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Purpose: To provide an overview and evaluate the performance of mortality prediction models for patients requiring extracorporeal membrane oxygenation (ECMO) support for refractory cardiocirculatory or respiratory failure. Methods: A systematic literature search was undertaken to identify studies developing and/or validating multivariable prediction models for all-cause mortality in adults requiring or receiving veno-arterial (V-A) or veno-venous (V-V) ECMO. Estimates of model performance (observed versus expected (O:E) ratio and c-statistic) were summarized using random effects models and sources of heterogeneity were explored by means of meta-regression. Risk of bias was assessed using the Prediction model Risk Of BiAS Tool (PROBAST). Results: Among 4905 articles screened, 96 studies described a total of 58 models and 225 external validations. Out of all 58 models which were specifically developed for ECMO patients, 14 (24%) were ever externally validated. Discriminatory ability of frequently validated models developed for ECMO patients (i.e., SAVE and RESP score) was moderate on average (pooled c-statistics between 0.66 and 0.70), and comparable to general intensive care population-based models (pooled c-statistics varying between 0.66 and 0.69 for the Simplified Acute Physiology Score II (SAPS II), Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score). Nearly all models tended to underestimate mortality with a pooled O:E > 1. There was a wide variability in reported performance measures of external validations, reflecting a large between-study heterogeneity. Only 1 of the 58 models met the generally accepted Prediction model Risk Of BiAS Tool criteria of good quality. Importantly, all predicted outcomes were conditional on the fact that ECMO support had already been initiated, thereby reducing their applicability for patient selection in clinical practice. Conclusions: A large number of mortality prediction models have been developed for ECMO patients, yet only a minority has been externally validated. Furthermore, we observed only moderate predictive performance, large heterogeneity between-study populations and model performance, and poor methodological quality overall. Most importantly, current models are unsuitable to provide decision support for selecting individuals in whom initiation of ECMO would be most beneficial, as all models were developed in ECMO patients only and the decision to start ECMO had, therefore, already been made.

Contains fulltext : 252132.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIM: Polycystic liver disease (PLD) is related to hepatomegaly which causes an increased mechanical pressure on the abdominal wall. This may lead to abdominal wall herniation (AWH). We set out to establish the prevalence of AWH in PLD and explore risk factors. METHODS: In this cross-sectional cohort study, we assessed the presence of AWHs from PLD patients with at least 1 abdominal computed tomography or magnetic resonance imaging scan. AWH presence on imaging was independently evaluated by two researchers. Data on potential risk factors were extracted from clinical files. RESULTS: We included 484 patients of which 40.1% (n = 194) had an AWH. We found a clear predominance of umbilical hernias (25.8%, n = 125) while multiple hernias were present in 6.2% (n = 30). Using multivariate analysis, male sex (odds ratio [OR] 2.727 p

Item does not contain fulltext OBJECTIVE: This study aimed to develop and investigate the performance of a deep learning model based on a convolutional neural network (CNN) for the automatic segmentation of polycystic livers at CT imaging. METHOD: This retrospective study used CT images of polycystic livers. To develop the CNN, supervised training and validation phases were performed using 190 CT series. To assess performance, the test phase was performed using 41 CT series. Manual segmentation by an expert radiologist (Rad1a) served as reference for all comparisons. Intra-observer variability was determined by the same reader after 12 weeks (Rad1b), and inter-observer variability by a second reader (Rad2). The Dice similarity coefficient (DSC) evaluated overlap between segmentations. CNN performance was assessed using the concordance correlation coefficient (CCC) and the two-by-two difference between the CCCs; their confidence interval was estimated with bootstrap and Bland-Altman analyses. Liver segmentation time was automatically recorded for each method. RESULTS: A total of 231 series from 129 CT examinations on 88 consecutive patients were collected. For the CNN, the DSC was 0.95 ± 0.03 and volume analyses yielded a CCC of 0.995 compared with reference. No statistical difference was observed in the CCC between CNN automatic segmentation and manual segmentations performed to evaluate inter-observer and intra-observer variability. While manual segmentation required 22.4 ± 10.4 min, central and graphics processing units took an average of 5.0 ± 2.1 s and 2.0 ± 1.4 s, respectively. CONCLUSION: Compared with manual segmentation, automated segmentation of polycystic livers using a deep learning method achieved much faster segmentation with similar performance. KEY POINTS: • Automatic volumetry of polycystic livers using artificial intelligence method allows much faster segmentation than expert manual segmentation with similar performance. • No statistical difference was observed between automatic segmentation, inter-observer variability, or intra-observer variability.

