Genetic parameters for dry matter intake, energy balance, residual energy intake, and liability to diseases in German Holstein and Fleckvieh dairy cows.

Selection for feed efficiency (FE) is a hot topic in dairy cow breeding. Dry matter intake (DMI) and residual energy intake (REI) are mostly discussed as new selection traits. Selection for lower DMI or REI seems to increase FE if other traits, such as milk yield or health, are not affected negatively. However, genetic relationships with other traits have not been adequately investigated because of the difficulties in recording sufficient feed intake data for genetic evaluations. The aim of this study was to examine the genetic relationships between FE-related traits and liability to diseases throughout lactation. First, heritabilities for all traits are presented. Subsequently, genetic correlations between DMI, energy-corrected milk yield, energy balance (EB), and REI on the one hand and 3 disease categories (mastitis, claw and leg diseases, and all diseases) on the other throughout lactation in German Holstein (GH) dairy cows are illustrated. Production and health data from the projects optiKuh and eMissionCow were used. Data consisted of weekly observations recorded over a 325-wk period in 2,387 GH and over a 300-wk period in 632 Fleckvieh (FV) primiparous and multiparous dairy cows from 13 dairy research farms in Germany. Variance and covariance components were estimated univariately or bivariately with linear random regression models for production data and threshold random regression models for health data. Heritabilities for DMI, EB, and REI were on average 0.17 and 0.15, 0.14 and 0.15, as well as 0.11 and 0.14 in GH and FV, respectively. Heritabilities on the underlying scale for mastitis, claw and leg diseases, and all diseases were on average 0.17 and 0.16, 0.18 and 0.12, as well as 0.15 and 0.11 in GH and FV, respectively. In GH, almost all genetic correlations were negative, especially in early lactation. Within the first 50 d in milk, genetic correlations between DMI and REI on the one hand and disease categories on the other ranged from -0.25 to -0.14 for mastitis, from -0.31 to -0.13 for claw and leg diseases, and from -0.58 to -0.30 for all diseases. Consequently, selection for lower DMI or REI could lead to a higher liability to diseases, especially in early lactation. A possibility to mitigate these undesirable side effects could be lactation stage-specific selection for FE. For FV, further studies with more data are needed to assess genetic relationships.

Liability to diseases and their relation to dry matter intake and energy balance in German Holstein and Fleckvieh dairy cows.

Dairy cow efficiency is increasingly important for future breeding decisions. The efficiency is determined mostly by dry matter intake (DMI). Reducing DMI seems to increase efficiency if milk yield remains the same, but resulting negative energy balance (EB) may cause health problems, especially in early lactation. Objectives of this study were to examine relationships between DMI and liability to diseases. Therefore, cow effects for DMI and EB were correlated with cow effects for 4 disease categories throughout lactation. Disease categories were mastitis, claw and leg diseases, metabolic diseases, and all diseases. In addition, this study presents relative percentages of diseased cows per days in milk (DIM), repeatability, and cow effect correlations for disease categories across DIM. A total of 1,370 German Holstein (GH) and 287 Fleckvieh (FV) primiparous and multiparous dairy cows from 12 dairy research farms in Germany were observed over a period of 2 yr. Farm staff and veterinarians recorded health data. We modeled health and production data with threshold random regression models and linear random regression models. From DIM 2 to 305 average daily DMI was 22.1 kg/d in GH and 20.2 kg/d in FV. Average weekly EB was 2.8 MJ of NEL/d in GH and 0.6 MJ of NEL/d in FV. Most diseases occurred in the first 20 DIM. Multiparous cows were more susceptible to diseases than primiparous cows. Relative percentages of diseased cows were highest for claw and leg diseases, followed by metabolic diseases and mastitis. Repeatability of disease categories and production traits was moderate to high. Cow effect correlations for disease categories were higher for adjacent lactation stages than for more distant lactation stages. Pearson correlation coefficients between cow effects for DMI, as well as EB, and disease categories were estimated from DIM 2 to 305. Almost all correlations were negative in GH, especially in early lactation. In FV, the course of correlations was similar to GH, but correlations were mostly more negative in early lactation. For the first 20 DIM, correlations ranged from -0.31 to 0.00 in GH and from -0.42 to -0.01 in FV. The results illustrate that future breeding for dairy cow efficiency should focus on DMI and EB in early lactation to avoid health problems.

