Impaired antibacterial response of liver sinusoidal Vγ9+Vδ2+ T cells in patients with chronic liver disease.

OBJECTIVE: The liver acts as a frontline barrier against diverse gut-derived pathogens, and the sinusoid is the primary site of liver immune surveillance. However, little is known about liver sinusoidal immune cells in the context of chronic liver disease (CLD). Here, we investigated the antibacterial capacity of liver sinusoidal γδ T cells in patients with various CLDs. DESIGN: We analysed the frequency, phenotype and functions of human liver sinusoidal γδ T cells from healthy donors and recipients with CLD, including HBV-related CLD (liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC)), alcoholic LC and LC or HCC of other aetiologies, by flow cytometry and RNA-sequencing using liver perfusates obtained during living donor liver transplantation. We also measured the plasma levels of D-lactate and bacterial endotoxin to evaluate bacterial translocation. RESULTS: The frequency of liver sinusoidal Vγ9+Vδ2+ T cells was reduced in patients with CLD. Immunophenotypic and transcriptomic analyses revealed that liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD were persistently activated and pro-apoptotic. In addition, liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD showed significantly decreased interferon (IFN)-γ production following stimulation with bacterial metabolites and Escherichia coli. The antibacterial IFN-γ response of liver sinusoidal Vγ9+Vδ2+ T cells significantly correlated with liver function, and inversely correlated with the plasma level of D-lactate in patients with CLD. Repetitive in vitro stimulation with E. coli induced activation, apoptosis and functional impairment of liver sinusoidal Vγ9+Vδ2+ T cells. CONCLUSION: Liver sinusoidal Vγ9+Vδ2+ T cells are functionally impaired in patients with CLD. Bacterial translocation and decreasing liver functions are associated with functional impairment of liver sinusoidal Vγ9+Vδ2+ T cells.

Outcomes of Robotic Living Donor Right Hepatectomy From 52 Consecutive Cases: Comparison With Open and Laparoscopy-assisted Donor Hepatectomy.

OBJECTIVE: To investigate the feasibility and safety of RLDRH. SUMMARY OF BACKGROUND DATA: Data for minimally invasive living-donor right hepatectomy, especially RLDRH, from a relatively large donor cohort that have not been reported yet. METHODS: From March 2016 to March 2019, 52 liver donors underwent RLDRH. The clinical and perioperative outcomes of RLDRH were compared with those of CODRH (n = 62) and LADRH (n = 118). Donor satisfaction with cosmetic results was compared between RLDRH and LADRH using a body image questionnaire. RESULTS: Although RLDRH was associated with longer operative time (minutes) (RLDRH, 493.6; CODRH, 404.4; LADRH, 355.9; P < 0.001), mean estimated blood loss (mL) was significantly lower (RLDRH, 109.8; CODRH, 287.1; LADRH, 265.5; P = 0.001). Postoperative complication rates were similar among the 3 groups (RLDRH, 23.1%; CODRH, 35.5%; LADRH, 28.0%; P = 0.420). Regarding donor satisfaction, body image and cosmetic appearance scores were significantly higher in RLDRH than in LADRH. After propensity score matching, RLDRH showed less estimated blood loss compared to those of CODRH (RLDRH, 114.7 mL; CODRH, 318.4 mL; P < 0.001), but complication rates were similar among the three groups (P = 0.748). CONCLUSIONS: RLDRH resulted in less blood loss compared with that of CODRH and similar postoperative complication rates to CODRH and LADRH. RLDRH provided better body image and cosmetic results compared with those of LADRH. RLDRH is feasible and safe when performed by surgeons experienced with both robotic and open hepatectomy.

Presence of a survival benefit of HLA-incompatible living donor kidney transplantation compared to waiting or HLA-compatible deceased donor kidney transplantation with a long waiting time.