Dry deposition is an important removal mechanism for tropospheric ozone (O3). Currently, O3 deposition to oceans in atmospheric chemistry and transport models (ACTMs) is generally represented using constant surface uptake resistances. This occurs despite the role of solubility, waterside turbulence and O3 reacting with ocean water reactants such as iodide resulting in substantial spatiotemporal variability in O3 deposition and concentrations in marine boundary layers. We hypothesize that O3 deposition to the Arctic Ocean, having a relatively low reactivity, is overestimated in current models with consequences for the tropospheric concentrations, lifetime and long-range transport of O3. We investigate the impact of the representation of oceanic O3 deposition to the simulated magnitude and spatiotemporal variability in Arctic surface O3. We have integrated the Coupled Ocean-Atmosphere Response Experiment Gas transfer algorithm (COAREG) into the mesoscale meteorology and atmospheric chemistry model Polar-WRF-Chem (WRF) which introduces a dependence of O3 deposition on physical and biogeochemical drivers of oceanic O3 deposition. Also, we reduced the O3 deposition to sea ice and snow. Here, we evaluate WRF and CAMS reanalysis data against hourly averaged surface O3 observations at 25 sites (latitudes > 60∘ N). This is the first time such a coupled modeling system has been evaluated against hourly observations at pan-Arctic sites to study the sensitivity of the magnitude and temporal variability in Arctic surface O3 on the deposition scheme. We find that it is important to nudge WRF to the ECMWF ERA5 reanalysis data to ensure adequate meteorological conditions to evaluate surface O3. We show that the mechanistic representation of O3 deposition over oceans and reduced snow/ice deposition improves simulated Arctic O3 mixing ratios both in magnitude and temporal variability compared to the constant resistance approach. Using COAREG, O3 deposition velocities are in the order of 0.01 cm s−1 compared to ∼ 0.05 cm s−1 in the constant resistance approach. The simulated monthly mean spatial variability in the mechanistic approach (0.01 to 0.018 cm s−1) expresses the sensitivity to chemical enhancement with dissolved iodide, whereas the temporal variability (up to ±20 % around the mean) expresses mainly differences in waterside turbulent transport. The mean bias for six sites above 70∘ N reduced from −3.8 to 0.3 ppb with the revision to ocean and snow/ice deposition. Our study confirms that O3 deposition to high-latitude oceans and snow/ice is generally overestimated in ACTMs. We recommend that a mechanistic representation of oceanic O3 deposition is preferred in ACTMs to improve the modeled Arctic surface O3 concentrations in terms of magnitude and temporal variability.

In Colombia, industrialization and a shift towards intensified agriculture have led to increased emissions of air pollutants. However, the baseline state of air quality in Colombia is relatively unknown. In this study we aim to assess the baseline state of air quality in Colombia with a focus on the spatial and temporal variability in emissions and atmospheric burden of nitrogen oxides ( NOx = NO + NO2 ) and evaluate surface NOx , ozone ( O3 ) and carbon monoxide (CO) mixing ratios. We quantify the magnitude and spatial distribution of the four major NOx sources (lightning, anthropogenic activities, soil biogenic emissions and biomass burning) by integrating global NOx emission inventories into the mesoscale meteorology and atmospheric chemistry model, namely Weather Research and Forecasting (WRF) coupled with Chemistry (collectively WRF-Chem), at a similar resolution ( ∼25 km) to the Emission Database for Global Atmospheric Research (EDGAR) anthropogenic emission inventory and the Ozone Monitoring Instrument (OMI) remote sensing observations. The model indicates the largest contribution by lightning emissions (1258 Gg N yr −1 ), even after already significantly reducing the emissions, followed by anthropogenic (933 Gg N yr −1 ), soil biogenic (187 Gg N yr −1 ) and biomass burning emissions (104 Gg N yr −1 ). The comparison with OMI remote sensing observations indicated a mean bias of tropospheric NO2 columns over the whole domain (WRF-Chem minus OMI) of 0.02 (90 % CI: [ −0.43 , 0.70]) ×1015 molecules cm −2 , which is % of the mean column. However, the simulated NO2 columns are overestimated and underestimated in regions where lightning and biomass burning emissions dominate, respectively. WRF-Chem was unable to capture NOx and CO urban pollutant mixing ratios, neither in timing nor in magnitude. Yet, WRF-Chem was able to simulate the urban diurnal cycle of O3 satisfactorily but with a systematic overestimation of 10 parts per billion (ppb) due to the equally large underestimation of NO mixing ratios and, consequently, titration. This indicates that these city environments are in the NOx -saturated regime with frequent O3 titration. We conducted sensitivity experiments with an online meteorology–chemistry single-column model (SCM) to evaluate how WRF-Chem subgrid-scale-enhanced emissions could explain an improved representation of the observed O3 , CO and NOx diurnal cycles. Interestingly, the SCM simulation, showing especially a shallower nocturnal inversion layer, results in a better representation of the observed diurnal cycle of urban pollutant mixing ratios without an enhancement in emissions. This stresses that, besides application of higher-resolution emission inventories and model experiments, the diurnal cycle in boundary layer dynamics (and advection) should be critically evaluated in models such as WRF-Chem to assess urban air quality. Overall, we present a concise method to quantify air quality in regions with limited surface measurements by integrating in situ and remote sensing observations. This study identifies four distinctly different source regions and shows their interannual and seasonal variability during the last 1.5 decades. It serves as a base to assess scenarios of future air quality in Colombia or similar regions with contrasting emission regimes, complex terrain and a limited air quality monitoring network.

