Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1ß Signaling.

BACKGROUND: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. METHODS: Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. RESULTS: In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1ß response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. CONCLUSIONS: Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.

Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis.

VEGFR2 signaling in endothelial cells (ECs) is regulated by reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) and mitochondria, which plays an important role in postnatal angiogenesis. However, it remains unclear how highly diffusible ROS signal enhances VEGFR2 signaling and reparative angiogenesis. Protein disulfide isomerase A1 (PDIA1) functions as an oxidoreductase depending on the redox environment. We hypothesized that PDIA1 functions as a redox sensor to enhance angiogenesis. Here we showed that PDIA1 co-immunoprecipitated with VEGFR2 or colocalized with either VEGFR2 or an early endosome marker Rab5 at the perinuclear region upon stimulation of human ECs with VEGF. PDIA1 silencing significantly reduced VEGF-induced EC migration, proliferation and spheroid sprouting via inhibiting VEGFR2 signaling. Mechanistically, VEGF stimulation rapidly increased Cys-OH formation of PDIA1 via the NOX4-mitochondrial ROS axis. Overexpression of "redox-dead" mutant PDIA1 with replacement of the active four Cys residues with Ser significantly inhibited VEGF-induced PDIA1-CysOH formation and angiogenic responses via reducing VEGFR2 phosphorylation. Pdia1+/- mice showed impaired angiogenesis in developmental retina and Matrigel plug models as well as ex vivo aortic ring sprouting model. Study using hindlimb ischemia model revealed that PDIA1 expression was markedly increased in angiogenic ECs of ischemic muscles, and that ischemia-induced limb perfusion recovery and neovascularization were impaired in EC-specific Pdia1 conditional knockout mice. These results suggest that PDIA1 can sense VEGF-induced H2O2 signal via CysOH formation to promote VEGFR2 signaling and angiogenesis in ECs, thereby enhancing postnatal angiogenesis. The oxidized PDIA1 is a potential therapeutic target for treatment of ischemic vascular diseases.

Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.

AIMS: The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. METHODS AND RESULTS: In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1ß-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. CONCLUSION: Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis.

Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations: BCA: brachiocephalic arteries; FACS: fluorescence activated cell sorting; FITC: fluorescein-5-isothiocyanatel; IL1B: interleukin 1 beta; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; LSDs: lysosomal storage disorders; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MPS: mononuclear phagocyte system; PEGHDE: polyethylene glycol hexadecyl ether; PLA: polylactic acid; PLGA: poly-lactide-co-glycolic acid; SQSTM1/p62: sequestosome 1.

Sirolimus Attenuates Calcineurin Inhibitor-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma.

BACKGROUND: Calcineurin inhibitors (CNIs), which are potent immunosuppressants (ISs), increase the risk for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LTx). Epithelial-mesenchymal transition (EMT) is a key process in which epithelial cancer cells lose their polarity, resulting in cancer progression and metastasis. The aim of this study was to evaluate the effect of sirolimus (SRL) individually and in combination with other ISs to reduce EMT. METHODS: HCC SK-Hep1 cells were used and various ISs (SRL, tacrolimus, cyclosporine A, or mycophenolate mofetil) were administered at 2 dosages and in combination therapies. Mice were transplanted with SK-Hep1 cells (in the liver) and were monitored after 2 weeks. RESULTS: The in vitro treatment with SRL showed a dose-dependent attenuation of cell proliferation and migration in case of the individual and IS combination treatments; further, decreased levels of pro-EMT proteins, namely, N-cadherin, transforming growth factor-ß, ZEB1, Slug, and Snail were observed. In contrast, E-cadherin expression was upregulated after both the individual and IS combination treatments. These results were also observed in the samples from mice transplanted with the SK-Hep1 cells. CONCLUSION: The present study demonstrated that SRL reduced HCC metastasis by inhibiting EMT. Thus, our findings provide a rationale for the use of SRL in combination with ISs in HCC LTx patients.

Pure Laparoscopic Versus Open Right Hepatectomy in Live Liver Donors: A Propensity Score-matched Analysis.