HLA-incompatible living donor kidney transplantation (LDKT) is one of efforts to increase kidney transplantation opportunity for sensitized patients with kidney failure. However, there are conflicting reports for outcomes of HLA-incompatible kidney transplantation compared to patients who wait for HLA-compatible deceased donor kidney transplantation (DDKT) in the United States and United Kingdom. Waiting for an HLA-compatible DDKT is relatively disadvantageous in Korea, because the average waiting time is more than five years. To study this further, we compared outcomes of HLA-incompatible LDKT with those who wait for HLA-compatible DDKT in Korea. One hundred eighty nine patients underwent HLA-incompatible LDKT after desensitization between 2006 and 2018 in two Korean hospitals (42 with a positive complement-dependent cytotoxicity cross-match, 89 with a positive flow cytometric cross-match, and 58 with a positive donor-specific antibody with negative cross-match). The distribution of matched variables was comparable between the HLA-incompatible LDKT group and the matched control groups (waiting-list-only group; and the waiting-list-or-HLA-compatible-DDKT groups; 930 patients each). The HLA-incompatible LDKT group showed a significantly better patient survival rate compared to the waiting-list-only group and the waiting-list-or-HLA-compatible-DDKT groups. Furthermore, the HLA-incompatible LDKT group showed a significant survival benefit as compared with the matched groups at all strength of donor-specific antibodies. Thus, HLA-incompatible LDKT could have a survival benefit as compared with patients who were waitlisted for HLA-compatible DDKT or received HLA-compatible DDKT in Korea. This suggests that HLA-incompatible LDKT as a good option for sensitized patients with kidney failure in countries with prolonged waiting times for DDKT.

Subclassification of Microscopic Vascular Invasion in Hepatocellular Carcinoma.

OBJECTIVE: To investigate whether subclassification of microscopic vascular invasion (MiVI) affects the long-term outcome after curative surgical resection or liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA: The most important factor for TNM staging in HCC is MiVI, which includes all vascular invasions detected on microscopic examination. However, there is a broad spectrum of current definitions for MiVI. METHODS: In total, 412 consecutive patients with HCC who underwent curative surgical resection without any preoperative treatment or gross vascular invasion were histologically evaluated for MiVI. Patients with MiVI were subclassified into 2 groups: microvessel invasion (MI; n = 164) only and microscopic portal vein invasion (MPVI; n = 36). Clinicopathologic features were compared between 2 groups (MI vs MPVI), whereas disease-free survival (DFS) and overall survival (OS) after resection were analyzed among 3 groups (no vascular invasion [NVI] vs MI vs MPVI). These subclassifications were validated in a cohort of 197 patients with HCC who underwent LT. RESULTS: The MPVI group showed more aggressive tumor characteristics, such as higher tumor marker levels (alpha-fetoprotein, P = 0.006; protein induced by vitamin K absence-II, P = 0.001) and poorer differentiation (P = 0.011), than the MI group. In multivariate analysis, both MI and MPVI were independent prognostic factors for DFS (P = 0.001 and <0.001, respectively) and OS (P = 0.005 and <0.001, respectively). In the validation cohort, 5-year DFS was 89%, 67.9%, and 0% in the NVI, MI, and MPVI groups, respectively (P < 0.001), whereas 5-year OS was 79.1%, 55.0%, and 15.4%, respectively (P < 0.001). CONCLUSIONS: Based on subclassification of MiVI in HCC, MPVI was associated with more aggressive clinicopathologic characteristics and poorer survival than MI only. Therefore, the original MiVI classification should be divided into MI and MPVI.

Glomerular subepithelial microparticles - a footprint for podocyte injury.

The aim of this study was to clarify the nature and clinical significance of glomerular subepithelial microparticles (SMPs), located between the basal surface of the podocytes and the glomerular basement membrane. Ultrastructural morphology of 79 renal biopsy samples (obtained from 25 native and 54 transplanted kidneys), showing SMPs in the last 3 years, was reevaluated with regard to the podocyte changes and clinical condition of the patients. One hundred and nine SMPs were identified, with 32.9% of the samples having two or more per glomerulus. Overall, they were most frequently located in the open capillary loops (55%). However, in the native kidney samples with mesangial deposits, 64.3% of SMPs were present in the mesangium-bound areas. Each vesicle ranged from 46.9 to 87.1 nm, and vesicles were admixed with curved strands in larger SMPs. Diffuse effacement of the foot processes and condensation of the actin filaments were present in 56.0% and 62.4% of the samples, respectively. SMPs were associated with hematuria, proteinuria of ≥ 1 gm, and immune complex deposition in the patients with native kidneys, whereas they were related to hyperglycemia and elevated serum creatinine levels in the patients with renal allografts. Patients with native and transplanted kidneys most commonly presented with IgA nephropathy and allograft rejection, respectively. Finding SMPs in the renal biopsy samples is not rare and they may act as a footprint of podocyte injury caused by diverse etiologies. Considering their size, podocyte exosomes could be a possible source of SMPs.

Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus-based immunosuppression with basiliximab induction.

Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.

Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15.

BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in the human liver, can be activated by cytokines during viral infection without TCR stimulation. Here, we examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. We also examined the phenotype and function of MAIT cells from patients with acute viral hepatitis. METHODS: We obtained liver sinusoidal mononuclear cells from donor liver perfusate during liver transplantation and examined the effect of various cytokines on liver MAIT cells using flow cytometry and in vitro cytotoxicity assays. We also obtained peripheral blood and liver-infiltrating T cells from patients with acute hepatitis A (AHA) and examined the phenotype and function of MAIT cells using flow cytometry. RESULTS: IL-15-stimulated MAIT cells exerted granzyme B-dependent innate-like cytotoxicity in the absence of TCR/MR1 interaction. PI3K-mTOR signaling, NKG2D ligation, and CD2-mediated conjugate formation were critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with AHA exhibited activated and cytotoxic phenotypes with higher NKG2D expression. The innate-like cytotoxicity of MAIT cells was significantly increased in patients with AHA and correlated with serum alanine aminotransferase levels. CONCLUSIONS: Taken together, the results demonstrate that liver MAIT cells activated by IL-15 exert NKG2D-dependent innate-like cytotoxicity in the absence of TCR/MR1 engagement. Furthermore, the innate-like cytotoxicity of MAIT cells is associated with liver injury in patients with AHA, suggesting that MAIT cells contribute to immune-mediated liver injury. LAY SUMMARY: Immune-mediated liver injury commonly occurs during viral infections of the liver. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the human liver. Herein, we have identified a mechanism by which MAIT cells circumvent conventional T cell receptor interactions to exert cytotoxicity. We show that this innate-like cytotoxicity is increased during acute hepatitis A virus infection and correlates with the degree of hepatocyte injury.

Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.

BACKGROUND & AIMS: Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. METHODS: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. RESULTS: Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. CONCLUSIONS: Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. LAY SUMMARY: The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.

Renal safety of tenofovir disoproxil fumarate and entecavir with hepatitis B immunoglobulin in liver transplant patients.

Potent nucleos(t)ide analogues and hepatitis B immunoglobulin combinations are recommended after liver transplantation to prevent the recurrence of hepatitis B virus (HBV). Despite its proven efficacy, the renal safety of tenofovir disoproxil fumarate (TDF) has not been well established in liver transplant recipients. We aimed to assess the impacts of TDF and entecavir (ETV) on tubular and glomerular functions. We analysed 206 liver transplant patients treated with TDF (n = 102) or ETV (n = 104) plus hepatitis B immunoglobulin. Serum creatinine, phosphate and uric acid levels were measured. Proximal tubular dysfunction was defined as the presence of hypophosphatemia (<2 mg/dL) and hypouricemia (<2 mg/dL). Glomerular dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 accompanied by a ≥25% eGFR decline from baseline. During a median follow-up of 42.5 months, 48 patients developed proximal tubular dysfunction (30.4% and 16.3% in the TDF and ETV groups; P = .017). Serum levels of phosphate and uric acid were significantly lower in the TDF group post-LT. TDF (OR, 2.34; 95% CI, 1.16-4.69; P = .017) and low body mass index (OR, 2.11; 95% CI, 1.06-4.21; P = .034) were independent risk factors for proximal tubular dysfunction. The prevalence of glomerular dysfunction was not significantly different between the two groups (TDF 51.0% and ETV 54.8%; P = .582). TDF significantly increased the risk of proximal tubular dysfunction. Although the effect of TDF on glomerular function was comparable to that of ETV, glomerular dysfunction was common after liver transplant.

Transplant outcomes in positive complement-dependent cytotoxicity- versus flow cytometry-crossmatch kidney transplant recipients after successful desensitization: a retrospective study.