Residual energy intake, energy balance, and liability to diseases: Genetic parameters and relationships in German Holstein dairy cows.

Residual energy intake (REI) is an often-suggested trait for direct selection of dairy cows for feed efficiency. Cows with lower REI seem to be more efficient but are also in a more severe negative energy balance (EB), especially in early lactation. A negative EB leads to a higher liability to diseases. Due to this fact, this study aims to investigate the genetic relationship between REI and liability to diseases. Health and production data were recorded from 1,370 German Holstein dairy cows from 8 research farms over a period of 2 yr. We calculated 2 phenotypes for REI that considered the following energy sinks: milk energy content, metabolic body weight, body weight change, body condition score, and body condition score change. Genetic parameters were estimated with threshold or linear random regression models from days in milk (DIM) 1 to 305. Heritabilities for REI, EB, and all diseases ranged from 0.12 to 0.39, 0.15 to 0.31, and 0.09 to 0.20, respectively. Genetic correlations between selected DIM for REI and EB were higher for adjacent DIM than for more distant DIM. Pearson correlation coefficients between estimated breeding values (EBV) for REI and EB varied between 0.47 and 0.81; they were highest in mid lactation. Correlations between EBV for all diseases and REI as well as EB were negative, with lowest values in early lactation. Within the first 50 DIM, proportions of diseased days for cows with lowest EBV for REI were almost twice as high as for cows with highest EBV for REI. In conclusion, selecting dairy cows for lower REI should be treated with caution because of an unfavorable relationship with liability to diseases, especially in early lactation.

[Under the skin-A special manifestation of a systemic granulomatous disease]. / Unter die Haut ­ Eine besondere Manifestation einer granulomatösen Systemerkrankung.

Based on the case of a 33-year-old female patient with Löfgren's syndrome and skin changes in the region of a tattoo, this article describes tattoo sarcoidosis as a special manifestation of cutaneous sarcoidosis. Papulonodular changes that are strictly confined to a tattoo are highly suspicious for tattoo sarcoidosis. Interestingly, tattoo sarcoidosis is commonly associated with the involvement of other organs.

Esophageal bougination: a novel ex vivo endoscopic training model correlated with clinical data.

BACKGROUND: Esophageal bougination is a worldwide standard endoscopic procedure. Clinical methods and recommendations are based on clinical experiences only. Mechanical properties have never been described. Aim of the study was to establish a realistic ex vivo training model. Therefore, detailed assessment of relevant mechanical features of esophageal bougination should be evaluated ex vivo and in patient setting and correlated against. PATIENTS AND METHODS: A three-step concept was used to evaluate mechanical properties at stenosis level. First, insertion forces were evaluated in an ex vivo linear single stenosis model during steady mechanical insertion. Second, adding friction and properties of the pharynx and upper esophagus, the model was integrated in an artificial endoscopic training model (ELITE training model). Third, in vivo measurements were taken to correlate ex vivo data with parameters of a realistic patient setting. RESULTS: With the presented setup, we were able to assess insertion force and pressure levels in an artificial stricture using different sizes of commercially available standard bougies. In all models, there was a relevant increase in insertion force with higher stricture pressure levels. Insertion force levels in the ELITE model show higher levels compared to the linear stenosis model. Having regard to the maximum forces in patients, there is also a constant increase in mean insertion force according to higher bougie sizes, but lower forces were measured as in the ELITE model. DISCUSSION: The applied models are suitable to appraise mechanical properties of esophageal bougination in an ex vivo model and patient setting. Forces could be constituted reliable, significant increase was documented according to stenosis level and results were comparable to patient data. This was comparable to patient data. Further clinical evaluation in different kinds of stenosis is necessary.

Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men.