OBJECTIVE: The aim of the study was to present the safety and feasibility of pure laparoscopic donor right hepatectomy (PLDRH) in comparison with those of conventional donor right hepatectomy. SUMMARY BACKGROUND DATA: Although the use of PLDRH is gradually spreading worldwide, its outcomes, including the long-term outcomes in both donors and recipients, have not yet been evaluated in a large comparative study. METHODS: We retrospectively reviewed the medical records of 894 donors who underwent living donor liver transplantation between January 2010 and September 2018 at Seoul National University Hospital. We performed 1:1 propensity score matching between the PLDRH and conventional donor right hepatectomy groups. Subsequently, 198 donor-recipient pairs were included in each group. RESULTS: The total operation time (P < 0.001), time to remove the liver (P < 0.001), and warm ischemic time (P < 0.001) were longer in the PLDRH group. None of the donors required intraoperative transfusion or experienced any irreversible disabilities or mortalities. The length of postoperative hospital stay was significantly shorter in the PLDRH group (P < 0.001). The rate of complications in donors was similar between the 2 groups. Although other complication rates in recipients were, however, similar, the rates of early (P = 0.019) and late (P < 0.001) biliary complications in recipients were higher in the PLDRH group. There was no significant difference in overall survival and graft survival between the 2 groups. CONCLUSIONS: PLDRH is feasible when performed at an experienced living donor liver transplantation center. Further studies on long-term recipient outcomes including biliary complications are needed to confirm the safety.

Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation.

The interaction between neutrophils and endothelial cells is critical for the pathogenesis of vascular inflammation. However, the regulation of neutrophil adhesive function remains not fully understood. Intravital microscopy demonstrates that neutrophil DREAM promotes neutrophil recruitment to sites of inflammation induced by TNF-α but not MIP-2 or fMLP. We observe that neutrophil DREAM represses expression of A20, a negative regulator of NF-κB activity, and enhances expression of pro-inflammatory molecules and phosphorylation of IκB kinase (IKK) after TNF-α stimulation. Studies using genetic and pharmacologic approaches reveal that DREAM deficiency and IKKß inhibition significantly diminish the ligand-binding activity of ß2 integrins in TNF-α-stimulated neutrophils or neutrophil-like HL-60 cells. Neutrophil DREAM promotes degranulation through IKKß-mediated SNAP-23 phosphorylation. Using sickle cell disease mice lacking DREAM, we show that hematopoietic DREAM promotes vaso-occlusive events in microvessels following TNF-α challenge. Our study provides evidence that targeting DREAM might be a novel therapeutic strategy to reduce excessive neutrophil recruitment in inflammatory diseases.

Shear and Integrin Outside-In Signaling Activate NADPH-Oxidase 2 to Promote Platelet Activation.

[Figure: see text].

Demarcating the Exact Midplane of the Liver Using Indocyanine Green Near-Infrared Fluorescence Imaging During Laparoscopic Donor Hepatectomy.

Indocyanine green (ICG) near-infrared fluoroscopy has been recently implemented in pure laparoscopic donor hepatectomy (PLDH). This study aims to quantitatively evaluate the effectiveness of ICG fluoroscopy during liver midplane dissection in PLDH and to demonstrate that a single injection of ICG is adequate for both midplane dissection and bile duct division. Retrospective analysis was done with images acquired from recordings of PLDH performed without ICG (pre-ICG group) from November 2015 to May 2016 and with ICG (post-ICG group) from June 2016 to May 2017. 30 donors from the pre-ICG group were compared with 46 donors from the post-ICG group. The operation time was shorter (P = 0.002) and postoperative peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were lower (P = 0.031 and P = 0.019, respectively) in the post-ICG group than the pre-ICG group. Within the post-ICG group, the color intensity differences between the clamped versus nonclamped regions in the natural, black-and-white, and fluorescent modes were 39.7 ± 36.2, 89.6 ± 46.9, and 19.1 ± 36.8 (mean ± SD, P < 0.001), respectively. The luminosity differences were 37.2 ± 34.5, 93.8 ± 32.1, and 26.7 ± 25.7 (P < 0.001), respectively. Meanwhile, the time from when ICG was injected to when the near-infrared camera was turned on for bile duct visualization was 85.6 ± 25.8 minutes. All grafts received from the 46 donors were successfully transplanted. In conclusion, ICG fluoroscopy helps to reduce operation time and lower postoperative AST/ALT levels. ICG injection visualized with black-and-white imaging is most effective for demarcating the liver midplane during PLDH. A single intravenous injection of ICG is sufficient for midplane dissection as well as bile duct division.

Complications of polytetrafluoroethylene graft use in middle hepatic vein reconstruction in living donor liver transplantation: a retrospective, single-centre, long-term, real-world experience.

