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Objective High-frequency spinal cord stimulation (HF-SCS) is a potential method to provide natural and effective inspiratory muscle pacing in patients with ventilator-dependent spinal cord injuries. Experimental data have demonstrated that HF-SCS elicits physiological activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways. However, the activation thresholds, extent of activation, and optimal electrode configurations (i.e., lead separation, contact spacing, and contact length) to activate these neural elements remain unknown. Therefore, the goal of this study was to use a computational modeling approach to investigate the direct effects of HF-SCS on the spinal cord and to optimize electrode design and stimulation parameters. Materials and methods We developed a computer model of HF-SCS that consisted of two main components: 1) finite element models of the electric field generated during HF-SCS, and 2) multicompartment cable models of axons and motoneurons within the spinal cord. We systematically evaluated the neural recruitment during HF-SCS for several unique electrode designs and stimulation configurations to optimize activation of these neural elements. We then evaluated our predictions by testing two of these lead designs with in vivo canine experiments. Results Our model results suggested that within physiological stimulation amplitudes, HF-SCS activates both axons in the ventrolateral funiculi (VLF) and inspiratory intercostal motoneurons. We used our model to predict a lead design to maximize HF-SCS activation of these neural targets. We evaluated this lead design via in vivo experiments, and our computational model predictions demonstrated excellent agreement with our experimental testing. Conclusions Our computational modeling and experimental results support the potential advantages of a lead design with longer contacts and larger edge-to-edge contact spacing to maximize inspiratory muscle activation during HF-SCS at the T2 spinal level. While these results need to be further validated in future studies, we believe that the results of this study will help improve the efficacy of HF-SCS technologies for inspiratory muscle pacing.

Spinal cord stimulation (SCS) is a popular neurostimulation therapy for severe chronic pain. To improve stimulation efficacy, multiple modes are now used clinically, including conventional, burst, and 10-kHz SCS. Clinical observations have produced speculation that these modes target different neural elements and/or work via distinct mechanisms of action. However, in humans, these hypotheses cannot be conclusively answered via experimental methods. Therefore, we utilized computational modeling to assess the response of primary afferents, interneurons, and projection neurons to conventional, burst, and 10-kHz SCS. We found that local cell thresholds were always higher than afferent thresholds, arguing against direct recruitment of these local cells. Furthermore, although we observed relative threshold differences between conventional, burst, and 10-kHz SCS, the recruitment order was the same. Finally, contrary to previous reports, axon collateralization produced complex changes in activation thresholds of primary afferents. These results motivate future work to contextualize clinical observations across SCS paradigms. PERSPECTIVE: This article presents the first computational modeling study to investigate neural recruitment during conventional, burst, and 10-kilohertz spinal cord stimulation for chronic pain within a single modeling framework. The results provide insight into these treatments' unknown mechanisms of action and offer context to interpreting clinical observations.

Flash Floods are damaging natural hazards which often occur in the European Alps. Precipitation patterns and intensity may change in a future climate affecting their occurrence and magnitude. For impact studies, flash floods can be difficult to simulate due the complex orography and limited extent & duration of the heavy rainfall events which trigger them. The new generation convection-permitting regional climate models (CP-RCMs) improve the representation of the intensity and frequency of heavy precipitation. Therefore, this study combines such simulations with high-resolution distributed hydrological modelling to assess changes in flash flood frequency over the Alpine domain. We use output from a state-of-the-art CP-RCM to drive a high-resolution distributed hydrological wflow_sbm model covering most of the Alpine mountain range on an hourly resolution. First, the hydrological model was validated by comparing ERA5 driven simulation with streamflow observations from 130 stations (across Rhone, Rhine, Po, Adige and Danube basins). Second, a hourly wflow_sbm simulation driven by a CP-RCM downscaled ERAInterim simulation was compared to databases of past flood events to evaluate if the model can accurately simulate flash floods and to determine a suitable threshold definition for flash flooding. Finally, simulations of the future climate RCP 8.5 for the end-of-century (2096–2105) and current climate (1998–2007) are compared for which the CPRCM is driven by a Global Climate Model. The simulations are compared to assess if there are changes in flash flood frequency and magnitude using a threshold approach. Results show a similar flash flood frequency for autumn in the future, but a decrease in summer. However, the future climate simulations indicate an increase in the flash flood severity in both summer and autumn leading to more severe flash flood impacts.

