclic AMP, glutamine, glycine, barium of hypoosmotic exposure. It is suggested that cell volume changes exerted by hormones and amino acids play a crucial role in the regulation of hepatic proteolysis.

Endogenous fertility and the Henry George Theorem.

"Models of endogenous demographic change deal with population size as an additional object of the welfare analysis. In these models the overlapping-generations (OLG) model serves as the basic framework. In club theory, too, population size is treated as an endogenous variable. In local public goods (LPG) models, the so-called Henry George Theorem, which requires local public expenditures to be financed by a 100% tax on aggregate land rent, is known as a (first-order) condition for club efficiency. The present paper establishes and exploits an isomorphism between steady states of the OLG model and allocations of the LPG model. The paper revisits Samuelson's fallacy concerning his goldenest golden rule and it explores institutional arrangements that sustain the optimum growth of population."

Spatial dynamics and metropolitan change.

"This special issue presents contributions to a collaborative effort to analyze 'the dynamics of metropolitan processes and policies'....[It] contains four papers which focus on industrial change and economic restructuring; two papers deal with population relocation and migration processes; one paper contains a study of economic cycles in space and one paper treats the assessment of urban investment and urban renewal projects." The geographic focus is on the developed countries.

[Suburbanization caused by fiscal inequality]. / Suburbanisierung als Folge fiskalischer Inaquivalenz

PIP: The relationship between fiscal inequalities among central cities and suburban areas and migration to the suburbs is examined. The focus of the study is on questions related to resource sharing in the provision of goods and services that would benefit residents of both central cities and their suburbs. (summary in ENG, FRE)^ieng

Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic.

Selenium (Se), once known only for its potential toxicity, is now well established as an essential trace element for mammals. Insufficient Se intake predisposes to and manifests in a variety of diseases. Recent studies have proven that it is the synthesis of selenocysteine (Sec)-containing proteins, designated selenoproteins, which represents an essential prerequisite for regular development and a long and healthy life. New transgenic mouse models analysing those selenoproteins with proven enzymatic functions displayed particular phenotypes and highlighted essential Se-dependent processes in development, growth or against specific challenges. While there is a growing molecular understanding of and general agreement on the importance of sufficiently high Se intake and undisturbed selenoprotein biosynthesis, many of the recently identified selenoproteins are still uncharacterised, and the effects and consequences of supra-physiological Se dosages are not biochemically understood. With the recent definition of the human and mouse selenoproteomes and a growing number of available tools, the Se field is now geared for a great leap forward. Se biology has already broadened our knowledge about the genetic code and about protein translation. It now holds great promises also for a better understanding of some key aspects of cancer, inflammation, fertility and prevention of age-associated diseases.

Developmental motoneuron cell death and neurotrophic factors.

During the development of higher vertebrates, motoneurons are generated in excess. In the lumbar spinal cord of the developing rat, about 6000 motoneurons are present at embryonic day 14. These neurons grow out axons which make contact with their target tissue, the skeletal muscle, and about 50% of the motoneurons are lost during a critical period from embryonic day 14 until postnatal day 3. This process, which is called physiological motoneuron cell death, has been the focus of research aiming to identify neurotrophic factors which regulate motoneuron survival during this developmental period. Motoneuron cell death can also be observed in vitro when the motoneurons are isolated from the embryonic avian or rodent spinal cord. These isolated motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration during development and under pathophysiological conditions in neurodegenerative disorders. Accumulating evidence from such studies suggests that some specific requirements of motoneurons for survival and proper function may change during development. The focus of this review is a synopsis of recent data on such specific mechanisms.

TNF-alpha pretreatment prevents subsequent activation of cultured brain cells with TNF-alpha and hypoxia via ceramide.

We have developed a cellular model in which cultured astrocytes and brain capillary endothelial cells preconditioned with tumor necrosis factor-alpha (TNF-alpha) fail to upregulate intercellular adhesion molecule-1 (ICAM-1) protein (80% inhibition) and mRNA (30% inhibition) when challenged with TNF-alpha or exposed to hypoxia. Inasmuch as ceramide is known to mediate some of the effects of TNF-alpha, its levels were measured at various times after the TNF-alpha preconditioning. We present evidence for the first time that, in normal brain cells, TNF-alpha pretreatment causes a biphasic increase of ceramide levels: an early peak at 15-20 min, when ceramide levels increased 1.9-fold in astrocytes and 2.7-fold in rat brain capillary endothelial cells, and a delayed 2- to 3-fold ceramide increase that occurs 18-24 h after addition of TNF-alpha. The following findings indicate that the delayed ceramide accumulation results in cell unresponsiveness to TNF-alpha: 1) coincident timing of the ceramide peak and the tolerance period, 2) mimicking of preconditioning by addition of exogenous ceramide, and 3) attenuation of preconditioning by fumonisin B1, an inhibitor of ceramide synthesis. In contrast to observations in transformed cell lines, the delayed ceramide increase was transient and did not induce apoptosis in brain cells.