In living donor liver transplantation (LDLT) of the right lobe, polytetrafluoroethylene (PTFE) grafts may be used for anterior drainage. This study aimed to determine the risk factors of PTFE graft-associated complications. Data from patients who underwent LDLT of the right lobe with middle hepatic vein reconstruction using PTFE grafts between January 2005 and December 2012 were retrospectively reviewed. Among 360 patients, PTFE graft-associated complications occurred in 17 patients (group B) (4.7%); recipients without these complications comprised group A (95.3%). The 1-, 6- and 12-month patency rates were significantly lower in group B (P < 0.001, P = 0.002 and P = 0.007). In group B, eight patients (47.1%) required surgical intervention, three patients (17.6%) suffered from infectious complications, and 14 patients (82.4%) experienced PTFE graft migration into the adjacent organs, namely the common bile duct (n = 3, 17.6%), stomach (n = 1, 5.9%), duodenum (n = 5, 29.4%) and jejunum (n = 5, 29.4%). The proportion of recipients who underwent hepaticojejunostomy, had abdominal adhesions and received interventions in/around the liver after LDLT was higher in group B (P < 0.001). Although the incidence of PTFE graft-associated complication is low, close long-term follow-up is needed, especially in patients with risk factors.

Donor wound satisfaction after living-donor liver transplantation in the era of pure laparoscopic donor hepatectomy.

BACKGROUND: Donor safety and cosmetic outcome are the main concerns raised by most living-donors. Pure laparoscopic living-donor hepatectomy (PLLDH) can provide the balance between those concerns. No studies evaluated the donors' satisfaction after PLLDH. The aim of this study is to evaluate the donors' satisfaction after PLLDH compared with donors who underwent open approach. METHODS: We randomly assigned a questionnaire (Donor satisfaction questionnaire) to the donors, operated between 2011 and 2017, during their follow-up visits in the outpatient clinic. Donors who responded to the questionnaire were included in our study. Donors were divided into 3 groups: L group (conventional inverted L incision), M group (midline incision), and PL group (laparoscopic approach). RESULTS: 149 donors were included in our study. L group included 60 donors (40.3%), M group included 39 patients (26.2%), and PL group included 50 patients (33.5%). There were no significant differences between the groups regarding preoperative and perioperative outcomes apart from shorter operation time in PL group and higher wound infection in M group. Body image scale was significantly better in PL group (p = 0.001). Cosmetic scale was significantly higher in PL group (p = 0.001). Regarding self-confidence scale, it was significantly higher in PL group (p = 0.001). There was no significant difference between the groups regarding the sense of dullness or numbness on the scar (p = 0.113). CONCLUSION: PLLDH is safe and feasible for living-donor hepatectomy. Donors operated by pure laparoscopic approach have better satisfaction scores compared to conventional open approach.

Clinical Significance of De Novo Malignancy After Liver Transplant: A Single-Center Study.

BACKGROUND: Several studies have reported that solid organ transplant recipients have a high risk for malignant tumors because the suppressed immune system fails in preventing malignant transformations. De novo malignancy after transplantation is the most common cause of death in the late period after liver transplant (LT). This study investigated the clinical significance of de novo malignancy after LT, and it is the largest study based in Korea to report long-term follow-up results associated with de novo malignancy after LT. METHODS: Data of 1793 adults who underwent LT in Seoul National University Hospital were retrospectively collected, and medical charts and data from the Ministry of Public Administration and Security were reviewed to examine the causes of death and de novo malignancy status. The Fisher exact test and Kaplan-Meier survival analysis were used to analyze the data. RESULTS: Of the 1793 recipients, 27 died of de novo malignancies. Of 875 hepatocellular carcinoma (HCC) patients, 12 died, and of 918 non-HCC patients, 15 died. De novo malignancy was the main cause of death at 5 years after LT but was not in the initial 5 years. In Korea the most common cancers that developed after LT were gastric cancer (21.4%) and lymphoma (14.3%). De novo HCC in non-HCC cases was found in 2 patients. CONCLUSION: De novo malignancy is a key factor affecting long-term survival after LT. Therefore, regular screening and education are important for improving long-term survival and quality of life in these patients after LT.

Parietal Peritoneum as a Novel Substitute for Middle Hepatic Vein Reconstruction During Living Donor Liver Transplantation.

