Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability.

FtsJ RNA 2'-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2'-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient-derived cells. Loss of 2'-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

The new method of time-lag ligation for portosystemic shunt using coronary artery bypass graft occluder for adult living donor liver transplantation.

We performed a living donor liver transplantation (LDLT) for a 57-year-old man who had end-stage liver failure with portal hypertension and an inferior mesenteric vein-left testicular vein (IMV-LTV) shunt. At operation, we did not clamp the shunt but encircled it with a coronary artery bypass graft (CABG) occluder (Sumitomo Bakelite K.K., Japan), which was passed outside the body through the abdominal wall to time-lag ligation (TLL). On postoperative day (POD) 5, we observed decreased portal flow. We performed TLL of the shunt using the CABG occluder without re-laparotomy. The portal flow increased, while the portal vein pressure increased slightly. In LDLT, portosystemic shunt has been reported to be a cause of portal thrombus formation or graft liver atrophy due to decreased PV flow in the mid postoperative period. However, perioperative ligation of a portosystemic shunt may prevent regeneration of the grafted liver because of excessive portal hypertension. Therefore the technique of time-lag ligation of a portosystemic shunt using a CABG occluder may be a minimally invasive, useful method to achieve physiological liver graft regeneration.

Impact of intraportal donor-specific leukocyte transfusion for adult ABO-incompatible liver transplantation.

INTRODUCTION: We have reported that repeated donor-specific leukocyte transfusions (DSLT) via the portal vein allow rapid reduction of immunosuppressants and decrease the occurrence of acute cellular rejection. Herein, we examined the immunological benefits of DSLT in adult ABO-incompatible living donor liver transplantation (LDLT). MATERIALS AND METHODS: Ten adult patients (MELD score, 19.4 +/- 7.3; range, 12-29) underwent LDLT from ABO-incompatible donors from August 2003 to November 2007. The antirejection therapy included multiple perioperative plasmaphereses, splenectomy, and quadruple immunosuppression. In addition to these conventional approaches, we performed 4 intraportal administrations of DSLT after transplantation. RESULTS: There was no humoral rejection in any patient. Two patients experienced mild cellular rejection requiring steroid pulse therapy. Both donor-specific immunoglobulin (Ig)M and IgG A/B antibodies in all patients decreased following transplantation by 16 fold. By flow cytometry, donor type of CD56+NK T cells existed in the liver graft showing macrochimerism at 1 month after liver transplantation. Furthermore, interleukin (IL)-10 production of Th2 type cytokines was up-regulated after transplantation. Three patients died of sepsis and infection. The 5-year survival rate was 70% by the Kaplan-Meier method. CONCLUSION: Adult ABO-incompatible liver transplantation can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection using intraportal administration of DSLT. Donor type CD56+NK T cells may induce tolerance by a veto or an anti-idiotype network mechanism.

Coagulation and fibrinolytic systems during liver regeneration in the early period after adult living related partial liver transplantation.

In this study, we investigated the differences in the perioperative blood coagulation and fibrinolytic systems (BCF) between donor and recipient after adult living related partial liver transplantation (ALRPLT), with particular reference to serum plasminogen-activator inhibitor-1 (PAI-1) and soluble fibinogen level. The BCF were unstable in the recipient compared with the donor. The recipient fibrinolytic system was the same as the donor system except for PAI-1, which was remarkably increased on day 1 after transplantation in the recipient. The recipient is thought to have disseminated intravascular coagulation in the early period after ALRPLT. Soluble fibrinogen may be a useful marker for improvement in the BCF system. The elevation of PAI-1 in recipients on day 1 after transplantation may be a marker of injury from the shear stress from excessive portal hypertension after ALRPLT.

Thrombotic microangiopathy after ABO-incompatible living donor liver transplantation: a case report.