Aims: To investigate the potential of curcumin-loaded polylactic-co-glycolic acid nanoparticles (CUR-PLGA-NPs), alone and with electrostatic precipitation, for improving tissue uptake during pressurized intraperitoneal aerosol chemotherapy (PIPAC). Methods: Positively and negatively charged CUR-PLGA-NPs were delivered as PIPAC into inverted bovine urinary bladders ex vivo. The experiment was repeated with the additional use of electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (electrostatic PIPAC). Results: Positively charged CUR-PLGA-NPs increased depth of tissue penetration by 81.5% and tissue concentration by 80%. Electrostatic precipitation further improved the uptake of positively charged CUR-PLGA-NPs by 41.8%. Conclusion: The combination of positive charge and electrostatic precipitation have significant potential to improve tissue uptake of nanoparticles during intraperitoneal chemotherapy.

Goal: Retinal prosthesis performance is limited by the variability of elicited phosphenes. The stimulating electrode's position with respect to retinal ganglion cells (RGCs) affects both perceptual threshold and phosphene shape. We created a modeling framework incorporating patient-specific anatomy and electrode location to investigate RGC activation and predict inter-electrode differences for one Argus II user. Methods: We used ocular imaging to build a three-dimensional finite element model characterizing retinal morphology and implant placement. To predict the neural response to stimulation, we coupled electric fields with multi-compartment cable models of RGCs. We evaluated our model predictions by comparing them to patient-reported perceptual threshold measurements. Results: Our model was validated by the ability to replicate clinical impedance and threshold values, along with known neurophysiological trends. Inter-electrode threshold differences in silico correlated with in vivo results. Conclusions: We developed a patient-specific retinal stimulation framework to quantitatively predict RGC activation and better explain phosphene variations.

OBJECTIVES: Spinal cord stimulation (SCS) for pain is typically implemented in an open-loop manner using parameters that remain largely unchanged. To improve the overall efficacy and consistency of SCS, one closed-loop approach proposes to use evoked compound action potentials (ECAPs) recorded from the SCS lead(s) as a feedback control signal to guide parameter selection. The goal of this study was to use a computational modeling approach to investigate the source of these ECAP recordings and technical and physiological factors that affect their composition. METHODS: We developed a computational model that coupled a finite element model of lower thoracic SCS with multicompartment models of sensory axons within the spinal cord. We used a reciprocity-based approach to calculate SCS-induced ECAPs recorded from the SCS lead. RESULTS: Our model ECAPs contained a triphasic, P1, N1, P2 morphology. The model P2-N1 amplitudes and conduction velocities agreed with previous experimental data from human subjects. Model results suggested that the ECAPs are dominated by the activation of axons with diameters 8.7–10.0 μm located in the dorsal aspect of the spinal cord. We also observed changes in the ECAP amplitude and shape due to the electrode location relative to the vertebrae and spinal cord. CONCLUSION: Our modeling results suggest that clinically-effective SCS relies on the activation of a large number of axons within a narrow fiber diameter range and that several factors affect the composition of the ECAP recordings. These results can improve how we interpret and implement these recordings in a potential closed-loop approach to SCS.

Background: Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective: To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods: European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (

Spinal cord stimulation (SCS) is a neurostimulation treatment for patients suffering from refractory chronic pain. Thousands of SCS systems are implanted annually, yet its success rate remains suboptimal, largely because its therapeutic mechanisms of action are not well understood. The direct effects of SCS – i.e., which neuronal elements are activated directly by the electrical currents produced by SCS systems – remain unclear, precluding improvement. In this study, we used computational modeling to investigate which neuronal elements are activated directly by SCS, and how various physiological and technical factors influence the neural response. To simulate the neural response to SCS, we evaluated the SCS-produced voltage distributions using the finite element method and then applied these voltages to biophysical neuron models of local cells in the spinal cord's dorsal horn as well as primary afferent fibers. We performed this analysis for three common SCS paradigms – conventional (50 Hz), 10 kHz, and burst stimulation. Our results indicate that primary afferent fibers are recruited at lower stimulation amplitudes than local cells in the dorsal horn for all SCS paradigms. Furthermore, we observed that primary afferent collateralization patterns (i.e., number and spacing of collaterals) and medio-lateral electrode shift affected the neural response.