This study investigated the pharmacokinetics of inhaled terbutaline at rest and after exercise in normal and hot ambient conditions with respect to doping analysis. Thirteen trained young men participated in the study. Urine and blood samples were collected after inhalation of 4 mg terbutaline during three trials: exercise in hot ambient conditions (30-35 °C) (EXH), exercise in normal ambient conditions (20-25 °C) (EX), and rest (20-25 °C) (R). Exercise consisted of 130 min at various intensities. Adjustment of urine concentrations of terbutaline to a specific gravity (USG) of 1.02 g/mL was compared with no adjustment. Area under the serum concentration-time curve within the first 6 h was higher for EX (27 ± 3 ng/mL/h) (P ≤ 0.01) and EXH (25 ± 4 ng/mL/h) (P ≤ 0.05) than for R (20 ± 3 ng/mL/h). When unadjusted for USG, urine concentrations of terbutaline after 4 h were different in the order EXH > EX > R (P ≤ 0.01). When unadjusted for USG, urine concentrations of terbutaline were 299 ± 151 ng/mL higher (P ≤ 0.001) after 4 h compared with adjusted concentrations in EXH. Excretion rate of terbutaline was higher (P ≤ 0.001) for EX than for EXH and R within the first 0-1½ h. In conclusion, EXHs results in higher urine concentrations of terbutaline. This should be considered when evaluating doping cases of terbutaline.

Stable carbon isotope fractionation data between H(2)CO(3)(*) and CO(2)(g) extended to 120 °C.

RATIONALE: Literature data on experimentally derived equilibrium stable carbon isotope fractionation (10(3) lnα(13) C) between H2 CO3 (*) (H2 CO3 + CO2(aq) ) and gaseous CO2 (CO2(g) ) are so far only available up to 60 °C and were typically determined at or near atmospheric pressures. Here we experimentally expand this dataset to temperature and pressure conditions close to the supercritical state for CO2 . The objective is to improve the applicability of stable carbon isotopes as a tracer in environments where such conditions prevail. METHODS: Eighteen stable carbon isotope laboratory experiments were conducted in a steel vessel. Deionised water that was acidified with hydrochloric acid (HCl, 1 N) to a pH of 2.4 was equilibrated with CO2(g) at pressures (pCO2 ) of 55 bar for durations between 2 and 188 h. The experiments were conducted at 20, 60, 80, 100 and 120 °C. H2 CO3 (*) and CO2(g) were sampled separately and their carbon isotope ratios were determined by isotope ratio mass spectrometry. RESULTS: At 20 °C, average 10(3) lnα(13) CH2CO3 * -CO2(g) values of -1.0 ± 0.1 ‰ were observed with a preference for (12) C in H2 CO3 (*) consistent with previous research. At elevated temperatures of 120 °C, 10(3) lnα(13) CH2CO3 * -CO2(g) values decreased to an average value of -0.7 ± 0.1 ‰. The resulting temperature dependence for carbon isotope fractionation between H2 CO3 (*) and CO2(g) was 10(3) lnα(13) CH2CO3 * -CO2(g) = (0.0025 ± 0.0004) T(°C) - (1.0 ± 0.03) ‰. Carbon isotope equilibrium between H2 CO3 (*) and CO2(g) was reached within reaction times of 18 h and mostly within 5 h or less. CONCLUSIONS: 10(3) lnα(13) CH2CO3 * -CO2(g) data are now available for temperatures up to 120 °C and for pressures of up to 55 bar. The results suggest that higher pCO2 levels possibly shorten carbon isotope equilibration times. These data are critically important for using δ(13) C values as tracers, for instance at geological CO2 sequestration sites and corresponding natural analogues.

High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells.

Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin αB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001). Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL- as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti-cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL-containing therapy.

Long-term follow-up in patients with indeterminate Barrett esophagus.

BACKGROUND: Barrett esophagus (BE) is a major risk factor for adenocarcinoma of the distal esophagus. Reliable detection of BE during upper endoscopy is therefore mandatory. According to most guidelines, diagnosis of BE requires both endoscopy and histology for confirmation. However, since adenocarcinomas were also described in patients with indeterminate BE, i.e. endoscopic visible columnar metaplasia but no histological confirmation of goblet cells or vice versa, debate has risen on the risk of malignancy and the need for endoscopic surveillance in such patients. PATIENTS AND METHODS: The study was aimed to assess long-term follow-up data on 209 patients with indeterminate BE (on histopathology or endoscopy) initially examined between 1999 and 2000. Patients or referring physicians were contacted concerning the most recent endoscopic and histopathological results. RESULTS: Follow-up data could be assessed in 149/209 patients (65.1%) after a mean follow-up period of 9.4 years (SD ±2.4 years). Neoplasia was not reported for any patient. The previous endoscopic-histopathological diagnoses could be confirmed in 3 patients only. In the group with endoscopic diagnosis of BE but no histopathological confirmation, BE was described histopathologically in 1 patient during follow-up. CONCLUSION: Persistence of indeterminate BE is poor during long-term follow up. The risk of cancer appears to be negligible. Hence, surveillance of these patients appears equivocal.