Thrombotic microangiopathy (TMA) has rarely been reported in the setting of liver transplantation. Herein we have reported a successful case of TMA after ABO-incompatible living donor liver transplantation (LDLT) treated with plasma exchange and high-dose intravenous gamma-globulin infusion. A 50-year-old woman was diagnosed with hepatitis C virus-related cirrhosis. We performed an ABO-incompatible LDLT (group B to O) with preoperative plasma exchange to reduce the anti-B hemagglutinin titers to 1:8. The immunosuppressants consisted of tacrolimus, mycophenolate mofetil, and steroid. On postoperative day (POD) 8, her anti-B hemagglutinin titer suddenly increased to 1:64. The serum lactate dehydrogenase (LDH) level was grossly elevated (1518 IU/L). On POD 13, we suspected infection of an intra-abdominal hematoma (Serratia marcescens) which was drained surgically. On day 5 after the reoperation, thrombocytopenia developed with a platelet count of 3 x 10(4)/mm3. A peripheral blood film showed severe red blood cell (RBC) fragmentation. Thus, we made a clinical diagnosis of TMA and reduced the tacrolimus dose. We started intensive daily plasma exchange (4 L/d) with fresh frozen plasma and high-dose intravenous gamma-globulin infusions. One week thereafter, thrombocytopenia improved with reduced transfusion requirements. The peripheral blood film showed normal RBC morphology. The serum LDH returned to baseline levels. Four factors were considered to have caused TMA in this case: the prescription of tacrolimus, ABO-incompatible liver transplantation, bacterial infection, and surgical stress. These factors may have all contributed by causing significant endothelial injury and TMA.

Living related pancreas transplantation alone with enteric drainage in Japan: case report.

In this study, we report a living donor partial pancreas transplantation using intraportal donor-specific leukocyte transfusion (DSLT). The recipient was a 38-year-old woman who had type I diabetes mellitus for 17 years. Hypoglycemia occurred 2 or 3 times per week. Her hemoglobin A1c level was 9.0%, and she required 70 U of insulin almost every day. The donor was her 64-year-old father. The steroid-minimized immunosuppressive protocol included 1.5mg of thymoglobulin administered with a steroid bolus on days 0, 4, and 7 postoperatively. Steroids were never prescribed thereafter. Postoperative maintenance therapy included tacrolimus (FK506) and mycophenolate mofetil. In addition to these conventional approarches, we administered intraportal DSLT on days 0, 1, 4, and 7 after transplantation. The donor-specific leukocytes (40mL) had been separated from donor whole blood using an apheresis filter (Cellsorba EX; Asahi Kasei medical Co, Ltd, Tokyo, Japan). In the recipient operation, a segmental pancreas graft was transplanted into the right iliac cavity with enteric drainage with a pancreatic duct stent. Operation time was 6 hours. The postoperative course was uneventful. The patient was discharged on day 15 after transplantation. There was no acute rejection for six months after transplantation. The hemoglobin A1c level recovered to 5.1% with 6 U of insulin per day. At immunologic analysis, only interleukine-10 cytokine production was elevated at 7 days after transplantation. At flow cytometry cross-match analysis, the immunoglobulin M antibody decreased from day 7 after transplantation. We conclude that intraportal DSLT may be an effective adjunct to a steroid-free regimen.

Adult ABO-incompatible liver transplantation by intraportal transfusion of donor-specific antigen: a case report.

A 55-year-old-woman suffering from fluminant hepatitis owing to autoimmune hepatitis underwent ABO-incompatible liver transplantation (LRLD) of blood type A to B. In this study, we investigated whether a new immunosuppressive strategy by intraportal transfusion of donor-specific leukocytes (DSLT) separated from whole blood would yield immunological benefit in adult ABO-LRLD. The operative course was uneventful; she was discharged at 46 days postoperatively without humoral or cellular rejection. On immunologic analysis, 54.6% intrahepatic macrochimerism of donor type CD56+ T cells was recognized at 1 month after transplantation. The interleukin-10 Th2 cytokine level was increased on postoperative day 1. Adult ABO-incompatible liver transplantation can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection with our strategy of immunosuppression by intraportal administration of DSLT. Donor type CD56+ NKT cells may induce tolerance by a veto mechanism and/or an anti-idiotype network. ABO-incompatible liver transplantation may be improved by this strategy.

