Optimised endoscopic access for intrajejunal levodopa application in idiopathic Parkinson's syndrome.

Pump-guided intrajejunal levodopa administration is one of the indispensable forms of therapy in advanced Parkinson's syndrome, along with deep brain stimulation and subcutaneous apomorphine injection. The standard application of levodopa gel via a JET-PEG, i.e. a percutaneous endoscopic gastrostomy (PEG) with an inserted internal catheter into the jejunum, has not been unproblematic due to the restricted absorption area of the drug in the region of the flexura duodenojejunalis and especially due to the sometimes considerable accumulated complication rates of a JET-PEG. Causes of complications are mainly a non-optimal application technique of PEG and internal catheter as well as the often missing adequate follow-up care. This article presents the details of a-compared to the conventional technique-modified and optimised application technique, which has been clinically proven successfully for years. However, many details derived from anatomical, physiological, surgical and endoscopic aspects must be strictly observed during the application to reduce or avoid minor and major complications. Local infections and buried bumper syndrome cause particular problems. The relatively frequent dislocations of the internal catheter (which can ultimately be avoided by clip-fixing the catheter tip) also prove to be particularly troublesome. Finally, using the Hybrid technique, a new combination of an endoscopically controlled gastropexy with 3 sutures and subsequent central thread pull-through (TPT) of the PEG tube, the complication rate can be dramatically reduced and thus a decisive improvement achieved for patients. The aspects discussed here are highly relevant for all those involved in the therapy of advanced Parkinson's syndrome.

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.

[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.

Cultivation of porcine hepatocytes in polyurethane nonwovens as part of a biohybrid liver support system.

Many patients suffering from end-stage liver disease cannot be transplanted within reasonable time due to the shortage of donor organs. Bioartificial liver support systems may contribute to the liver regeneration or bridging the time until a liver graft for transplantation becomes available. Nonwovens with integrated oxygenation capacity have been developed and manufactured by melt blow technology using thermoplastic polyurethane. Capillary membranes for oxygenation were integrated into the nonwoven during the processing. The polyurethane nonwoven structures with adapted pore size and high pore volume allow high cell densities in the hepatocyte culture. The three-dimensional cell culture was housed by a flow bioreactor system and was integrated in a closed loop circulation with monitoring possibilities for pressure, pH, temperature, ammonia, and oxygen. Hepatocytes were isolated from rats or pigs by collagenase perfusion and infused into the medium-perfused circulation. Cells showed high viability and hepatocyte specific cytochrome P450-dependent metabolic function in culture (MEGX test).

Release of TNF-alpha from lipopolysaccharide (LPS)-stimulated Kupffer cells in serum- and nutrient-free medium.

In monocytes/macrophages LPS stimulation occurs by the binding of LPS and the serum component LPS-binding protein (LBP) to CD14. This study was conducted to investigate whether this mechanism also occurs in Kupffer cells. Rat Kupffer cells were stimulated for up to 8 h by LPS (0, 100 ng/ml, 10 microg/ml) in RPMI medium or in nutrient-free Krebs-Henseleit (KH) buffer. Some incubations were performed without serum, while in others serum was provided. TNF-alpha concentrations of the supernatants were measured by ELISA. LPS stimulation of Kupffer cells yielded the following results. In KH without any additives a considerable amount of TNF-alpha was released. Incubation in RPMI without serum caused twice as much TNF-alpha to be released as when KH was used. The addition of autologous serum to RPMI did not increase TNF-alpha response. These results provide evidence that a substantial part of TNF-alpha release by LPS-stimulated Kupffer cells occurs in a serum- and thus LBP-independent way.

RANTES in the postoperative course after liver transplantation.

RANTES (regulated upon activation, normal T-cell expressed and secreted), an inflammatory cytokine, promotes accumulation and activation of leukocytes. In 67 liver transplantations, systemic concentrations of RANTES were correlated to graft survival and incidence of rejection. RANTES levels either increased to highly elevated levels at day 14 (84 +/- 64 ng/ml; group 1; n = 43) or remained within the limit of healthy controls (19 +/- 11 ng/ml at day 14; group 2; n = 24). The 100-day graft function rate was 0.91 in group 1 and 0.63 in group 2 (P = 0.002). The risk ratio for rejection during the first 100 days was increased 2.2-fold in group 2 compared to group 1 (P = 0.02). High postoperative release of RANTES after liver transplantation, a beneficial factor, may reflect a general systemic immunological activation. It can be concluded that high early systemic RANTES levels may play a role in immunological recognition leading to a tolerance of the liver graft.

Endotoxemia in organ donors: graft function following liver transplantation.