The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell’s energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy. We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options. A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS. The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD. We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.

Purpose Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. Methods Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. Results The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. Conclusion German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Objective Spinal cord stimulation (SCS) is a common neurostimulation therapy to treat chronic pain. Computational models represent a valuable tool to study the potential mechanisms of action of SCS and to optimize the design and implementation of SCS technologies. However, it is imperative that these computational models include the appropriate level of detail to accurately predict the neural response to SCS and to correlate model predictions with clinical outcomes. Therefore, the goal of this study was to investigate several anatomic and technical factors that may affect model-based predictions of neural activation during thoracic SCS. Approach We developed computational models that consisted of detailed finite element models of the lower thoracic spinal cord, surrounding tissues, and implanted SCS electrode arrays. We positioned multicompartment models of sensory axons within the spinal cord to calculate the activation threshold for each sensory axon. We then investigated how activation thresholds changed as a function of several anatomical variables (e.g. spine geometry, dorsal rootlet anatomy), stimulation type (i.e. voltage-controlled vs. current-controlled), electrode impedance, lead position, lead type, and electrical properties of surrounding tissues (e.g. dura conductivity, frequency-dependent conductivity). Main results Several anatomic and modeling factors produced significant percent differences or errors in activation thresholds. Rostrocaudal positioning of the cathode with respect to the vertebrae had a large effect (up to 32%) on activation thresholds. Variability in electrode impedance produced significant changes in activation thresholds for voltage-controlled stimulation (38% to 51%), but had little effect on activation thresholds for current-controlled stimulation (less than 13%). Changing the dura conductivity also produced significant differences in activation thresholds. Significance This study demonstrates several anatomic and technical factors that can affect the neural response to SCS. These factors should be considered in clinical implementation and in future computational modeling studies of thoracic SCS.

Background and Aims: Black boys (6–8 years of age) were shown to have higher pulse wave velocity with potential early vascular compromise. We aimed to compare predefined urinary metabolites in black and white boys to explore associations of pulse wave velocity with these metabolites. Methods and Results: We included 40 white and 40 black apparently healthy boys between the ages of 6 and 8 years. Femoral pulse wave velocity was measured along with various metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) methods. Pulse wave velocity and diastolic blood pressure were higher in the black compared to the white boys (both p ≤ 0.002). Isovalerylcarnitine was lower and 1-metylhistidine tended to be lower (p = 0.002 and p = 0.073, respectively), whereas L-proline levels tended to be higher (p = 0.079) in the black compared to the white boys. In single, partial, and multiple regression analyses, pulse wave velocity correlated inversely with β-alanine (β = –0.414; p = 0.008) and 1-methylhistidine (β = –0.347; p = 0.032) and positively with L-proline (β = 0.420; p = 0.008), threonic acid (β = 0.977; p = 0.033), and malonic acid (β = 0.348; p = 0.030) in black boys only. Conclusion: Our study is the first to discover the associations of pulse wave velocity with β-alanine, 1-methylhistidine, and L-proline in children from South Africa, which may suggest potential early compromise in cardiac protective metabolic pathways in black boys as young as 6 years of age.

