Rationale: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown. Objective: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage (young FTG) in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy. Methods and Results: Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion (MCAO). We performed FTG three days after MCAO using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged stroke mice receiving young FTG had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected four SCFA-producers (Bifidobacterium longum, Clostridium symbiosum, Faecalibacterium prausnitzii and Lactobacillus fermentum) for transplantation. These SCFA-producers alleviated post-stroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged stroke mice. Conclusions: This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via "post-stroke bacteriotherapy" following the replenishment of youthful gut microbiome via modulation of immunologic, microbial and metabolomic profiles in the host.

Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD.

The primary aim of this single-center, phase 1 exploratory study was to investigate the safety, feasibility, and impact on intrahepatic hemodynamics of a fresh frozen plasma (FFP)-based perfusate in ex situ liver normothermic machine perfusion (NMP) preservation. Using an institutionally developed perfusion device, 21 livers (13 donations after brain death and 8 donations after circulatory death) were perfused for 3 hours 21 minutes to 7 hours 52 minutes and successfully transplanted. Outcomes were compared in a 1:4 ratio to historical control patients matched according to donor and recipient characteristics and preservation time. Perfused livers presented a very low resistance state with high flow during ex situ perfusion (arterial and portal flows 340 ± 150 and 890 ± 70 mL/minute/kg liver, respectively). This hemodynamic state was maintained even after reperfusion as demonstrated by higher arterial flow observed in the NMP group compared with control patients (220 ± 120 versus 160 ± 80 mL/minute/kg liver, P = 0.03). The early allograft dysfunction (EAD) rate, peak alanine aminotransferase (ALT), and peak aspartate aminotransferase (AST) levels within 7 days after transplantation were lower in the NMP group compared with the control patients (EAD 19% versus 46%, P = 0.02; peak ALT 363 ± 318 versus 1021 ± 999 U/L, P = 0.001; peak AST 1357 ± 1492 versus 2615 ± 2541 U/L, P = 0.001 of the NMP and control groups, respectively). No patient developed ischemic type biliary stricture. One patient died, and all other patients are alive and well at a follow-up of 12-35 months. No device-related adverse events were recorded. In conclusion, with this study, we showed that ex situ NMP of human livers can be performed safely and effectively using a noncommercial device and an FFP-based preservation solution. Future studies should further investigate the impact of an FFP-based perfusion solution on liver hemodynamics during ex situ normothermic machine preservation. Liver Transplantation 26 215-226 2020 AASLD.Among the strategies employed to improve liver allograft utilization, ex situ normothermic machine perfusion (NMP) preservation has drawn increasing interest in the last decade. The potential advantage of this technology over static cold storage is the ability to enhance preservation along with the capacity to assess and improve graft viability. This is of particular importance when considering organs from extended criteria donors. (1) The type of perfusion solution plays a critical role in the success of NMP. Clinical studies in ex situ preservation have employed packed red blood cells (PRBCs) as oxygen carriers in combination with a colloid extracellular solution (Gelofusine, B Braun, Melsungen, Germany), (2)(3)(4) Steen solution (Gelofusine, B Braun), (5) and 5% albumin (6)(7)(8) ). Fresh frozen plasma (FFP), the most physiological of all extracellular fluids, has never been tested liu et al.

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Portal vein thrombosis (PVT) is commonly encountered during liver transplantation (LT). Depending on the grade of thrombosis, varied management strategies are indicated. The aims of this study are to clarify the contemporary role of renoportal anastomosis (RPA) in patients with splanchnic vein thrombosis (SVT) undergoing LT and to systematically analyze all reported cases of RPA. A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta‐ Analyses statement guidelines. The study was limited to studies reported in English between January 1997 and May 2017. Only retrospective single center studies were included in the analysis. A total of 66 patients with SVT were reported to have undergone RPA during LT. Transient renal dysfunction was reported in 12 patients (18.1%), variceal hemorrhage in 2 patients (3%), early portal vein (PV) re‐thrombosis in 2 patients (3%), chronic renal dysfunction in 2 patients (3%), and late PV re‐thrombosis in 1 patient (1.5%). The overall patient and graft survival were each 80%. This analysis illustrates the decades‐long evolution of a technique practiced across the field of transplantation. Postoperative complications and graft survival appear to be encouraging, even in the setting of SVT.

Photodynamic therapy is under intense investigation as a possible adjuvant for the treatment of malignant tumors of the central nervous system. It relies on the fact that photosensitizers are selectively taken up or retained by malignant tissue. However, most brain tumors are accompanied by substantial vasogenic edema as a consequence of blood-brain barrier disruption within the tumor, leading to extravasation and propagation of plasma constituents into the surrounding brain tissue. Systemically administered photosensitizers may enter healthy tissue together with the edema fluid, possibly leading to sensitization of tissues outside the tumor. To test this hypothesis, vasogenic edema was induced by cold injury to the cortex in rats. The edema thus obtained is highly reproducible and very similar to tumor-associated edema. Just after injury induction, Photofrin II (PF-II), a commonly used photosensitizing agent, was administered at a dose of 5 mg per kilogram of body weight along with fluorescein isothiocyanate (FITC)-labeled albumin to mark edema advancement. After 1, 4, 12, or 24 hours, the brains were removed and frozen, and cryosections were studied with high-sensitivity video fluorescence microscopy for edema extravasation within the lesion and propagation of PF-II into the surrounding gray matter. PF-II advanced with edema along the corpus callosum underlying the cortex to a distance of 5 mm from the lesion after 4 hours. With the exception of the lesion, PF-II fluorescence returned to baseline after 24 hours, indicating subsequent washout. Propagation was comparable to the spreading of FITC-marked albumin. The authors conclude that photosensitizers spread with edema, an observation that may be pertinent to a number of questions concerning photodynamic therapy of cerebral tumors.

This is the first study to investigate the association of TLR and CD86 with RAS. We found a significant association between TLR4 rs10759931 polymorphism and RAS. Confirmatory studies in other populations and functional investigations are needed to determine the role of TLR4 in RAS.

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