Predictive mathematical models of cancer signalling pathways.

Complex intracellular signalling networks integrate extracellular signals and convert them into cellular responses. In cancer cells, the tightly regulated and fine-tuned dynamics of information processing in signalling networks is altered, leading to uncontrolled cell proliferation, survival and migration. Systems biology combines mathematical modelling with comprehensive, quantitative, time-resolved data and is most advanced in addressing dynamic properties of intracellular signalling networks. Here, we introduce different modelling approaches and their application to medical systems biology, focusing on the identifiability of parameters in ordinary differential equation models and their importance in network modelling to predict cellular decisions. Two related examples are given, which include processing of ligand-encoded information and dual feedback regulation in erythropoietin (Epo) receptor signalling. Finally, we review the current understanding of how systems biology could foster the development of new treatment strategies in the context of lung cancer and anaemia.

Tandem repeated irritation in aged skin induces distinct barrier perturbation and cytokine profile in vivo.

BACKGROUND: The barrier perturbation pattern and molecular markers of inflammation upon tandem repeated irritation in chronologically aged skin have not been previously studied. OBJECTIVES: We aimed to investigate the barrier impairment kinetic and in vivo cytokine profile following sequential irritation with sodium lauryl sulfate (SLS) and undiluted toluene (Tol) in aged compared with young skin. METHODS: Four fields on the volar forearm of healthy aged and young volunteers (median age, respectively, 63.9 and 32.6 years) were sequentially exposed to 0.5% SLS and undiluted toluene in a controlled tandem repeated irritation test; an adjacent nontreated field served as control. The permeability barrier function was monitored by repeated measurements of transepidermal water loss (TEWL), capacitance and erythema every 24 h up to 96 h. The stratum corneum cytokines were harvested by sequential tape stripping and quantified by multiplex bead array and enzyme-linked immunosorbent assay. RESULTS: Compared with young skin, aged skin was characterized by delayed and/or less pronounced alterations in the visual irritation score, TEWL, chromametry a*-value and capacitance, assessed by the respective Δ-values for each parameter and monitoring time point. In both groups, exposure to SLS/SLS, SLS/Tol and Tol/SLS resulted in decreased interleukin (IL)-1α levels, whereas the application of Tol/Tol induced an increase in IL-1α. Furthermore, decreased IL-1 receptor antagonist (IL-1RA) levels and a lower IL-1RA/IL-1α ratio were found following repeated exposure to the irritants. CONCLUSIONS: Our results provide evidence for selective alterations in the cytokine profile and distinct barrier impairment kinetic following tandem repeated irritation with SLS and Tol in aged compared with young skin in vivo.

Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures.

BACKGROUND AND STUDY AIMS: The accurate diagnosis of indeterminate pancreaticobiliary strictures presents a clinical dilemma. Probe-based confocal laser endomicroscopy (pCLE) offers real-time in vivo microscopic tissue examination that may increase sensitivity for the detection of malignancy. the objective of this study was to develop and validate a standard descriptive classification of pcle in the pancreaticobiliary system. PATIENTS AND METHODS: A total of 102 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with pCLE to assess indeterminate pancreaticobiliary strictures were enrolled in a multicenter registry; 89 of these patients were evaluable. Information and data on the following were collected prospectively: clinical, ERCP, tissue sampling, pCLE, and follow-up. A uniform classification of pCLE findings ("Miami Classification") was developed, consisting of a set of image interpretation criteria. Thereafter, these criteria were tested through blinded consensus review of 112 randomized pCLE videos from 47 patients, and inter-observer variability was assessed in 42 patients . RESULTS: A consensus definition of the specific criteria of biliary and pancreatic pCLE findings for indeterminate strictures was developed. Single-image interpretation criteria did not have a high enough sensitivity for predicting malignancy. However, combining two or more criteria significantly increased the sensitivity and predictive values. The characteristics most suggestive of malignancy included the following: thick white bands (>20 µm), or thick dark bands (>40 µm), or dark clumps or epithelial structures. These provided sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 33%, 80%, and 80% compared with 48%, 100%, 100%, and 41% for standard tissue sampling methods. Inter-observer variability was moderate for most criteria. CONCLUSION: The Miami Classification enables a structured, uniform, and reproducible description of pancreaticobiliary pCLE. Combining individual characteristics improves the sensitivity for the detection of malignancy.