ObjectiveComputational current flow models of spinal cord stimulation (SCS) are widely used in device development, clinical trial design, and patient programming. Proprietary models of varied sophistication have been developed. An open-source model with state-of-the-art precision would serve as a standard for SCS simulation.ApproachWe developed a sophisticated SCS modeling platform, named Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) model. This platform consists of realistic and detailed spinal cord and ancillary tissues anatomy derived based on prior imaging and cadaveric studies. Represented tissues within the T9-T11 spine levels include vertebrae, intravertebral discs, epidural space, dura, CSF, white-matter, gray-matter, dorsal and ventral roots and rootlets, dorsal root ganglion, sympathetic chain, thoracic aorta, epidural space vasculature, white-matter vasculature, and thorax. As an exemplary, a bipolar SCS montage was simulated to illustrate the model workflow from the electric field calculated from a finite element model (FEM) to activation thresholds predicted for individual axons populating the spinal cord.Main ResultsCompared to prior models, RADO-SCS meets or exceeds detail for every tissue compartment. The resulting electric fields in white and gray-matter, and axon model activation thresholds are broadly consistent with prior stimulations.SignificanceThe RADO-SCS can be used to simulate any SCS approach with both unprecedented resolution (precision) and transparency (reproducibility). Freely available online, the RADO-SCS will be updated continuously with version control.

The Biointerfaces Interlaboratory Committees, the student organization for the Biointerfaces Institute at the University of Michigan, organized and executed an 8 hour “BioHackathon” on the broadly defined clinical topic of ‘Aging.’ The event began with experts in the field (a clinician and an engineer) highlighting the areas of greatest need in which engineers could improve the lives of the aging population. Attendees separated into teams based on shared interests in pursuing specific needs, and rapidly developed need statements and solution models to help the elderly. Solutions ranged from a smart toothbrush to help detect pneumonia in early stages, to small clothing pads to help reduce the impact of falls on hip fractures. Based on a follow-up anonymous internet survey, the attendees indicated they enjoyed the event, and would likely attend a similar event in the future. We conclude by reflecting upon the event, and suggest ways in which we could improve the style of the event for future hackathons.

Background: Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF. Methods: E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS. Results: Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8–2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3). Conclusions: Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority.

Spinal cord stimulation (SCS) is a widely-used therapy for chronic pain management. Computational models provide a valuable tool to study the effects of SCS on the nervous system. However, it is critical that these models include sufficient detail to correlate model predictions with clinical effects, including patient-specific data. Therefore, in this study, we developed a patient-specific computer model for a patient undergoing SCS to treat neuropathic pain. The patient-specific model predicted sensory threshold estimates that were consistent with the corresponding clinical measurements. These results demonstrate the potential for patient-specific computer models to quantitatively describe the axonal response to SCS and to address scientific questions related to clinical SCS.

OBJECTIVE Despite the widespread use of spinal cord stimulation (SCS) for chronic pain management, its neuromodulatory effects remain poorly understood. Computational models provide a valuable tool to study SCS and its effects on axonal pathways within the spinal cord. However, these models must include sufficient detail to correlate model predictions with clinical effects, including patient-specific data. Therefore, the goal of this study was to investigate axonal activation at clinically relevant SCS parameters using a computer model that incorporated patient-specific anatomy and electrode locations. METHODS We developed a patient-specific computer model for a patient undergoing SCS to treat chronic pain. This computer model consisted of two main components: 1) finite element model of the extracellular voltages generated by SCS and 2) multicompartment cable models of axons in the spinal cord. To determine the potential significance of a patient-specific approach, we also performed simulations with standard canonical models of SCS. We used the computer models to estimate axonal activation at clinically measured sensory, comfort, and discomfort thresholds. RESULTS The patient-specific and canonical models predicted significantly different axonal activation. Relative to the canonical models, the patient-specific model predicted sensory threshold estimates that were more consistent with the corresponding clinical measurements. These results suggest that it is important to account for sources of interpatient variability (e.g., anatomy, electrode locations) in model-based analysis of SCS. CONCLUSIONS This study demonstrates the potential for patient-specific computer models to quantitatively describe the axonal response to SCS and to address scientific questions related to clinical SCS.

A meta-analytic review of 33 studies and 41 independent samples was conducted of the effectiveness of community-based mental health and behavioral programs for low-income urban youth. Findings indicated positive effects, with an overall mean effect of 0.25 at post-test. While this is comparable to previous meta-analytic intervention research with more diverse samples, it stands in contrast to findings of the school-based review (0.08 at post-test) focused on this population. The current review found type of intervention to significantly moderate effects, with effects highest for programs that were environmentally based. In fact, effect sizes for programs that did not target the environment were not significant. Findings are discussed with an emphasis on environmental influences, including the differing contexts affecting school- versus community-based interventions conducted with low-income, urban youth.