Successful super-small-for-size graft liver transplantation by decompression of portal hypertension via splenectomy and construction of a mesocaval shunt: a case report.

We performed a successful super-small-for-size graft liver transplantation by decompressing portal hypertension via splenectomy and a mesocaval shunt. A 46-year-old woman with Child-Pugh class C liver cirrhosis associated with Wilson's disease underwent a living donor liver transplantation (LDLT). The donor had an anomalous portal vein, hepatic vein, and bile duct, so we had to use the right lateral segment for the graft. Preoperative computed tomographic (CT) volumetry showed the volume of this area to be 433 mL; graft-to-recipient weight ratio (GRWR) was 0.72; and graft-to-standard liver volume (GV/SLV) was 39.0%. However, the real volume of the resected right lateral segment was 281 g; GRWR was 0.47; and GV/SLV was 25.3%--a super-small-for-size graft. After implantation, congestion of the small graft was severe due to excessive portal hypertension. Therefore, we tried decompressing the portal vein. First, we performed splenectomy which reduced the portal pressure which remained excessive. Second, a mesocaval shunt was constructed decreasing the portal pressure from 38 to 30 cm H2O. Additionally, we initiated continuous portal injection of prostaglandin E1. The postoperative course was not smooth, but the general status slowly recovered. Over 25 cm H2O of portal hypertension was observed until postoperative day 21 when it improved. At last, the recipient was discharged on postoperative day 156. Accurate preoperative CT volumetry is important to obtain sufficient graft volume. Our case may be one of the smallest-for-size grafts that was successfully transplanted. Management of excessive portal hypertension is important for LDLT, especially using a small-for-size graft. Splenectomy and construction of a mesocaval shunt may be useful strategies to decompress the portal vein.

Dietary intake of tin in Japan, and the effects on intake of canned food and beverage consumption.

The study reported herein was initiated to examine dietary tin intake (Sn-D) in Japan to elucidate the possible effects of consumption of canned food (including beverages) on Sn-D, and to compare the intake among regions and between the two sexes in reference to the current provisional tolerable weekly intake and intake in other countries. Urinary tin levels (Sn-U) were also studied. Duplicate diet samples (24 h) together with records of food intake were collected in 1999-2004 from 111 adult residents in four areas of Japan. After exclusion of incomplete samples, 95 valid samples were subjected to determination of tin by inductively coupled plasma mass spectrometry (ICP-MS) after acid digestion. Among the 95 cases, 37 women additionally provided urine samples. Distribution of Sn-D was markedly skewed. Median Sn-D was 5.6 microg day(-1) for total subjects, which was about one-tenth of the values previously reported for the Japanese population; the difference was most probably attributable to the difference in the methods of determination. Consumption of canned foods led to a substantial increase in Sn-D. Thus, the median Sn-D for canned food consumers of 35.7 microg day(-1), was eight-fold higher than the median Sn-D for non-consumers of 4.5 microg day(-1). Sn-U (as corrected for creatinine concentration) distributed log-normally with a geometric mean of 2.0 microg (g cr)(-1). No effect of canned food consumption was evident on Sn-U. When compared internationally, Sn-D for the Japanese population was substantially lower than Sn-D for populations in other industrialized countries.

Comparison between human-telomerase reverse transcriptase mRNA and alpha-fetoprotein mRNA as a predictive value for recurrence of hepatocellular carcinoma in living donor liver transplantation.

