Background
Sarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic‐obese patients might be ...reduced, possibly leading to more post‐operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection.
Methods
In 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix® software. Muscle mass and body‐fat% were calculated. Predefined cut‐off values for sarcopenia and the top two body‐fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease.
Results
A total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(‐obese) and non‐sarcopenic(‐obese) patients. Obese patients showed significantly reduced liver function 295 (95–508) vs. 358 (96–684) µg/kg/h, P = 0.018 and a trend towards larger liver size 1694 (1116–2685) vs. 1533 (869–2852) mL, P = 0.079 compared with non‐obese patients. Weight (r = −0.40), body surface area (r = −0.32), estimated body‐fat% (r = −0.43) and body mass index (r = −0.47) showed a weak but significant negative (all P < 0.05) correlation with liver function. Moreover, body‐fat% was identified as an independent factor negatively affecting the liver function.
Conclusion
Sarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.
Postresectional liver failure is the most frequent cause of fatal outcome following liver surgery. Diminished preoperative liver function in the elderly might contribute to this. Therefore, the aim ...of the present study was to evaluate preoperative liver function in patients <60 or >70 years of age scheduled for liver resection.
All consecutive patients aged <60 or >70 years who are about to undergo elective liver surgery between 2011 and 2013 and underwent the methacetin breath liver function test (LiMAx) preoperatively were included. Histologic assessment of the resected liver gave insight into background liver disease. Correlation between age and liver function was calculated with Pearson's test.
Fifty-nine patients were included, 31 were aged <60 and 28 were aged >70 years. General patient characteristics and liver function LiMAx values (340 (137-594) vs. 349 (191-530) μg/kg/h, p = 0.699) were not significantly different between patients aged <60 and >70 years. Moreover, no correlation between age and preoperative liver function LiMAx values was found (R = 0.04, p = 0.810).
Liver function did not seem to differ between younger and older patients.
Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related ...psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1
neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1
specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.
Intestinal ischemia-reperfusion (IR) injury is associated with high mortality rates, which have not improved in the past decades despite advanced insight in its pathophysiology using in vivo animal ...and human models. The inability to translate previous findings to effective therapies emphasizes the need for a physiologically relevant in vitro model to thoroughly investigate mechanisms of IR-induced epithelial injury and test potential therapies. In this study, we demonstrate the use of human small intestinal organoids to model IR injury by exposing organoids to hypoxia and reoxygenation (HR). A mass-spectrometry-based proteomics approach was applied to characterize organoid differentiation and decipher protein dynamics and molecular mechanisms of IR injury in crypt-like and villus-like human intestinal organoids. We showed successful separation of organoids exhibiting a crypt-like proliferative phenotype, and organoids exhibiting a villus-like phenotype, enriched for enterocytes and goblet cells. Functional enrichment analysis of significantly changing proteins during HR revealed that processes related to mitochondrial metabolism and organization, other metabolic processes, and the immune response were altered in both organoid phenotypes. Changes in protein metabolism, as well as mitophagy pathway and protection against oxidative stress were more pronounced in crypt-like organoids, whereas cellular stress and cell death associated protein changes were more pronounced in villus-like organoids. Profile analysis highlighted several interesting proteins showing a consistent temporal profile during HR in organoids from different origin, such as NDRG1, SDF4 or DMBT1. This study demonstrates that the HR response in human intestinal organoids recapitulates properties of the in vivo IR response. Our findings provide a framework for further investigations to elucidate underlying mechanisms of IR injury in crypt and/or villus separately, and a model to test therapeutics to prevent IR injury.
Photosystem II (PS II) inhibitors halt electron flow within the photosynthetic electron transport chain, thereby leading to increased oxidative stress. As a result, their addition to mesotrione, ...which inhibits carotenoid biosynthesis by inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), is complementary. Field and greenhouse experiments were conducted in 2002 and 2003 to investigate the joint action of POST mesotrione plus PS II inhibitor herbicide combinations. The joint action of mesotrione plus PS II inhibitors was investigated across five plant species, three PS II inhibitors, and two moisture environments to determine their influence on the joint action response. Rates of mesotrione evaluated ranged from 4.4 to 87.6 g ai/ha alone and in combination with reduced rates of atrazine, bromoxynil, and metribuzin. In the field, all combinations of mesotrione at 8.8, 17.5, and 35.0 g/ha plus atrazine, bromoxynil, or metribuzin were synergistic for necrosis 6 d after treatment (DAT) on sunflower. Addition of atrazine at 280 g/ha to mesotrione at 8.8 g/ha increased velvetleaf leaf necrosis by 18 to 47%. In the greenhouse, the addition of bromoxynil at 70 g/ha to mesotrione at 17.5 g/ha increased leaf necrosis by 23 to 34% and biomass reduction by 38 to 47%. Synergism on Palmer amaranth occurred similarly under both normal and dry moisture environments at application. Plant height at application was found to influence detection of synergism on the whole-plant level.
Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), ...consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures.
ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40-47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra- vs extracellular ML locations.
Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 µg(Fe)/mL and 225 µg(Fe)/mL, respectively. ML at a concentration of 225 µg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures.
Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.
Background: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not ...been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. Methods: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. Results: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. Conclusions: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.
Background
Computerized radiological image analysis (radiomics) enables the investigation of image-derived phenotypes by extracting large numbers of quantitative features. We hypothesized that ...radiomics features may contain prognostic information that enhances conventional body composition analysis. We aimed to investigate whether body composition-associated radiomics features hold additional value over conventional body composition analysis and clinical patient characteristics used to predict survival of pancreatic ductal adenocarcinoma (PDAC) patients.
Methods
Computed tomography images of 304 patients undergoing elective pancreatic cancer resection were analysed. 2D radiomics features were extracted from skeletal muscle and subcutaneous and visceral adipose tissue (SAT and VAT) compartments from a single slice at the third lumbar vertebra. The study population was randomly split (80:20) into training and holdout subsets. Feature ranking with Least Absolute Shrinkage Selection Operator (LASSO) followed by multivariable stepwise Cox regression in 1000 bootstrapped re-samples of the training data was performed and tested on the holdout data. The fitted regression predictors were used as “scores” for a clinical (C-Score), body composition (B-Score), and radiomics (R-Score) model. To stratify patients into the highest 25% and lowest 25% risk of mortality compared to the middle 50%, the Harrell Concordance Index was used.
Results
Based on LASSO and stepwise cox regression for overall survival, ASA ≥3 and age were the most important clinical variables and constituted the C-score, and VAT-index (VATI) was the most important body composition variable and constituted the B-score. Three radiomics features (SATI_original_shape2D_Perimeter, VATI_original_glszm_SmallAreaEmphasis, and VATI_original_firstorder_Maximum) emerged as the most frequent set of features and yielded an R-Score. Of the mean concordance indices of C-, B-, and R-scores, R-score performed best (0.61, 95% CI 0.56–0.65, p<0.001), followed by the C-score (0.59, 95% CI 0.55-0.63, p<0.001) and B-score (0.55, 95% CI 0.50–0.60, p=0.03). Kaplan-Meier projection revealed that C-, B, and R-scores showed a clear split in the survival curves in the training set, although none remained significant in the holdout set.
Conclusion
It is feasible to implement a data-driven radiomics approach to body composition imaging. Radiomics features provided improved predictive performance compared to conventional body composition variables for the prediction of overall survival of PDAC patients undergoing primary resection.
Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment ...for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible.
A fully integrated 3D basin model was built to study the lithospheric structural evolution and the thermal history of the offshore part of the Gippsland Basin to investigate the type, timing and ...magnitude of its initial opening mechanism and their effects on source rocks. The applied workflow included seismic interpretation of major faults and magmatic features, seismic reinterpretation of existing main stratigraphic boundaries and adjustment of the basement topography. Different scenarios for a McKenzie-type basal heat flow evolution were tested based on a two-step inversion approach, which translates the thickness changes of lithospheric layers into basal heat flow. Finally, a crustal layer model was assigned to the existing 3D numerical basin model and the effects on thermal maturation of petroleum source rocks were investigated. The results of the calibrated inversion model suggest intense lithospheric stretching and mantle upwelling during the Early Cretaceous caused initial breakup and subsidence of the Gippsland Basin. This syn-rift phase was accompanied by increasing basal heat flow from initially ∼50 mW/m
2
to a maximum of 80-90 mW/m
2
. The resulting upwelled Moho with an associated crustal thickness of locally only 8 km agrees with geophysical observations. Elevated paleogeothermal gradients between 50 and 60 °C/km prevailed from ca 120 to 80 Ma. Episodes of compression, uplift, erosion, and thermal subsidence resulted in fast and continuous cooling during the early post-rift and a constant basal heat flow of 45-50 mW/m
2
since the Eocene. Two main pulses of petroleum generation were identified in the Paleocene and in the Miocene-Pliocene. This novel two-step crustal layer inversion method allows a detailed reconstruction of the thermal history of rift basins and can provide useful information about the maturation of petroleum source rocks.
KEY POINTS
A temperature history reconstruction of the Gippsland Basin is given based on a large-scale numerical 3D model.
Tectonically induced strong variability in paleoheat flows is recognised.
Strong maturation and petroleum generation developed during the Paleogene and Neogene.
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