BACKGROUND: Despite the obvious survival benefit compared to that among waitlist patients, outcomes of positive crossmatch kidney transplantation (KT) are generally inferior to those of human leukocyte antigen (HLA)-compatible KT. This study aimed to compare the outcomes of positive complement-dependent cytotoxicity (CDC) crossmatch (CDC + FC+) and positive flow cytometric crossmatch (CDC-FC+) with those of HLA-compatible KT (CDC-FC-) after successful desensitization. METHODS: We retrospectively analyzed 330 eligible patients who underwent KTs between June 2011 and August 2017: CDC-FC- (n = 274), CDC-FC+ (n = 39), and CDC + FC+ (n = 17). Desensitization protocol targeting donor-specific antibody (DSA) involved plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab with/without bortezomib for positive-crossmatch KT. RESULTS: Death-censored graft survival and patient survival were not different among the three groups. The median estimated glomerular filtration rate was significantly lower in the CDC + FC+ group than in the compatible group at 6 months (P < 0.001) and 2 years (P = 0.020). Biopsy-proven rejection within 1 year of CDC-FC-, CDC-FC+, and CDC + FC+ were 15.3, 28.2, and 47.0%, respectively. Urinary tract infections (P < 0.001), Pneumocystis jirovecii pneumonia (P < 0.001), and cytomegalovirus viremia (P < 0.001) were more frequent in CDC-FC+ and CDC + FC+ than in CDC-FC-. CONCLUSIONS: This study showed that similar graft and patient survival was achieved in CDC-FC+ and CDC + FC+ KT compared with CDC-FC- through DSA-targeted desensitization despite the higher incidence of rejection and infection than that in compatible KT.

Patient Selection by Tumor Markers in Liver Transplantation for Advanced Hepatocellular Carcinoma.

Although far advanced hepatocellular carcinoma (HCC) is generally considered a contraindication for liver transplantation (LT), biologically favorable tumors among them could show acceptable results. However, it is still unclear which tumors can be treated with LT. Data were collected on adult patients who underwent LT for HCC beyond the Milan criteria in 8 Korean LT centers between January 2000 and June 2013. Far advanced HCC was defined as HCC with the largest tumor ≥ 10 cm, 10 or more tumor nodules, or accompanying macrovascular invasion. A total of 688 patients, including 169 with far advanced HCC, were enrolled in this study. The 5-year overall and recurrence-free survival rates were 60.4% and 55.1%, respectively, for all patients but only 28.7% and 24.8%, respectively, for patients with far advanced HCC (P < 0.001). Both preoperative alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II) were significant risk factors for HCC recurrence after LT. In particular, AFP + PIVKA-II combined was a better predictor than either marker alone. Of all far advanced HCC patients with available AFP and PIVKA-II levels, 45 (30.8%) had low AFP + PIVKA-II (≤300) and their 5-year overall and recurrence-free survival rate were 47.8% and 53.4%, respectively, which were acceptable and significantly superior to those of patients with AFP (ng/mL) + PIVKA-II (nAU/mL) > 300 (21.0% and 10.8%, respectively; P < 0.001). In conclusion, patients with favorable HCC had acceptable outcomes after LT even when their tumors were extremely advanced. AFP + PIVKA-II gave reliable information about the tumor biology of far advanced HCC. Liver Transplantation 00 000-000 2018 AASLD.

Rituximab and hepatitis B reactivation in HBsAg-negative/ anti-HBc-positive kidney transplant recipients.

Background: Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. Methods: We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014. Patients were divided into rituximab ( n = 49) or control ( n = 123) groups. All patients were observed for HBV reactivation, which was defined as the reappearance of hepatitis B surface antigen or HBV DNA. Results: During the follow-up period (median, 58 months; range, 4-95 months), five patients (10.2%) in the rituximab group and two patients (1.6%) in the control group experienced HBV reactivation (P = 0.003). In the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died due to hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5-22 months). By contrast, no patients in the control group experienced severe hepatitis. The status of hepatitis B surface antibody was similar between groups. Rituximab desensitization [hazard ratio (HR), 9.18; 95% confidence interval (CI), 1.74-48.86; P = 0.009] and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05-21.23, P = 0.04) were significant risk factors for HBV reactivation. Conclusions: Rituximab desensitization for incompatible kidney transplantation significantly increased the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients. Therefore, close monitoring of HBV DNA is required in these patients.

Clinical significance of lactate clearance for the development of early allograft dysfunction and short-term prognosis in deceased donor liver transplantation.