Translocation of endotoxin (LPS) to the portal-venous system is produced by multiple factors. In the case of normal liver function, LPS is rapidly cleared from the portal blood by Kupffer cells; in impaired liver function, LPS can reach the systemic circulation. The objective of this study was to investigate whether elevated donor endotoxin levels affect graft function in the recipient. LPS levels in donor plasma were measured in 14 consecutive liver transplantations. Grafts with donor LPS levels < or = 12 pg/ml had a function probability of 100% after 600 days (n = 10). LPS concentrations of > 12 pg/ml in donor plasma led to loss of function in 75% of the liver grafts (n = 4; P = 0.003; Wilcoxon). Elevated LPS values in donor plasma seem to impair the prognosis of the grafts and could predict poor graft function as early as at the time of brain death.

The quality of a liver graft.

Because transplantation success is influenced by the quality of the graft, the objective of this study was to find parameters to evaluate transplant livers in the recipient centre. In 64 liver grafts, the venous effluates of a portal back-table flush were investigated for various parameters. Amongst them, glutathione S-transferase (GST), glutamate dehydrogenase (GLDH) and the leucocyte count were found superior in predicting graft survival. Using the combination of these parameters, 100-day graft survival of between 95% (all parameters positive) and 0% (all parameters negative) was predicted. We concluded that good liver grafts are characterized by a low width of injury (cytosolic component: GST), a low depth of injury (mitochondrial component: GLDH), as well as by a potential to induce tolerance (passenger leucocytes). Perfusate analysis seems to be a valuable tool to recognize problematic grafts in advance and to quantify the "graft factor" in considerations concerning quality control.

Influence of perioperative sHLA I concentrations on the histological development of the liver graft.

Soluble HLA I (sHLA I) in human serum are ascribed an immunoregulatory role in the context of organ transplantation. Based on histological findings, the objective of the current study was to evaluate the protective influence of sHLA I in liver transplantation from the time point of reperfusion. The sHLA I concentrations in serum samples derived from the liver vein immediately after reperfusion (flush catheter) of 38 patients with liver transplantations were determined by ELISA. The postoperative histological findings of the transplant biopsies were categorized according to rejection, endothelialitis, cholestasis, and necrosis, as well as fatty degeneration. An evaluation according to Kaplan-Meier showed a lower incidence for all of these factors in liver grafts with high sHLA concentrations (P < 0.05). We conclude that low sHLA I concentrations during reperfusion correlate with later complications, thus indicating that sHLA I may have protective potential in liver transplantation.

The postoperative course of gamma-glutamyl transpeptidase--a marker of cytomegalovirus (CMV) replication risk?

Cytomegalovirus (CMV) infection is a common complication in the postoperative course of liver transplantation. In order to start early prophylactic therapy, but to avoid unnecessary treatment, or expensive screening, a desirable goal in post-transplant monitoring is to find appropriate markers in standard laboratory diagnostics. In the present study, the results of a 6-week CMV replication monitoring schedule by the pp65 antigenemia assay in 100 liver graft recipients were included. The activities of transaminases, glutamate dehydrogenase and gamma-glutamyl transpeptidase (gamma-GT) were measured by routine laboratory methods. In contrast to the transaminases, the serum activity of gamma-GT increased during the first postoperative week. The maximum levels were 246 +/- 211 U/l in patients without (n = 46) and 140 +/- 89 U/l in patients with early CMV replication (n = 54; p = 0.02). Patients with gamma-GT levels below 200 U/l on the 5th postoperative day (n = 72) had a CMV replication risk of 65%, whereas those patients with gamma-GT levels above this threshold had a risk of 30% (n = 28; p = 0.0007; relative risk = 2.9). These findings provide a routinely usable marker for the identification of patients at an increased risk of CMV replication. It can be considered that these phenomena may be caused by an additional immunosuppressive effect of the CMV virus.

TNF-alpha and its receptors mediate graft rejection and loss after liver transplantation.

Tumour necrosis factor-alpha (TNF-alpha) plays a pivotal role in the immune response and mediates inflammation by its receptors (TNF-RI and TNF-RII), as observed during rejection episodes and impaired graft function after liver transplantation. TNF-alpha and its receptors were analysed by an ELISA technique in serum samples from 77 consecutive liver transplantations in 63 patients. Samples were collected preoperatively from donors and recipients and then daily in the first two postoperative weeks. Peak levels of TNF-alpha and its soluble receptors (sTNF-RI and sTNF-RII) in the first and second postoperative week correlated with the extent of reperfusion injury. Impaired graft functions correlated with high sTNF-RI levels preoperatively (> 5 ng/ml, p = 0.01) and in the postoperative period (> 16 ng/ml, p = 0.02). Significantly increased TNF-alpha (> 25 pg/ml, p = 0.009) and sTNF-RI levels (> 5 ng/ml, p = 0.05) were found in donors of grafts with a high rejection risk. Elevated levels of TNF-alpha in the postoperative period correlated with an increased rejection risk (> 90 pg/ml, p = 0.02). The activity of the immune system with high concentrations of TNF-alpha and its receptors both in the recipient and the transplant donor seems to play an essential role in allograft development.