Contains fulltext : 238413.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIMS: Patients suffering from polycystic liver disease (PLD) can develop large liver volumes, leading to physical and psychological complaints, reducing quality of life. There is an unmet need for new therapies in these patients. Estrogen seems to be a promising target for new therapies. In this review, we summarize the available experimental and epidemiological evidence to unravel the role of estrogens and other female hormones in PLD, to answer clinical questions and identify new targets for therapy. METHODS: We identified all experimental and epidemiologial studies concerning estrogens or other female hormones and PLD, to answer pre-defined clinial questions. RESULTS: Female sex is the most important risk factor for the presence and severity of disease; estrogen supplementation enhances liver growth and after menopause, liver growth decreases. Experimental studies show the presence of the estrogen receptors alfa and beta on cystic cholangiocytes, and increased in vitro growth after administration of estrogen. CONCLUSIONS: Based on the available evidence, female PLD patients should be discouraged from taking estrogen-containing contraceptives or hormone replacement therapy. Since liver growth rates decline after menopause, treatment decisions should be based on measured liver growth in postmenopausal women. Finally, blockage of estrogen receptors or estrogen production is a promising target for new therapies.

Dry deposition is an important removal mechanism for tropospheric ozone (O3). Currently, O3 deposition to oceans in atmospheric chemistry and transport models (ACTMs) is generally represented using constant surface uptake resistances. This is despite the fact that considering the role of solubility, waterside turbulence and O3 reacting with ocean water reactants such as iodide and dissolved organic matter results in substantial spatiotemporal variability in O3 deposition and concentrations in marine boundary layers. We hypothesize that O3 deposition to the cold Arctic ocean, with relatively low reactivity, is also overestimated in current models with consequences for background concentrations, lifetime of O3 and long-range transport of O3. In this study, we investigate the role of the representation of oceanic O3 deposition to the simulated magnitude and spatiotemporal variability in Arctic surface O3. This study also serves as a preparatory study to understand the year-round Arctic O3 concentration and deposition flux measurements as part of the MOSAiC field campaign. Furthermore, it is also important to enhance our understanding and quantification of Arctic ocean-atmosphere exchange of O3 and other climate-active trace gases given the anticipated opening of the Arctic ocean. We have coupled the Coupled Ocean-Atmosphere Response Experiment Gas transfer algorithm (COAREG) to the mesoscale meteorology and atmospheric chemistry model Polar-WRF-Chem (WRF) and introduced a dependence of O3 deposition on ocean waterside turbulent mixing conditions and biogeochemical composition. We have also reduced the O3 deposition to sea ice and snow. Here, we evaluate the performance of WRF and the CAMS reanalysis data against hourly-averaged surface O3 observations at 25 sites (latitudes > 60º N) including the ASCOS campaign observations. This is the first time such a coupled modelling system has been evaluated against hourly observations at Pan-Arctic sites to study the sensitivity of the deposition scheme to the magnitude and short-term temporal variability in Arctic surface O3. We also analyze the impact of nudging WRF to the synoptic conditions from the ECMWF ERA5 reanalysis data on simulated Arctic meteorology and comparison of observed and simulated O3 concentrations. We show that the more mechanistic representation of O3 deposition over oceans and reduced snow/ice deposition improves simulated Arctic O3 mixing ratios both in terms of magnitude but also regarding observed temporal variability. Using the newly implemented approach, O3 deposition velocities have been simulated in the order of 0.01 cm s−1 compared to ~0.05 cm s−1 in the constant surface uptake resistance approach. The simulated spatial variability in the mechanistic approach (0.01 to 0.018 cm s−1) expresses the sensitivity to chemical enhancement with dissolved iodide whereas the temporal variability (up to ±20 % around the mean) expresses differences in waterside turbulent transport. The bias for all observational sites above 70º N reduced from −7.7 ppb to 0.3 ppb with nudging and the revision to ocean and snow/ice deposition. Our study confirms that O3 deposition to oceans and snow/ice is overestimated in current models. We recommend that a mechanistic representation of oceanic O3 deposition is used in ACTMs to improve the representation of Arctic surface O3 concentrations in terms of magnitude and short-term temporal variability. The revised ocean-atmosphere exchange representation can be further refined using the MOSAiC flux measurements as well as complementary observations such as sea ice and ocean water iodide concentrations.