This retrospective study evaluated lactate clearance (LC), measured at 6, 12, 18, and 24 hours after reperfusion, as a predictor of early allograft dysfunction (EAD) and short-term outcomes in patients receiving deceased donor liver transplantation. Of 181 transplant recipients, 44 (24.3%) developed EAD and had lower LCs than those who did not develop EAD. A receiver operating characteristic analysis showed that LC determined at 6 hours showed the highest area under curve value of 0.828 (95% confidence interval [CI]: 0.755-0.990) for predicting the development of EAD at a cutoff value of 25.8% with 76.7% sensitivity and 77.9% specificity. LC values that fell below the cutoff values were significantly associated with EAD in a multivariate analysis, with values at 6 hours having the highest adjusted odds ratio (11.891, 95% CI: 4.469-31.639). In-hospital and 6 month mortalities were higher in patients with LC values below the cutoffs compared with those above the cutoff values at each time point. Thus, LC calculated shortly after reperfusion of an allograft is significantly discriminative for the development of EAD and is associated with short-term prognosis after deceased donor liver transplantation.

Successful launch of an ABO-incompatible kidney transplantation program to overcome the shortage of compatible living donors: experience at a single center
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AIMS: ABO-incompatible (ABOi) kidney transplantation (KT) is being increasingly performed to overcome donor shortages. However, debate persists regarding the post-transplant outcomes of ABOi KT vs. that of ABO-compatible (ABOc) KT. METHODS: A total 454 recipients who underwent living-donor KT (LDKT) between June 2010 and July 2014 at Severance Hospital (Seoul) were retrospectively reviewed. 100 ABOi and 354 ABOc KTs were compared. Recipients with a pretransplant positive crossmatch to their donors, pretransplant donor-specific anti-HLA antibody (DSA), or high panel reactive antibody (PRA ≥ 50%) were excluded from both the ABOi and ABOc KT groups. Finally, the authors compared the transplant outcomes of 95 of these ABOi KTs and 121 ABOc KTs performed over the same period. RESULTS: No significant difference in incidence of biopsy-proven acute rejection was observed between the ABOi and ABOc KT groups (p = 0.230), and group glomerular filtration rate of ABOi KT was comparable to that of ABOc KT (p > 0.05 at all time points). 3-year death-censored graft survival rates were similar (96.8 vs. 96.6%, respectively; p = 0.801). However, the incidences of postoperative bleeding, cytomegalovirus infection, fungal infection, and serious infection rates were significantly higher after ABOi KT. CONCLUSIONS: In this study, graft renal function and survival after ABOi KT were excellent, and the incidence of acute rejection was similar to that of ABOc KT. However, efforts are needed to reduce hemorrhagic and infectious complications after ABOi KT. ABOi KT can be a good strategy to overcome ABO antibody barriers and relieve donor shortage.
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Inhibitory effects of the essential oils α-longipinene and linalool on biofilm formation and hyphal growth of Candida albicans.

Candida albicans is one of the most common fungal pathogens, and causes systemic and invasive infections in humans. C. albicans biofilms are composed of yeast and hyphal and pseudohyphal elements, and the transition of yeast to the hyphal stage could be a virulence factor. In this study, diverse essential oils were initially investigated for anti-biofilm activity against C. albicans strains, and cascarilla bark oil and helichrysum oil and their components α-longipinene (a major constituent of both) and linalool were found to markedly inhibit biofilm formation without affecting planktonic cell growth. Moreover, α-longipinene and linalool were found to synergistically reduce biofilm formation. Notably, treatments with cascarilla bark oil, helichrysum oil, α-longipinene, or linalool clearly inhibited hyphal formation, and this appeared to be largely responsible for their anti-biofilm effect. Furthermore, the two essential oils, α-longipinene and linalool, reduced C. albicans virulence in Caenorhabditis elegans.

The effect of rituximab dose on infectious complications in ABO-incompatible kidney transplantation.