The German pension insurance has in recent years developed a comprehensive programme for quality assurance in rehabilitation, and has implemented the programme into routine practice. Different aspects of rehabilitation are evaluated with differentiated instruments. Issues dealt with inter alia include the quality of rehabilitative care in a narrower sense, the structure and organisation of the rehabilitation centres, as well as quality from the patients' perspective. On the whole, positive results predominate. Big differences in quality however have been found between the rehabilitation centres. The data collections and data evaluations carried out make a continuous process of quality assurance reporting possible for use by rehabilitation centres and pension insurance agencies. This will enable targeted initiatives for quality improvement. The methods and procedures of quality assurance are enhanced at regular intervals, and the scope of quality assurance is extended. Thus, rehab quality assurance is also expanded to cover ambulant rehabilitation or rehabilitation of children and young people.

The spreading of liquid alkanes over surfaces plays an important role in applications such as lubrication, painting, and printing. To make significant advances in these fields, it is essential to increase our understanding of the interactions between alkanes and surfaces. Long-chain alkanes form two typical adsorption structures on a surface--the parallel phase and the standing-up phase. The most thermodynamically stable structure is the parallel phase, in which the alkane molecules lie flat on the surface. If the temperature is slightly below the bulk melting point, then alkanes form a thermodynamically stable standing-up phase on top of an existing parallel layer. At lower temperatures, the standing-up phase becomes metastable. Using atomic force microscopy, we have found that the standing-up alkane layer consists of multiple domains, indicating that the standing-up layer forms through a multinucleation process during the liquid-solid transition on the surface. If, however, the temperature is above the melting point, then we have found that the standing-up layer shrinks to a droplet and leaves a residue on its original position. During the spreading of an alkane droplet, the parallel layer forms on the substrate surface surrounding the droplet by adsorption from the vapor, which precedes the arrival of the liquid. There has been uncertainty, however, as to whether the parallel layer moves with the liquid alkane or remains stationary during spreading. In this study, we used the residue left on the parallel layer as a landmark to monitor the movement of the parallel layer during the spreading of an alkane droplet. Using this landmark, we found that the parallel layer remained stationary on the substrate, indicating that the liquid alkane spreads on a stationary parallel layer surface. Therefore, this study reveals that the surface properties of the parallel layer--not the surface properties of the substrate--control the spreading and wetting of a liquid alkane.

After several years of preparation the German Society of Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft fur Anasthesiologie und Intensivmedizin - DGAI) has, during its annual conference 2007, officially launched the DGAI CPR registry. After implementation of the dataset ”primary care” in 2004, the datasets ”definite care" and ”long-term process" have now been released. The completed, internet based database is open for any interested person or institution as a tool for quality management. Data may be recorded online, and basic analyses be performed immediately. Beyond that benchmarks with other institutions are possible, by including the well accepted Utstein style on international level too.

In 13 patients, mean age 57 (31-78) years, with malignant melanoma of the vulva, 7 of the tumors occurred on the Labia majora, 4 on the Labia minora and 2 on the clitoris. 8 cases involved nodular malignant melanomas, 2 cases each involved a superficial-spreading form and an acrolentiginous form, and one case involved a non-classifiable malignant melanoma. According to histological criteria 10 of 13 tumors showed a high risk of metastasising. At the time of diagnosis one of the patients was in stage II and one in stage III of the disease. Of the 13 patients, 6 died, as a result of the tumor, 5 within the first 2 years. The mean survival time was 15 (6-28) months. In three other cases the disease has reached an advanced stage: stage Ib, II or III. Up to now only 4 patients have remained symptom free, the symptom free interval averaging 62 (33-84) months. This investigation confirms the special characteristics of malignant melanomas of the vulva, which are the predominance of tumors having a bad prognosis and the rapidly progressing course of the disease.