Multimodal endoscopic therapy for multifocal intraepithelial neoplasia and superficial esophageal squamous cell carcinoma - a case series.

Local endoscopic procedures are increasingly used and accepted treatments for unifocal superficial esophageal squamous cell carcinoma (SESCC). In multifocal SESCC, esophagectomy with or without chemoradiotherapy is often regarded as standard therapy. However, a combination of local endoscopic resection and new techniques such as radiofrequency ablation may play an increasing role in the treatment of selected patients with multifocal SESCC. The aim of this series was to evaluate the feasibility of a multimodal endoscopic approach. We report a case series of six consecutive patients from a European tertiary center who underwent endoscopic treatment for multifocal SESCC. The treatment comprised endoscopic mucosal resection using the cap technique or endoscopic submucosal dissection, in combination with radiofrequency ablation. The main outcome measure was complete tumor eradication after therapy and during the follow-up period. Using such an approach, complete eradication of cancer was achieved in all patients during follow-up. No major adverse events occurred. In conclusion, in selected patients with multifocal or residual SESCC, local resection techniques in combination with radiofrequency ablation may be safe and potentially curative alternative treatments.

Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.

Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the host's immune system in controlling the devastating course of metastatic renal cell carcinoma. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a 'mixed response', and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens.

Natural orifice transluminal endoscopic surgery: cardiopulmonary safety of transesophageal mediastinoscopy.

BACKGROUND AND STUDY AIMS: Physiological reactions during natural orifice transluminal endoscopic surgery (NOTES) mediastinoscopy may lead to cardiorespiratory depression. The aim of the current study was to assess cardiopulmonary changes during transesophageal mediastinoscopy in an acute porcine model. METHODS: Transesophageal mediastinoscopy was performed under general anesthesia in eight female pigs with a bodyweight of 39 +/- 6 kg. Mediastinal access was achieved via a submucosal tunnel. The cardiac index and global end-diastolic volume index (reflecting preload) were measured every 3 minutes by transpulmonary thermodilution. The following parameters were also recorded: mediastinal pressure, heart rate, mean arterial pressure, systemic vascular resistance index (SVRI; reflecting afterload), peak inspiratory pressure, pH, pCO (2), and pO (2). RESULTS: In three animals, small tears in the parietal pleura resulted in tension pneumothoraces. The associated cardioplumonary deterioration was fatal in one pig. The other two pigs recovered after decompression with a chest tube. In the remaining five animals there were only mild hemodynamic and respiratory changes during mediastinoscopy. There was a significant ( P = 0.005) but minor transient fall in cardiac index, which correlated with a small rise in SVRI (r = - 0.857, P < 0.001). In the pigs with uncomplicated mediastinoscopy, on-demand insufflation via the endoscope resulted in median mediastinal pressures of 4.5 mm Hg (range 2.3 - 10.2 mm Hg). Overall, mediastinal and thoracic structures could be identified without difficulty via the transesophageal approach. CONCLUSIONS: NOTES mediastinoscopy carries a substantial risk of inadvertent development of a pneumothorax. Otherwise, it leads to negligible hemodynamic and pulmonary changes. In conclusion, close monitoring for the presence of a pneumothorax during NOTES mediastinoscopy appears to be mandatory.

Probe-based confocal laser endomicroscopy compared with standard four-quadrant biopsy for evaluation of neoplasia in Barrett's esophagus.