BACKGROUND: Although autologous, cryopreserved, or artificial vascular grafts can be used as interpositional vascular substitutes for middle hepatic vein (MHV) reconstruction during living donor liver transplantation (LDLT), they are not always available, are limited in size and length, and are associated with risks of infection. This study aimed to evaluate the parietal peritoneum as a novel substitute for MHV reconstruction during LDLT. METHODS: Prospectively collected data of 15 patients who underwent LDLT using the right liver with reconstruction of MHV using the recipients' own parietal peritoneum graft were retrospectively reviewed. RESULTS: The 1-, 2-, 3-, and 5-mo patency rates were 57.1%, 57.1%, 57.1%, and 28.6%, respectively. Among the 15 cases assessed, the most recent 6 cases showed patent graft flow until discharge with 1-, 2-, 3-, and 5-mo patency rates of 80.0%, 80.0%, 80.0%, and 20.0%, respectively. All patients survived with tolerable liver function tests. There were no significant congestion-related problems, except for 1 patient who experienced MHV thrombosis requiring aspiration thrombectomy and stent insertion. There were no infection-related complications. All patients survived to the final follow-up, with a minimum follow-up duration of 8 mo. When comparing the latter 6 cases of peritoneal grafts and the recent 28 cases of conventional polytetrafluorethylene graft, the overall patency rate of the polytetrafluorethylene group was higher (P = 0.002). There were no major differences other than long-term patency rate. CONCLUSIONS: Parietal peritoneum may be a novel autologous substitute for MHV reconstruction during LDLT.

Bridging and downstaging role of trans-arterial radio-embolization for expected small remnant volume before liver resection for hepatocellular carcinoma.

Backgrounds/Aims: To evaluate our initial experience of bridging role of trans-arterial radio-embolization (TARE) before major hepatectomy for hepatocellular carcinoma (HCC) in risky patients with small expected remnant liver volume (ERLV). Methods: We reviewed the data of patients with HCC who underwent major hepatectomy after TARE during the period between March and December 2017. Patients included had uni-lobar large HCC (＞5 cm) requiring major hepatectomy with small ERLV. Results: Five patients were included in our study. All patients were Child Pugh class A. A single session of TARE was applied in all patients. None developed any adverse events related to irradiation. The mean tumor size at baseline was 8.4 cm and 6.1 cm after TARE (p=0.077). The mean % of tumor shrinkage was 24.5%. ERLV improved from 354.6 ml at baseline to 500.8 ml after TARE (p=0.012). ERLV percentage improved from 27.2% at baseline to 38.1% after TARE (p=0.004). The mean % of ERLV was 39.5%. The mean interval time between TARE and resection was 99.6 days. Four patients (80%) underwent right hemi-hepatectomy and one patient (20%) underwent extended right hemi-hepatectomy. The mean operation time was 151 minutes, and mean blood loss was 56 ml. The mean hospital stay was 13.8 days, and one patient (20%) developed postoperative morbidity. After a mean follow-up of 15 months, all patients were alive with no recurrence. Conclusions: Yttrium-90 TARE can play a bridging role before major hepatectomy for borderline resectable HCC in risky patients with small ERLV.

Sirolimus Prolongs Survival after Living Donor Liver Transplantation for Hepatocellular Carcinoma Beyond Milan Criteria: A Prospective, Randomised, Open-Label, Multicentre Phase 2 Trial.

Sirolimus (SRL) has been reported to benefit patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). This study aimed to compare SRL with tacrolimus (TAC) in living-donor LT (LDLT) recipients beyond the Milan criteria. This study was initially designed to enrol 45 recipients who underwent LDLT for HCC beyond the Milan criteria. At 1 month after LT, the patients were randomly assigned to either SRL or TAC-based treatment, with both groups receiving mycophenolate mofetil. The primary outcome was three-year recurrence-free survival (RFS) and the secondary outcome was overall survival (OS). A total of 42 patients completed the study. HCC recurrence occurred in 8 of 22 (36.4%) patients in the SRL group and in 5 of 22 (25%) patients in the TAC group. No differences in RFS and OS were found between the two groups in simple comparison. The type of immunosuppressant remained a nonsignificant factor for recurrence in multivariate analysis; however, SRL significantly prolonged OS (TAC hazard ratio: 15 [1.3-172.85], p = 0.03) after adjusting for alpha-fetoprotein and positron emission tomography standardised uptake value ratio (tumour/background liver). In conclusion, SRL does not decrease HCC recurrence but prolongs OS after LDLT for HCC beyond the Milan criteria.

Repurposing pyridoxamine for therapeutic intervention of intravascular cell-cell interactions in mouse models of sickle cell disease.