Contains fulltext : 220117.pdf (Publisher’s version ) (Open Access) Introduction: Polycystic liver disease (PLD) is a rare disease defined by the growth of hepatic cysts and occurs either isolated or as an extrarenal manifestation of polycystic kidney disease. While surgery has been the mainstay in treatment of symptomatic PLD, recently discovered regulatory mechanisms affecting hepatic cystogenesis provide potential new therapies to reduce hepatic cyst burden.Areas covered: This review summarizes intracellular pathways and therapeutic targets involved in hepatic cystogenesis. While drugs that target cAMP, mTOR and bile acids were evaluated in clinical trials, investigation in autophagy, Wnt and miRNA signaling pathways are still in the pre-clinical phase. Recent epidemiological data present female hormones as a promising therapeutic target. Additionally, therapeutic advances in renal cystogenesis are reviewed for their potential application in treatment of hepatic cysts.Expert opinion: Further elucidation of the pathophysiology of hepatic cystogenesis is needed to provide additional targets and improve the efficacy of current treatments. The most promising therapeutic target in PLD is the female hormone pathway, given the increased severity in women and the harmful effects of exogenous estrogens. In addition, combining current pharmaceutical and surgical therapies can lead to improved outcomes. Lastly, the rarity of PLD creates the need to share expertise internationally.

In Colombia, industrialization and a shift towards intensified agriculture have led to increased emissions of air pollutants. However, the baseline state of air quality in Colombia is relatively unknown. In this study we aim to assess the baseline state of air quality in Colombia with a focus on the spatial and temporal variability in emissions and atmospheric burden of nitrogen oxides (NOx = NO + NO2) and evaluate surface NOx, ozone (O3) and carbon monoxide (CO) mixing ratios. We quantify the magnitude and spatial distribution of the four major NOx sources (lightning, anthropogenic activities, soil biogenic emissions and biomass burning), by integrating global NOx emission inventories into the mesoscale meteorology and atmospheric chemistry model WRF-Chem. The comparison with in situ measurements is bound to urban areas whereas the use of remote sensing data allows to also evaluate air quality in remote regions. WRF-Chem was set up for a domain centered over Colombia with a similar resolution as OMI observed NO2 vertical columns as well as the EDGAR anthropogenic emission inventory, both providing information on a ~20 km resolution. However, this apparently poses a challenge regarding comparison with these urban observations. Air mass factors were recalculated based on the vertical distribution of NO2 within WRF-Chem, with respect to the coarse (1° x 1°) a priori profiles. The main reason for recalculation is a more consistent satellite-model comparison but it also reduced the mean bias. WRF-Chem was, on average, able to provide good estimates for tropospheric NO2 columns with an averaged difference of 0.02 x 1015 molecules cm-2, which is 2 columns are overestimated in regions with abundant modeled lightning emissions and underestimated in regions where biomass burning emissions dominate in the model. This result reflects the high contribution by lightning emissions (1258 Gg N yr-1) and the low contribution by biomass burning emissions (104 Gg N yr-1) to total NOx emissions within the WRF-Chem domain. WRF-Chem was unable to capture NOx and CO urban pollutant mixing ratios, both in timing and magnitude. Yet, WRF-Chem was able to simulate the urban diurnal cycle of O3 satisfactory but with a systematic overestimation of 10 ppb due to the equally large underestimation of NO mixing ratios and, consequently, titration. This indicates that these city environments are in the NOx saturated regime with frequent O3 titration. We also applied an online meteorology-chemistry single column model (SCM) to evaluate how enhanced emissions and different representation of advection and mixing conditions could explain an improved representation of the observed O3 and NOx diurnal cycles. The SCM appears to indeed better represent the observed diurnal cycle of urban pollutant mixing ratios. But, interestingly, this result did not require an enhancement in the emissions, indicating that the role of boundary layer dynamics and advection should be considered besides the use of high-resolution models and emissions inventories to realistically simulate urban air quality. Results obtained in this study provide insight in the magnitude, distribution and temporal evolution of different sources of pollution in Colombia and its surrounding territories. This study not only identifies different source regions, but also shows the interannual variability of these sources during the last one and a half decade using satellite data. Furthermore, this study shows that relatively coarse anthropogenic emission inventories can give reasonable results regarding the diurnal cycle of urban pollutant mixing ratios with a careful consideration of advection and mixing conditions. It serves as a base to assess scenarios of future air quality in Colombia, or similar regions with distinct contrasting emission regimes and a limited air quality monitoring network, as a function of further industrialization and land use changes.

Purpose Despite all innovations in continuous flow left ventricular assist devices (cfLVAD) wound infections are still leading factors for morbidity and mortality in VAD patients. Over the last years, cold atmospheric plasma (CAP) has been safely and effectively used to treat superficial infections. Thus, in this study we present our results using CAP for the treatment of superficial driveline infections (SDI). Methods We describe a two center experience with 25 patients (21male, 4 female) and 32 treatments, who were implanted between 2012 and 2018 and developed a SDI in the follow up. 17 cases were treated inhospital, 9 in an outpatient clinic and 6 were treated in both. All wounds were treated with CAP (kinPen MED) starting from the day of diagnosis. Results The average number of CAP applications per case was 11.2 times (1-49), median duration of hospital stay due to SDI was 25 days (5-106). 19 cases were additional treated with antibiotics (59%). In 9 cases (28%) occurred an ascending driveline infection (ADI) requiring surgical revision. The 3 month event free survival was 23 cases (72 %). There were no adverse side effects of CAP therapy observed and there were no abnormalities of cfLVAD during CAP treatment. Conclusion In our study we demonstrate that CAP therapy could be effectively and safely applied in cfLVAD patients with SDI. Using CAP 72% of our cases with SDI were prevented from ADI. Future studies have to show if ambulant CAP therapy of superficial cfLVAD wound infections has the potential to prevent progression of infection or to avoid SDI infection at all as prophylactic therapy.