The role of electrical and potassium (K + )-induced depolarisation on choline-acetyltransferase (ChAT) activity in human and mouse neocortical slices was studied. When [ 3 H ]-ACh release was evoked by two K + stimulations in human neocortex, the mean S 2 / S 1 ratio was significantly below unity. ChAT inhibitors, like bromo-acetylcholine and ocadaic acid, raised this ratio by 79 and 63%, respectively, suggesting that the diminished S 2 / S 1 value in the absence of ChAT inhibitors reflected an increased ChAT activity at S 2 following K + depolarisation at S 1 . When stimulated electrically, however, the S 2 / S 1 ratio in human neocortex was near unity and ocadaic acid remained without effect. In parallel experiments on mouse neocortical slices, the S 2 / S 1 ratio was near unity in both electrically or K + -evoked [ 3 H ]-ACh release and was not altered by ChAT inhibition. ChAT activity following K + depolarisation was also determined directly. ChAT activation in human neocortical slices was highest at 10 and 20 mM K + . ChAT activity in mouse neocortical tissue was not altered by K + depolarisation. These results suggest that in human, but not in mouse, neocortex ChAT activity may be increased due to ongoing K + depolarisation. This increase of ChAT activity supports a cholinergic degeneration hypothesis which has been entitled “autocannibalism” by Wurtman [TINS 15 (1992) 177].

In den Bayerischen Alpen nahe dem Tegernsee wurden je drei voll bewaldete Kleineinzugsgebiete von 5–16 ha Grose als Versuchsflachen in den geologischen GroseinheitenFlysch und Kalkalpin (Hauptdolomit) ausgewahlt. Kernpunkt des Versuchsansatzes ist es, Zusammenhange zwischen Waldzustand, Bodenzustand und Abflus- und Abtragsverhalten zu untersuchen und zu quantifizieren. Dazu werden durch forstliche Hiebsmasnahmen unterschiedliche Waldschadenszustande simuliert. Im Herbst 1992 wurden durch forstliche Masnahmen im Gebiet Flysch Sonnseite 1 ca. 40%, auf Flysch Schattseite ca. 30% des aufstockenden Bestandes entnommen. Das Gebiet Flysch Sonnseite 2 blieb als Kontrollflache unverandert.

We evaluated the direct effects of glucocorticoids on intracellular sodium content and cellular transport systems. Cytosolic free sodium concentration ([Na+]i) was measured in intact human lymphocytes using the sodium-sensitive fluorescent dye sodium-binding benzofuran-isophthalate. Administration of dexamethasone for 60 min increased lymphocytic [Na+]i from 17.6 +/- 2.0 mmol/L to 24.3 +/- 3.9 nmol/L (n = 12; P < 0.01). The dexamethasone-induced [Na+]i increase was abolished in the absence of extracellular sodium, by mifepristone and by actinomycin D. The dexamethasone-induced [Na+]i increase was also seen after inhibition of Na+,K(+)-ATPase by 1 mmol/L ouabain. The present results indicate that dexamethasone produces a trans-plasma membrane sodium influx probably by early occurring genomic effects.

Injury and stress are accompanied by a characteristic hormonal response and altered energy utilisation. Hyperglycaemia and negative nitrogen (N) balance are the leading symptoms of the metabolic changes in the post-operative state. In a prospective, randomised study the efficacy and metabolic effects of glucose-xylitol (GX) 35% (1:1) versus glucose (G) 40% were investigated in patients undergoing major surgery. METHOD. Twenty-four patients undergoing abdomino-thoracic oesophageal cancer surgery were treated in a standardised manner. Total parenteral nutrition was administered over 6 days (kg body wt.-1/day): day of surgery 1-1.25 g carbohydrate (CH); 1st postoperative day (POD) 1.5 g CH, 1 g amino acids (AA); 2nd POD 3 g CH, 1.5 g AA, 1.0 g fat; from 3rd POD 3 g CH, 1.5 g AA, 1.5 g fat (CH GX35% (n = 12) or G40% (n = 12), AA Intrafusin 15%, fat Intralipid 20%). Daily and cumulative N balances, blood-G profiles, blood chemistry, and physical parameters were determined. Glucagon and insulin profiles, CH losses, and oxalic acid secretion were measured. RESULTS. Both groups were comparable for age, body mass index, clinical and physical parameters, and blood chemistry. Mean cumulative N balances after 6 days were -12.0 +/- 16.3 g N for GX35% and -5.6 +/- 19.4 g N for G40% (n.s.; Wilcoxon, P < 0.05). Blood G was similar for both groups with values ranging from 130 to 240 mg/dl on the day of surgery and below 150 mg/dl on the consecutive days. In each group 1 patient needed additional insulin therapy. Glucagon and insulin levels did not show a significant difference between the groups. CONCLUSION. No difference in tolerance and efficacy of nutritional support by GX versus G at a dose of 3 g.kg body wt.-1.d in oesophagectomised patients could be observed. Similar blood G profiles were in accordance with comparable glucagon and insulin levels. Because of the high standard deviations of N balances, differences in efficacy could not be proven. A significantly lower level of pseudocholinesterase (PCHE) for G40% on day 7 might indicate enhanced hepatic protein synthesis in the GX group.