BACKGROUND: Rituximab (RIT) improves the outcomes of ABO-incompatible (ABOi) kidney transplantation (KT), but it has been associated with infectious complications. The aim of this study was to investigate infectious complications according to the dose of RIT in ABOi KT. METHODS: We analyzed 213 recipients [118 ABO-compatible (ABOc) KT and 95 ABOi KT] who underwent living donor KT between 2010 and 2014. ABOi KT patients were categorized by RIT dose: standard RIT (375 mg/m(2), n = 76) versus reduced RIT (200 mg, n = 19). All patients received basiliximab and maintained on triple immunosuppression consisting of tacrolimus, prednisone and mycophenolate mofetil. Infectious complications and post-transplant outcomes were analyzed for 1 year following KT. RESULTS: The rates of overall infectious complications among the three groups were comparable (22.9% in ABOc KT, 38.2% in standard RIT and 26.3% in reduced RIT, P = 0.069). In the standard RIT group, hepatitis B virus reactivation occurred in three recipients (3.9%) with hepatitis B surface antigen[-]/anti-hepatitis B core antibody[+]. Three cases (3.9%) of Pneumocystis jirovecii pneumonia occurred in the standard RIT group. Serious infections developed in 13 of the ABOc KT (11.0%), 20 from the standard RIT group (26.3%) and 2 from the reduced RIT group (10.5%, P = 0.015). Standard-dose RIT was found to be an independent risk factor for serious infections [hazard ratio: 2.59 (95% confidence interval: 1.33-5.07), P = 0.005]. There were no significant differences in rejection, renal function, graft survival and patient survival between standard and reduced RIT groups. CONCLUSIONS: Standard RIT increased the risk of serious infection when compared with reduced-dose RIT. Reduced-dose RIT might be sufficient for ABOi KT without increasing the risk of serious infection.

The clinical behavior of transplantable recurrent hepatocellular carcinoma after curative resection: implications for salvage liver transplantation.

BACKGROUND: This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT). METHODS: The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for ≥12 months or control of a recurrent tumor within the MC by active locoregional treatment. RESULTS: After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P < 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age >50 years and an indocyanine green retention at 15 min >10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence. CONCLUSIONS: The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.

Anti-biofilm, anti-hemolysis, and anti-virulence activities of black pepper, cananga, myrrh oils, and nerolidol against Staphylococcus aureus.

The long-term usage of antibiotics has resulted in the evolution of multidrug-resistant bacteria. Unlike antibiotics, anti-virulence approaches target bacterial virulence without affecting cell viability, which may be less prone to develop drug resistance. Staphylococcus aureus is a major human pathogen that produces diverse virulence factors, such as α-toxin, which is hemolytic. Also, biofilm formation of S. aureus is one of the mechanisms of its drug resistance. In this study, anti-biofilm screening of 83 essential oils showed that black pepper, cananga, and myrrh oils and their common constituent cis-nerolidol at 0.01 % markedly inhibited S. aureus biofilm formation. Furthermore, the three essential oils and cis-nerolidol at below 0.005 % almost abolished the hemolytic activity of S. aureus. Transcriptional analyses showed that black pepper oil down-regulated the expressions of the α-toxin gene (hla), the nuclease genes, and the regulatory genes. In addition, black pepper, cananga, and myrrh oils and cis-nerolidol attenuated S. aureus virulence in the nematode Caenorhabditis elegans. This study is one of the most extensive on anti-virulence screening using diverse essential oils and provides comprehensive data on the subject. This finding implies other beneficial effects of essential oils and suggests that black pepper, cananga, and myrrh oils have potential use as anti-virulence strategies against persistent S. aureus infections.

Fumigant toxicity of summer savory and lemon balm oil constituents and efficacy of spray formulations containing the oils to B- and neonicotinoid-resistant Q-biotypes of Bemisia tabaci (Homoptera: Aleyrodidae).

An assessment was made of the fumigant toxicity of 36 constituents from lemon balm oil (LBO) and summer savory oil (SSO) and another additional nine previously identified compounds of the oils, as well as of the control efficacy of four experimental spray formulations containing individual oils (0.5 and 0.1% sprays) and spinosad 10% suspension concentrate (SC) to females from B- and neonicotinoid-resistant Q-biotypes of Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae). Based on 24-h LC50 values, Q-biotype females (0.20 microg/cm3) were 40 times less susceptible to dichlorvos than B-biotype females (0.005 microg/cm3). Thymol (LC50, 0.35 microg/cm3) and carvacrol (0.56 microg/cm3) were the most toxic compounds toward Q-biotype females, followed by (1S)-(-)-borneol, alpha-terpineol, nerol, linalool, and carvone (1.06-1.38 microg/cm3). The toxicity of these compounds was virtually identical toward both biotype females, indicating that the terpenoids and the insecticides (neonicotinoids and dichlorvos) do not share a common mode of action or elicit cross-resistance. The 0.5% spray of LBO, SSO, and spinosad 10% SC resulted in >90% mortality toward both biotype females. Global efforts to reduce the level of toxic synthetic insecticides in the agricultural environment justify further studies on LBO- and SSO-derived materials as potential contact-action fumigants for the control of B. tabaci populations.