The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.

Purpose Various options of temporary mechanical circulatory support (tMCS) have shown to improve survival but only little data exist on bleeding complications during the time of tMCS using different devices. The aim of this study was to compare bleeding complications in patients undergoing extracorporeal life support (ECLS) and Impella therapy. Methods We retrospectively analyzed all 40 patients who underwent veno-arterial ECLS + Impella 2.5 (ECMELLA) and subsequent change to Impella 5.0 therapy in our institution between May 2016 and May 2019. 23 patients were excluded from the study because both deviceswere explanted at the same time or the patient died on tMCS. Anticoagulation protocol was comparable in both groups consisting of aPTT 50 - 60 sec. We reviewed and compared the number of transfused blood products during the time of ECMELLA and Impella 5.0support. Results 17 patients who were successfully weaned from ECLS and underwent subsequent Impella 5.0 implantation via the axillary artery without any periprocedural complications were in included in our study. We compared the period of ECMELLA support with the period of Impella 5.0 support in the same patient cohort. Mean patients age was 54.8 ± 7.7 years and 15 (88.2%) patients were male. Acute cardiogenic shock due to ST-elevation myocardial infarction was the main indication for tMCS in 73.3%, 52.9% of the patients underwent cardiopulmonary resuscitation. Mean duration of ECMELLA and Impella 5.0 therapy did not differ significantly (10.1 ± 5.5 days vs. 11.2 ± 5.5 days, p= 0.576). The average number of packed red blood cells (PRBC) that were transfused during ECMELLA support was significantly higher than during Impella 5.0 support (29.2 ± 18.7 vs 11.7 ± 12.2, p Conclusion The need for transfusion of blood products decreases significantly under Impella 5.0 therapy compared to patients on extracorporeal life support. To improve outcome and to increase survival rates in these patients we recommend that extracorporeal membrane oxygenation should be replaced by Impella 5.0 as soon as possible, particularly whenever LV support alone is sufficient.

Cerebrospinal fluid (CSF) is a complex fluid filling the ventricular system and surrounding the brain and spinal cord. Although the bulk of CSF is created by the choroid plexus, a significant fraction derives from the interstitial fluid in the brain and spinal cord parenchyma. For this reason, CSF can often be used as a source of pharmacodynamic and prognostic biomarkers to reflect biochemical changes occurring within the brain. For instance, CSF biomarkers can be used to diagnose and track progression of disease as well as understand pharmacokinetic and pharmacodynamic relationships in clinical trials. To facilitate the use of these biomarkers in humans, studies in preclinical species are often valuable. This review summarizes methods for preclinical CSF collection for biomarkers from mice, rats, and nonhuman primates. In addition, dosing directly into CSF is increasingly being used to improve drug levels in the brain. Therefore, this review also summarizes the state of the art in CSF dosing in these preclinical species.

Cerebrospinal fluid (CSF) is a complex fluid filling the ventricular system and surrounding the brain and spinal cord. Although the bulk of CSF is created by the choroid plexus, a significant fraction derives from the interstitial fluid in the brain and spinal cord parenchyma. For this reason, CSF can often be used as a source of pharmacodynamic and prognostic biomarkers to reflect biochemical changes occurring within the brain. For instance, CSF biomarkers can be used to diagnose and track progression of disease as well as understand pharmacokinetic and pharmacodynamic relationships in clinical trials. To facilitate the use of these biomarkers in humans, studies in preclinical species are often valuable. This review summarizes methods for preclinical CSF collection for biomarkers from mice, rats, and nonhuman primates. In addition, dosing directly into CSF is increasingly being used to improve drug levels in the brain. Therefore, this review also summarizes the state of the art in CSF dosing in these preclinical species.