The placebo effect in healthy volunteers: influence of experimental conditions on physiological parameters during phase I studies.

1. Although placebo administration is now commonly used as a control condition during clinical pharmacology studies conducted in healthy volunteers, data in placebo-treated subjects usually receive little attention. 2. The profile of several physiological and hormonal parameters was reviewed during the placebo sessions of five double-blind phase I studies involving hospitalisation of healthy volunteers for 2 weeks or more. 3. A clear trend towards an increase in heart rate, which culminated at about 10 beats min-1 at the end of the placebo period was observed, whereas both systolic and diastolic blood pressures remained globally unchanged. 4. Increases in the time to sleep initiation or in asthenia self-ratings during the placebo sessions suggested poor neuropsychiatric tolerability of experimental conditions in some of the studies. 5. In conclusion, all these data confirm that subjects change during the course of these studies. This is an important reason for conducting phase I studies under double-blind placebo-controlled conditions and to refrain from within-group comparisons (vs baseline, first-day effect).

Zolpidem and rebound insomnia--a double-blind, controlled polysomnographic study in chronic insomniac patients.

In a parallel-group, placebo-controlled, polysomnographic study with randomization, the possible occurrence of rebound insomnia was evaluated in 24 patients suffering from moderate to severe chronic insomnia and receiving either triazolam 0.5 mg, zolpidem 10 mg, or placebo. Treatment duration was 27 nights, followed by three placebo-controlled withdrawal nights. Both drugs showed significant efficacy compared to placebo during the active treatment period. A trend toward tolerance was noted in the triazolam group but not in the zolpidem one. The increase in total sleep time in the zolpidem group was accompanied by an increase in the number of sleep cycles. When active treatment was discontinued, clear rebound insomnia was present in the triazolam group while it was not possible to observe any rebound in the placebo and zolpidem groups. Subjective feelings of the patients, which were assessed by means of visual analog scales, correlated well with polysomnographic data. Our findings tend to indicate that, even after long-term treatment, zolpidem does not induce rebound insomnia or daytime anxiety.

The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies.

In contrast to the plethora of publications on placebo effects in patients, very little is known about placebo effects in healthy volunteers during clinical pharmacology studies. We therefore reviewed the adverse events spontaneously reported during placebo administration in 109 double-blind, placebo-controlled studies involving 1228 volunteers. The overall incidence of adverse events in the healthy volunteers during placebo administration was 19%. As expected, complaints were more frequent after repeated dosing (28%) and in elderly subjects (26%). Overall, the most frequent adverse events were headache (7%), drowsiness (5%), and asthenia (4%), with some variation depending on study design and population. In conclusion, these data shed new light on the impact of experimental conditions on the results of safety evaluations in healthy volunteers participating in clinical pharmacology studies.

Placental transfer and perinatal pharmacokinetics of betaxolol.

Betaxolol levels in blood were monitored in the perinatal period in 28 pregnant hypertensive women and in their babies. In the mothers betaxolol concentrations at delivery ranged from less than 1 to 115 ng.ml-1 after doses of 10 to 40 mg.day-1. The apparent blood half-life was 15.6 to 22.1 h mean (19 h). Umbilical cord levels indicated a rapid equilibrium between fetal and maternal units (ratio 0.93) within few hours after dosing. Milk betaxolol concentrations, measured in few cases, exceeded those in blood by a factor of 3. Amniotic fluid concentrations were similar to those observed in maternal venous blood and umbilical cord blood. In neonates, the blood betaxolol half-life ranged from 14.8 to 38.5 h, with a definite trend towards a negative correlation with gestational age. A 11-61% rise in the betaxolol concentration was observed in 64% of the neonates during the first 12 h of extrauterine life. The data indicate that betaxolol kinetics is not altered in pregnant women and they stress the need for careful and prolonged (72-96 h) intensive monitoring of neonates born to hypertensive mothers treated with beta-blocking agents.

Betaxolol: a pilot study of its pharmacological and therapeutic properties in pregnancy.

Twenty two pregnant women with mild to moderate hypertension were treated with betaxolol (10-40 mg/day), a cardioselective beta adrenoceptor blocking agent. The analysis of the changes from the baseline confirmed the antihypertensive effect of the drug with a mean decrease in SBP of 11.8 mm Hg and in DBP of 8.3 mm Hg. A diastolic BP less than 90 mm Hg was obtained in 20 patients after the first day of therapy. Fetal safety, assessed by ultrasonography and cardiotocographic recording was excellent. The 22 mothers gave birth to 23 live born babies (one twin pregnancy). Mean Apgar scores were 8.3 and 9.1 at 1 and 5 min. Only 1 newborn had an Apgar score less than 7. Three newborns suffered from fetal distress and 1 from threat for causes not related to therapy. At 9 months follow-up, all 23 babies were in good health. These data suggest that betaxolol is effective in reducing maternal blood pressure without any deleterious effect on the foetus and the newborn.