In a controlled, prospective multi-centre study, defibrillation by emergency medical technicians (EMTs) was compared with the current standard of care in Germany--defibrillation by emergency physicians (EPs)-in order to answer the following questions: can EMTs in a two-tiered emergency medical services (EMS) system with physicians in the field defibrillate earlier than, and as safely as EPs? Does defibrillation by EMTs (study group) affect survival rate and long-term prognosis of patients in ventricular fibrillation (VF), as compared with the current national standards in resuscitation (basic cardiopulmonary resuscitation (CPR) by EMTs, and defibrillation by physicians: control group?Prior to the onset of the study, all EMTs completed retraining in basic life support (BLS). Randomly assessed EMTs were then trained to use semi-automatic defibrillators. With the help of on-line tape recordings, the complete resuscitation sequence was evaluated. Follow-up of the patients was carried out with the help of the Glasgow Coma Scale as well as Pittsburgh Cerebral and Overall Performance Categories.A total of 159 patients with VF were included in the study. In 121 cases, collapse was witnessed. Of the patients receiving defibrillation by EMTs 25% were discharged from hospital alive, compared to 24% of the patients defibrillated by EPs. Of the study patients 67% were defibrillated within 12 min, while the percentage of control patients was 46%. Study patients were defibrillated earlier (P0.01), the return of spontaneous circulation (ROSC) was achieved earlier (P0.05), and the rate of patients requiring no adrenalin during resuscitation was higher in the study group (P0.05). The total amount of adrenalin administered in the study group was lower (P0.05). No statistically significant differences were found concerning the neurologic long-term prognosis.In our study, EMT defibrillation was equally effective as defibrillation by EPs, but failed to improve survival rates or long-term outcome of patients in VF significantly, compared to EP defibrillation. Due to a reduction in the time intervals from collapse to defibrillation and to ROSC, as well as in adrenalin doses, by EMT-defibrillation, EMTs in Germany should defibrillate if they reach a patient prior to an EP, provided they have received continuous medical training and supervision.

We investigated whether different procedures during general anaesthesia alter platelet activation in vivo and/or activate coagulation and fibrinolysis. Forty-one healthy adult patients, scheduled for elective ophthalmic surgery under general anaesthesia, were studied with regard to changes of plasma beta-thromboglobulin (beta TG, index of platelet activation), thrombin-antithrombin III-complex (TAT, index of activation of coagulation) and d-dimer (index of fibrinolysis) during anaesthesia. The patients underwent either inhalation anaesthesia with enflurane and nitrous oxide or balanced anaesthesia with enflurane (0.5% end-tidal concentration) and alfentanil. Ten minutes after intubation the beta TG level was significantly reduced compared to the preoperative value in both general anaesthesia groups. Balanced anaesthesia caused a moderate but significant increase of TAT values at 10 min after extubation. No significant change in d-dimer levels was seen. Presuming a minimal effect of the surgical procedure on the determined variables, we conclude that none of the anaesthetic procedures induces platelet activation and fibrinolysis. The clinical relevance of the moderate coagulation activation during balanced anaesthesia remains to be investigated.