Purpose Despite all innovations in continuous flow left ventricular assist devices (cfLVAD) wound infections are still leading factors for morbidity and mortality in VAD patients. Over the last years, cold atmospheric plasma (CAP) has been safely and effectively used to treat superficial infections. Thus, in this study we used CAP the first time intraoperativly and postoperativly in patients with ascending driveline infections (DI) and device related infections (DRI). Methods We describe a two center experience with nine patients (HVAD n=8; HeartMate III n=1), who were implanted between 08/2013 and 03/2018 and developed a DI or DRI in the follow up. Five patients had an ascending DI, one patient with recurrent ascending DI, one patient had a substernal abscess, one patient had first a sternal abscess and after the follow up an ascending DI and another patient first an ascending DI and after the follow up a subxiphoidal abscess. All wounds were treated with CAP (kinPen MED) starting intraoperatively (n=11), after surgical wound debridement and after wound closure postoperatively during wound dressing. Five wounds were additional treated with vacuum therapy till secondary surgical wound closure. Bacteria specific antibiotic therapy was given for all patients. Results Median time from implantation to device related infections was 18.5 (3 to 60) months. CAP applications was done on average 20 times per wound (6 to 50), median time of CAP therapy was 38.6 (6 to 150) days. In the follow-up after 3 months the healing of 10 wounds was normal. Wound infection recurrence happened in one wound after primarily closure (n=6), and in one wound of a patient with vacuum therapy (n=5). There were no adverse side effects of CAP therapy observed and there were no abnormalities of cfLVAD during CAP treatment. Conclusion In our study we demonstrate that CAP therapy could be effectively and safely applied in cfLVAD patients with device related wound infections. Future studies have to show if early CAP therapy of superficial cfLVAD wound infections has the potential to prevent progression of infection to avoid surgical debridement.

Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lackingin vivo. In this study, anin vivostable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.

Overgewicht en obesitas zijn chronische aandoeningen die veel begeleiding en zorg kosten. De huisarts is de enige zorgprofessional die de hele setting in beeld heeft: hij ziet vaak de opeenvolgende generaties van een gezin. En juist de huisarts kan, als middelpunt van het lokale multidisciplinaire netwerk, een begin maken met de preventie. De huisarts hoeft niet de hele begeleiding van obese patienten op zich te nemen, maar kan wel de bal aan het rollen brengen. Investeren in preventie voorkomt symptoombestrijding later. Bewegen en gezonde voeding zijn belangrijke preventieve maatregelen. De BeweegKuur is een uitstekende manier gebleken om patienten aan te zetten tot een actievere leefstijl. Voor de aanpak van overgewicht en obesitas bij kinderen is een speciale aanpak noodzakelijk.

The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed.

Therapeutic approaches for Alzheimer's disease (AD) are guided by four disease characteristics: amyloid plaques, neurofibrillar tangles (NFT), neurodegeneration, and dementia. Amyloid plaques are composed largely of 4 kDa beta-amyloid (Abeta) peptides, with the more amyloidogenic, 42 amino acid form (Abeta42) as the primary species. Because multiple, rare mutations that cause early-onset, familial AD lead to increased production or aggregation of Abeta42, amyloid therapeutics aim to reduce the amount of toxic Abeta42 aggregates. Amyloid-based therapies include gamma-secretase inhibitors and modulators, BACE inhibitors, aggregation blockers, catabolism inducers, and anti-Abeta biologics. Tangles are composed of paired helical filaments of hyperphosphorylated tau protein. Tau-based therapeutics include kinase inhibitors, microtubule stabilizers, and catabolism inducers. Therapeutic strategies for neurodegeneration target multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative damage, and inflammation or stimulation of neuronal viability. Although not disease modifying, cognition enhancers are important to treat the symptom of dementia. Strategies for cognition enhancement include cholinesterase inhibitors, and other approaches to enhance the signaling of cholinergic and glutamatergic neurons. In summary, plaques, tangles, neurodegeneration and dementia guide the development of multiple therapeutic approaches for AD and are the subject of this review.

A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.

We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.

In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

After neoadjuvant radiochemotherapy and surgery, there is no general agreement about whether postoperative chemotherapy is necessary. With the help of clinical and pathohistologic data, prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it.Ninety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy (November 4, 1997 and June 15, 2004) without distant metastases and an R0 (microscopically complete) resection were evaluated. Adjuvant chemotherapy (5-fluorouracil or 5-fluorouracil/folinic acid) was given to 65 of 95 patients (68.4 percent). The disease-free survival rate after 36 months was chosen as the target parameter (median follow-up, 36 months).The five-year survival rate for all patients was 80.3 +/- 5.6 percent; the five-year disease-free survival was 78.1 +/- 5.1 percent; the five-year local control rate was 94.2 +/- 5.1 percent. In the univariate and multivariate analysis of the disease-free survival, the pathohistologic lymph node status after radiochemotherapy (ypN) was the only significant prognostic parameter. Disease-free survival (36 months) for patients without lymph node metastases (ypN0) was excellent, independent of whether they had received postoperative chemotherapy (n = 43; 87.5 +/- 6.0 percent) or not (n = 29; 87.7 +/- 6.7 percent). Patients with ypN2 status have, despite chemotherapy, a poor disease-free survival at 30 +/- 17.6 percent after 36 months.These retrospective data suggest that, for some patients, postoperative chemotherapy can be spared. For patients with ypN2 status, an intensification of the postoperative chemotherapy should be considered. Further evaluation in prospective studies is urgently recommended.