BACKGROUND AND STUDY AIMS: Surveillance of Barrett's esophagus includes endoscopic inspection with biopsy of suspicious lesions followed by four-quadrant biopsy of the remaining mucosa. We assessed the ability of probe-based confocal laser endomicroscopy (pCLE) to replace biopsy in the endoscopic evaluation of patients with Barrett's esophagus in a prospective and controlled setting. PATIENTS AND METHODS: A total of 68 patients who were referred for endoscopic assessment of Barrett's esophagus were included across three centers. pCLE recordings were interpreted live during the examination as well as in a blinded manner at least 3 months after endoscopy. pCLE diagnosis of neoplasia based on pre-defined criteria was compared with histopathology from suspicious as well as four-quadrant biopsies. RESULTS: A total of 670 pairs of biopsies and pCLE video sequences were available for analysis, with neoplasia (high-grade dysplasia or cancer) being histologically diagnosed in 8.3 %. Specificity and negative predictive value of pCLE in excluding neoplasia was 0.97 (90 %CI 0.95 - 0.98) and 0.93 (0.91 - 0.95) for the blinded evaluation, and 0.95 (0.90 - 0.98) and 0.92 (0.90 - 0.94) for the on-site assessment. Positive predictive values (PPVs) and sensitivity were rather poor for both settings (46 %/28 % [blinded] and 18 %/12 % [on-site], respectively). CONCLUSIONS: pCLE can be regarded as non-inferior to endoscopic biopsy in excluding neoplasia of Barrett's esophagus mucosa. However, due to its low PPV and sensitivity, pCLE may currently not replace standard biopsy techniques for the diagnosis of Barrett's esophagus and associated neoplasia. Further technical development of pCLE and a better understanding of its role in relation to other imaging technologies are necessary.

Identifiability and observability analysis for experimental design in nonlinear dynamical models.

Dynamical models of cellular processes promise to yield new insights into the underlying systems and their biological interpretation. The processes are usually nonlinear, high dimensional, and time-resolved experimental data of the processes are sparse. Therefore, parameter estimation faces the challenges of structural and practical nonidentifiability. Nonidentifiability of parameters induces nonobservability of trajectories, reducing the predictive power of the model. We will discuss a generic approach for nonlinear models that allows for identifiability and observability analysis by means of a realistic example from systems biology. The results will be utilized to design new experiments that enhance model predictiveness, illustrating the iterative cycle between modeling and experimentation in systems biology.

Infected necrosis in severe pancreatitis--combined nonsurgical multi-drainage with directed transabdominal high-volume lavage in critically ill patients.

BACKGROUND: Infection of pancreatic necrosis is a life-threatening complication during the course of acute pancreatitis. In critically ill patients, surgical or extended endoscopic interventions are associated with high morbidity and mortality. Minimally invasive procedures on the other hand are often insufficient in patients suffering from large necrotic areas containing solid or purulent material. We present a strategy combining percutaneous and transgastric drainage with continuous high-volume lavage for treatment of extended necroses and liquid collections in a series of patients with severe acute pancreatitis. PATIENTS AND METHODS: Seven consecutive patients with severe acute pancreatitis and large confluent infected pancreatic necrosis were enrolled. In all cases, the first therapeutic procedure was placement of a CT-guided drainage catheter into the fluid collection surrounding peripancreatic necrosis. Thereafter, a second endosonographically guided drainage was inserted via the gastric or the duodenal wall. After communication between the separate drains had been proven, an external to internal directed high-volume lavage with a daily volume of 500 ml up to 2,000 ml was started. RESULTS: In all patients, pancreatic necrosis/liquid collections could be resolved completely by the presented regime. No patient died in the course of our study. After initiation of the directed high-volume lavage, there was a significant clinical improvement in all patients. Double drainage was performed for a median of 101 days, high-volume lavage for a median of 41 days. Several endoscopic interventions for stent replacement were required (median 8). Complications such as bleeding or perforation could be managed endoscopically, and no subsequent surgical therapy was necessary. All patients could be dismissed from the hospital after a median duration of 78 days. CONCLUSION: This approach of combined percutaneous/endoscopic drainage with high-volume lavage shows promising results in critically ill patients with extended infected pancreatic necrosis and high risk of surgical intervention. Neither surgical nor endoscopic necrosectomy was necessary in any of our patients.