Adherent neutrophils on vascular endothelium positively contribute to cell-cell aggregation and vaso-occlusion in sickle cell disease. In the present study, we demonstrated that pyridoxamine, a derivative of vitamin B6, might be a therapeutic agent to alleviate intravascular cell-cell aggregation in sickle cell disease. Using real-time intravital microscopy, we found that one oral administration of pyridoxamine dose-dependently increased the rolling influx of neutrophils and reduced neutrophil adhesion to endothelial cells in cremaster microvessels of sickle cell disease mice challenged with hypoxia-reoxygenation. Short-term treatment also mitigated neutrophil-endothelial cell and neutrophil-platelet interactions in the microvessels and improved the survival of sickle cell disease mice challenged with tumor necrosis factor-α. The inhibitory effects of pyridoxamine on intravascular cell-cell interactions were potentiated by co-treatment with hydroxyurea. We observed that long-term (5.5 months) oral treatment with pyridoxamine significantly diminished the adhesive function of neutrophils and platelets and down-regulated the expression of E-selectin and intercellular adhesion molecule-1 on the vascular endothelium in tumor necrosis factor-α-challenged sickle cell disease mice. Ex vivo studies revealed that the surface amount of αMß2 integrin was significantly decreased in stimulated neutrophils isolated from sickle cell disease mice treated with pyridoxamine-containing water. Studies using platelets and neutrophils from sickle cell disease mice and patients suggested that treatment with pyridoxamine reduced the activation state of platelets and neutrophils. These results suggest that pyridoxamine may be a novel therapeutic and a supplement to hydroxyurea to prevent and treat vaco-occlusion events in sickle cell disease.

Influence of Body Mass Index ≥30 on Pure Laparoscopic Donor Right Hepatectomy.

BACKGROUND Pure laparoscopic donor right hepatectomy (PLDRH) for donors with obesity has not been previously investigated. This study aimed to investigate the influence of donor obesity (BMI ≥30 kg/m²) on and clinical outcomes after PLDRH. MATERIAL AND METHODS Records of all living donors who underwent PLDRH between November 2015 and May 2018 and open conventional donor right hepatectomy (CDRH) between January 2011 and October 2015 at Seoul National University Hospital were retrospectively reviewed. The donors were divided into 3 groups: PLDRH BMI ≥30, PLDRH BMI <30, and CDRH BMI ≥30. RESULTS Donors in the PLDRH BMI ≥30 group (n=7) were compared with those in the PLDRH BMI <30 (n=65; control 1) and CDRH BMI ≥30 (n=8; control 2) groups. Graft weight was significantly heavier in PLDRH BMI ≥30 than in control 1 (P=0.012). The lowest hemoglobin (Hb) value was higher (P=0.014) and ΔHb% was lower (P=0.005) in PLDRH BMI ≥30 than in control 1. Similarly, the lowest Hb value was higher (P=0.021) and ΔHb% was lower (P<0.001) in PLDRH BMI ≥30 than in control 2. The peak alanine aminotransferase (ALT) (P=0.029) and ΔALT% were higher in PLDRH BMI ≥30 than in control 2. No significant differences in hospital stay and postoperative complications were found between PLDRH BMI ≥3 and control 1, as well as between PLDRH BMI ≥3 and control 2. CONCLUSIONS This study revealed that PLDRH is feasible in donors with obesity.

Wearable recording video technology for surgical training in living donor liver transplantation.

BACKGROUNDS/AIMS: As the development of surgical video recording technologies, educational videos have become widely utilized for trainee education. However, the current forms of surgical video are limited because they do not show all the roles of the participants. Aim of this study is to make optimal training material about living donor liver transplantation for residents and fellows using wearable recording system. METHODS: Three video clips about procedure of liver transplantation were made. A head mount was used to fix the camera on the surgeon or assistant's head. Anastomosis of vessels, bench operation and trocar insertion for laparoscopic donor hepatectomy were recorded. Each video clips were edited including indicators, subtitles, and narration. The edited videos were shown to 20 General Surgery trainees (18 residents, 2 fellows) and we received feedback. The results of the questionnaire were quantitatively analyzed to show how efficient and informative it is compared to existing educational materials. RESULTS: Sixteen of the 20 trainees (80%) responded that this video helped them improve their surgical skills. Eighteen trainees (90%) responded that they gained new knowledge through this video. Sixteen trainees (80%) responded that the action camera image material was more educational than existing text-based and video-based materials, with an average score of 8.5 and 6.5 (action camera materials vs. text-based materials, respectively). CONCLUSIONS: A head-mounted action camera video recording system is a good model for making high-quality educational video modules and can be a useful teaching tool for living donor liver transplantation.