Neoadjuvant radiation or chemoradiation is currently the treatment of choice for patients with locally advanced carcinoma of the rectum. To assess the effects of chemoradiation on tumour regression and on uninvolved mesorectal lymph nodes, a consecutive series of 76 patients receiving neoadjuvant chemoradiation and a stage-adapted control series of 57 patients without pretreatment were studied. Densities of cells positive for CD4 (T-helper cells), CD8 (cytotoxic T-cells), CD83 (mature dendritic cells), and CD57 (natural killer cells) were determined on immunostains. Tumour regression was graded, and presence or absence of extramural tumour was recorded. The densities of CD4+ T-lymphocytes and CD83+ dendritic cells in the paracortex of mesorectal lymph nodes were observed to be significantly reduced, as were the densities of CD57+ cells in the follicles; densities of CD8+ T-lymphocytes did not differ. Strong, moderate and poor tumour regression was observed in 29, 25, and 22 cases, respectively. For 12 patients, absence of extramural vital or regressing tumour was recorded, indicating pretherapeutic overstaging. The results bring to mind that neoadjuvant chemoradiation as a side effect may have a negative impact on anti-tumour immunity. Together with the drawback of overstaging the results argue for a careful selection of patients.

Aims : The term tumour ‘budding’ has been coined for the detachment of tumour cells from the neoplastic glands of adenocarcinomas and is presumed to be an early step in the metastatic process. A limited number of studies have shown budding to be an adverse prognostic factor. Methods and results : All primary single, non-metachronous TNM stage I/II colorectal carcinomas without neoadjuvant treatment resected in the years 1994–1999 were included (n = 186). Tumour buds were counted in pan-cytokeratin immunostains in a 0.785-mm2 field of vision (250 ×). During follow-up 21 patients had distant metastases and 12 patients died of their disease. Budding was determined at 14 and 20.46, median and mean, respectively (range 0–120). A cut-off of 25 was found to be sensitive (0.76) and specific (0.739). Kaplan–Meier survival analysis showed high budding to be a strong adverse prognosticator. By Cox regression, high budding together with venous angioinvasion were independent prognostic factors. Conclusions : This study confirms the prognostic value of budding in a contemporary series of colorectal carcinomas that by TNM were low risk. Technically easy, rapid and robust to determine, budding quantified in pan-cytokeratin stains significantly aids in the identification of high-risk patients and is recommended for more general use in surgical pathology.

gamma-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). gamma-Secretase inhibitors reduce brain beta-amyloid peptide (Abeta), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human beta-amyloid precursor protein (APP) are valuable models to examine the dynamics of Abeta changes with gamma-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a gamma-secretase inhibitor, showed dose- and time dependent reductions of Abeta in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Abeta levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Abeta in plaques showed reductions in CSF Abeta in the absence of measurable changes in plaque Abeta in the brain after up to 2 weeks of treatment. Hence, CSF Abeta levels were a valuable measure of gamma-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8(+) thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity.

We have examined 118 oral squamous cell carcinomas, 72 oral leukoplakias, 12 cases of cheilitis and 65 of oral lichen planus for the presence of human papillomavirus (HPV) 6/11, 16 and 18 DNA by PCR/Southern blot hybridization. HPV DNA were found in 51/118 carcinomas (43.2%), in 16/72 (22.2%) leukoplakias, 3/12 (25.0%) cheilitic lesions and 10/65 (15.4%) lichen planus cases. These differences were even stronger when analyzing separately for the high-risk types HPV 16 and 18 as compared to low-risk types 6/11. HPV 16 and 18 DNA were present in 41/118 (34.7%) oral carcinomas, 12/72 (16.7%) leukoplakias, 2/12 (16.7%) cheilitic lesions and 6/65 (9.2%) lichen planus. In contrast to this, oral carcinomas displayed the lowest HPV 6/11 detection rate (4.2%), compared with 11.1% for leukoplakias, 8.3% for cheilitic lesions and 7.7% in lichen planus. These results indicate a successive increase of the detection rate of HPV 16 and 18 from low level in non or questionably preneoplastic lesions (lichen planus) to preneoplastic lesions (leukoplakia and cheilitis) and to oral carcinoma. In conclusion, our results suggest an association of oral carcinogenesis and infection with the high-risk HPV types 16 and 18.

Aims: Microvessel densities in cancers have been shown to be a prognostic factor for some types of cancer. For colorectal cancer, however, the situation is far from clear. Methods: A consecutive series of 173 colorectal carcinomas was investigated, and to these were added 55 liver metastases originating from colorectal cancer. Microvessels were counted in hotspots (factor VIII immunostaining, 0.74 mm2). The capillary architecture was scored according to the degree of order and envelopment of the neoplastic glands. Endothelial proliferation was determined by factor VIII/Ki67 double labelling. Results: Mean microvessel densities were 51.8 for colorectal carcinomas (range 8–140) and 31.9 for liver metastases (range 3–101). Stratification according to stage, depth of infiltration and nodal involvement showed a significant inverse relation with increase. Mean microvessel densities in primaries were significantly higher than in metastases. Kaplan–Meier analysis showed a significantly higher cancer-specific survival for high microvessel densities (median as cut-off) and for a more ordered microvascular architecture. Endothelial proliferation in carcinomas was significantly higher than in normal mucosa. Conclusions: Contrary to other types of cancer, for colorectal cancer high microvessel densities confer good rather than poor prognosis. We hypothesize that neoangiogenesis, though extant in colorectal cancer, is not rate-limiting in the metastatic cascade.

