Exploring the ability of the variable-resolution Community Earth System Model to simulate cryospheric–hydrological variables in High Mountain Asia

Earth system models (ESMs) can help to improve the understanding of climate-induced cryospheric–hydrological impacts in complex mountain regions, such as High Mountain Asia (HMA). Coarse ESM grids, however, have difficulties in representing cryospheric–hydrological processes that vary over short distances in complex mountainous environments. Variable-resolution (VR) ESMs can help to overcome these limitations through targeted grid refinement. This study investigates the ability of the VR Community Earth System Model (VR-CESM) to simulate cryospheric–hydrological variables such as the glacier surface mass balance (SMB) over HMA. To this end, a new VR grid is generated, with a regional grid refinement up to 7 km over HMA. Two coupled atmosphere–land simulations are run for the period 1979–1998. The second simulation is performed with an updated glacier cover dataset and includes snow and glacier model modifications. Comparisons are made to gridded outputs derived from a globally uniform 1∘ CESM grid, observation-, reanalysis-, and satellite-based datasets, and a glacier model forced by a regional climate model (RCM). Climatological biases are generally reduced compared to the coarse-resolution CESM grid, but the glacier SMB is too negative relative to observation-based glaciological and geodetic mass balances, as well as the RCM-forced glacier model output. In the second simulation, the SMB is improved but is still underestimated due to cloud cover and temperature biases, missing model physics, and incomplete land–atmosphere coupling. The outcomes suggest that VR-CESM could be a useful tool to simulate cryospheric–hydrological variables and to study climate change in mountainous environments, but further developments are needed to better simulate the SMB of mountain glaciers

Experimentally induced incomplete burst fractures - a novel technique for calf and human specimens

Background: Fracture morphology is crucial for the clinical decision-making process preceding spinal fracture treatment. The presented experimental approach was designed in order to ensure reproducibility of induced fracture morphology. Results: The presented method resulted in fracture morphology, found in clinical classification systems like the Magerl classification. In the calf spine samples, 70% displayed incomplete burst fractures corresponding to type A3.1 and A3.2 fractures. In all human samples, superior incomplete burst fractures (Magerl A3.1) were identified by an independent radiologist and spine surgeon. Conclusions: The presented set up enables the first experimental means to reliably model and study distinct incomplete burst fracture patterns in an in vitro setting. Thus, we envisage this protocol to facilitate further studies on spine fracture treatment of incomplete burst fractures

Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads.

Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia-reperfusion injury that occurs in the complex route of the graft from "harvest to revascularization". Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach.

The total damage inflicted on the liver before transplantation is associated with severalsurgical manipulations, such as organ recovery, washout of the graft, cold conservation in organpreservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation.Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alterna-tive to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation inrats (4◦C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide,comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessedin a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L)and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented theformation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP).In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcircu-latory disturbances in steatotic grafts during preservation and revascularization. All of these resultslead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation.In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, whichhas already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence,the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a uniquesolution/perfusate when hypothermic static and preservation strategies are used, either separately orcombined, easing the logistics and avoiding the mixture of different solutions/perfusates, especiallywhen fatty liver grafts are used. Further research regarding new therapeutic and pharmacologicalinsights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in staticand dynamic graft preservation strategies for clinical liver transplantation purpos

Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: An update

Aldehyde dehydrogenase 2 (ALDH2) is best known for its critical detoxifying role in liver alcohol metabolism. However, ALDH2 dysfunction is also involved in a wide range of human pathophysiological situations and is associated with complications such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases and aging. A growing body of research has shown that ALDH2 provides important protection against oxidative stress and the subsequent loading of toxic aldehydes such as 4-hydroxy-2-nonenal and adducts that occur in human diseases, including ischemia reperfusion injury (IRI). There is increasing evidence of its role in IRI pathophysiology in organs such as heart, brain, small intestine and kidney; however, surprisingly few studies have been carried out in the liver, where ALDH2 is found in abundance. This study reviews the role of ALDH2 in modulating the pathways involved in the pathophysiology of IRI associated with oxidative stress, autophagy and apoptosis. Special emphasis is placed on the role of ALDH2 in different organs, on therapeutic "preconditioning" strategies, and on the use of ALDH2 agonists such as Alda-1, which may become a useful therapeutic tool for preventing the deleterious effects of IRI in organ transplantation

Strict Selection Alone of Patients Undergoing Liver Transplantation for Hilar Cholangiocarcinoma is Associated with Improved Survival

Liver transplantation for hilar cholangiocarcinoma (hCCA) has regained attention since the Mayo Clinic reported their favorable results with the use of a neo-adjuvant chemoradiation protocol. However, debate remains whether the success of the protocol should be attributed to the neo-adjuvant therapy or to the strict selection criteria that are being applied. The aim of this study was to investigate the value of patient selection alone on the outcome of liver transplantation for hCCA. In this retrospective study, patients that were transplanted for hCCA between 1990 and 2010 in Europe were identified using the European Liver Transplant Registry (ELTR). Twenty-one centers reported 173 patients (69%) of a total of 249 patients in the ELTR. Twenty-six patients were wrongly coded, resulting in a study group of 147 patients. We identified 28 patients (19%) who met the strict selection criteria of the Mayo Clinic protocol, but had not undergone neo-adjuvant chemoradiation therapy. Five-year survival in this subgroup was 59%, which is comparable to patients with pretreatment pathological confirmed hCCA that were transplanted after completion of the chemoradiation protocol at the Mayo Clinic. In conclusion, although the results should be cautiously interpreted, this study suggests that with strict selection alone, improved survival after transplantation can be achieved, approaching the Mayo Clinic experience

Polyethylene Glycol 35 as a perfusate additive for mitochondrial and glycocalyx protection in HOPE liver preservation

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation

The relevance of the UPS in the fatty liver graft preservation: a new approach for IGL-1 and HTK solutions

The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS

Aldehyde Dehydrogenase 2 (ALDH2) in Rat Fatty Liver Cold Ischemia Injury

Institut George Lopez-1 (IGL-1) and Histidine-tryptophan-ketoglutarate (HTK) solutions are proposed as alternatives to UW (gold standard) in liver preservation. Their composition differs in terms of the presence/absence of oncotic agents such as HES or PEG, and is decisive for graft conservation before transplantation. This is especially so when fatty (steatotic) livers are used since these grafts are more vulnerable to ischemia insult during conservation. Their composition determines the extent of the subsequent reperfusion injury after transplantation. Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, has been reported to play a protective role in warm ischemia-reperfusion injury (IRI), but its potential in fatty liver cold ischemic injury has not yet been investigated. We evaluated the relevance of ALDH2 activity in cold ischemia injury when fatty liver grafts from Zucker Obese rats were preserved in UW, HTK, and IGL-1 solutions, in order to study the mechanisms involved. ALDH2 upregulation was highest in livers preserved in IGL-1. It was accompanied by a decrease in transaminases, apoptosis (Caspase 3 and TUNEL assay), and lipoperoxidation, which was concomitant with the effective clearance of toxic aldehydes such as 4-hydroxy-nonenal. Variations in ATP levels were also determined. The results were consistent with levels of NF-E2 p45-related factor 2 (Nrf2), an antioxidant factor. Here we report for the first time the relevance of mitochondrial ALDH2 in fatty liver cold preservation and suggest that ALDH2 could be considered a potential therapeutic target or regulator in clinical transplantation