Background The diagnosis of biliary disease, namely malignant disorders, is frequently hampered by the inconclusive cytology. We investigated prospectively the frequency of molecular changes in p53 and ras compared with cytology in patients with primary or secondary hepato-biliary disease. Material and methods We investigated 118 consecutive patients, aged 24-89 with the following clincal diagnoses: choledocho/cholecystolithiasis (28), cholangiocellular carcinoma (21), gall bladder tumor (8), liver metastasis (3), autoimmune disease (8), chronic pancreatitis (16), pancreatic carcinoma (11), papillary disease (4), hepatic cirrhosis (6), cholangitis (2), anomalies (2), and normal (9). Bile was aspirated during routine endoscopic retrograde cholangio pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). DNA was prepared freshly from a native aliquot, p53 mutations were detected by polymerase chain reaction (PCR) for exons 5 through 8 followed by TGGE. PCR for ras mutations was performed as RFLP-PCR with sequencing. Results In four cases, mutations in p53 could be found in exons 6 and 7. Twenty-two samples showed ras mutations; ras mutations were found in choledocholithiasis (4/28), bile duct (5/21), gall bladder (3/8) and pancreatic (1/11) carcinoma, liver metastasis (3/3), ulcerative colitis (2/3), PSC (1/2), and chronic pancreatitis (1/16). Cytology was clearly positive in seven cases, suspicious in three other, inconclusive in six, and negative in the rest. The molecular analysis resulted in a sensitivity of 33% and specificity of 87%, respectively, for the diagnosis of a malignant condition. Conclusion PCR for p53 and ras mutations may aid the diagnosis of primary and secondary (metastatic) hepatobiliary disease if a malignant condition of the bile ducts and the liver is suspected and cytology is inconclusive or negative. However, the incidence of p53 and ras mutations in bile seems less frequent than in other malignant conditions of the gastrointestinal tract and the pancreas and lower than in tissue, leaving a poor sensitiviy and specificity. Nevertheless, the presence of a p53 and/or ras mutation per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or inconclusive.

Anisakiasis or "herring worm disease" is one of the most important parasitic diseases of the gastrointestinal tract in Japan. In 1988 Lorenz and Warzok published 8 cases of intestinal anisakiasis in Eastern Germany. In 1988 Spehn et al. reported a case of gastric anisakiasis in an AIDS patient. Here, we describe a case of gastric anisakiasis in Germany with an impressive serious clinical course. The symptoms--acute abdominal cramps, severe chest pain, diarrhoea, sub-febrile temperatures and leucocytosis--followed 4 h after consumption of raw herring, which was homemade pickled in vinegar. The conventional and the endoscopic ultrasonography showed a thickened gastric wall made of mainly thickened submucosa. The larvae of Anisakis in the gastric mucosa were found and extracted endoscopically. Acute and severe abdominal pain after eating raw fish is an indication for early gastroscopy. The endoscopical extraction of possible larvae is the only effective therapy, as anthelmintics against nematodes (mebendazole, albendazole, thiabendazole) are ineffective.

We studied the p53 mutational spectra of 34 lip and 60 intra-oral squamous-cell carcinomas and examined possible etiological and prognostic correlations for these tumor sites. For the p53 analysis of exons 5–8, we used PCR/TGGE screening followed by DNA sequencing. Mutations were found in 18/34 (53%) lip and 22/60 (38%) intra-oral carcinomas. The p53 mutational spectrum of the intra-oral carcinomas comprised transitions and transversions in nearly equal frequency (11 to 10). In comparison, transitions were 3.5 times more frequent than transversions (14 to 4) in carcinomas of the lip. The predominant types of base change found in intra-oral tumors were G:C-to-T:A transversions and G:C-to-A:T transitions (32% each), while in lip tumors G:C-to-A:T transitions (70%) were the most frequent. The rate of lip tumors with mutations was higher in non-smokers (8/13) than in smokers (9/20). In contrast, p53 mutations in intra-oral tumors clustered in smokers (18/47 vs. 2/10). G:C-to-T:A transversions, regarded as tobacco smoke–associated in lung cancer, were found in 2 moderate and 4 heavy smokers with intra-oral cancer. This base substitution was found in none of our lip cancers. In lip tumors, a high rate of mutations occurred at dipyridine sites (13/18); among these were 8 C-to-T transitions and 1 CC-to-TT tandem base transition. These changes are characteristic of DNA damage caused by UV light. The presence of mutational events at the DNA-binding surface of the p53 protein may correlate with poor clinical outcome. However, we could not find any statistically significant correlations between p53 status and survival. Only the recurrence-free interval was significantly shortened in cases with mutations affecting residues of the DNA-binding surface of the p53 protein. Int. J. Cancer 88:82–86, 2000. © 2000 Wiley-Liss, Inc.