OBJECTIVE: In this study we compared the potential roles of preoperative human-telomerase reverse transcriptase (h-TERT) mRNA versus alpha-fetoprotein (AFP) mRNA expression in the peripheral blood as a tool to predict prognosis and tumor recurrence after living donor liver transplantation (LDLT) in hepatocellular carcinoma (HCC) patients. PATIENTS AND METHODS: We examined 14 patients with unresectable HCC who underwent LDLT. Six patients displayed stage IVA HCC that deviated from the Milan criteria, while the rest of the patients fell within the limitations of the Milan criteria. We analyzed the relationship between preoperative h-TERT mRNA or AFP mRNA expression in the peripheral blood and survival without recurrence. RESULTS: There was no significant difference between the survival curves without recurrence of those patients who did versus did not meet the Milan criteria. There was also no significant difference between the survival curves without recurrence among patients with positive versus negative AFP mRNA expression. However, there was a significant difference (P = .005) between the survival curves without recurrence of those patients with positive preoperative h-TERT mRNA expression versus those who either had an initially negative preoperative h-TERT mRNA or who converted from positive to negative after neoadjuvant immunochemotherapy. CONCLUSIONS: h-TERT mRNA seemed to prove more valuable than AFP mRNA not only to assess preoperative treatment modalities and postoperative patient surveillance, but also to evaluate prospective LDLT patients with HCC. Moreover, use of h-TERT mRNA could potentially expand the indications for transplantation to patients outside the Milan criteria.

Surgical procedures for decompression of excessive shear stress in small-for-size living donor liver transplantation--new hepatic vein reconstruction.

We have reported that acute elevation of portal pressure, reflecting wall shear stress of sinusoidal endothelial cells, triggers liver regeneration after partial hepatectomy and that excessive portal hypertension induces liver failure. For prevention of excessive shear stress in small-for-size living donor liver transplantation (LDLT), we developed a new hepatic vein reconstruction to expand the anastomotic site. Fourteen adult patients, who underwent LDLT, were divided into two groups: previous end-to-end hepatic vein reconstruction in nine patients (group P) and the new method in five patients (group N). The outside middle and left hepatic veins of the graft were incised and enlarged to 40 mm. The vena cava was cut 40 mm longitudinally. The graft was positioned a quarter turn counterclockwise with the hepatic vein of the graft anastomosed end-to-side to the vena cava longitudinally. Postoperative portal pressures and serum total bilirubin levels of these two groups showed portal pressure in group N to rapidly decrease below 25 cm H2O following LDLT. No cases showed posttransplanted hyperbilirubinemia above 10 mg/dL in group N; however, all cases were small-for-size grafts. Moreover, serum total bilirubin levels in group N were significantly lower than those in group P. This procedure is simple despite not using a venous patch. If the hepatic vein is narrow or obstructed, such as in Budd-Chiari syndrome, the procedure is applicable. Even in small-for-size grafts, excessive tension did not occurred at the portal vein or hepatic artery anastomoses. Moreover, it is possible to avoid outflow block and posttransplanted hyperbilirubinemia.

Biliary reconstruction and complications of left lobe living donor liver transplantation.

Postoperative biliary tract complications remain one of the most serious problems facing patients who undergo living donor liver transplantation. The aim of this study was to analyze the clinical implications of three methods of biliary reconstruction in left lobe adult living donor liver transplantation. We retrospectively compared three groups of patients who underwent various biliary reconstructions: those who had Roux-en-Y hepaticojejunostomy (HJ) (n = 11); duct to duct hepaticohepaticostomy (HH) with an external stent (n = 11); or HH with T-tube (n = 6). The median follow-up for each group was 29, 28, and 8 months, respectively. Bile leaks were observed in 45.5% of both the HJ and the HH with external stent groups. Biliary anastomotic strictures occurred in 9.1% of the Roux-en-Y HJ patients and in 27.2% of those who had HH with an external stent. No biliary complications were observed in the HH over a T-tube group (P = .049). Biliary reconstruction using HH with a T-tube may decrease the incidence of biliary complications. Despite the relatively short follow-up, these encouraging preliminary results warrant further studies of this biliary reconstruction technique for left lobe adult living donor liver transplantations.

Inferior mesenteric venous left renal vein shunting for decompression of excessive portal hypertension in adult living related liver transplantation.

In the present study, we investigated the effect of decompression of excessive portal hypertension by inferior mesenteric venous (IMV) left renal vein shunting in 7 cirrhotic patients with esophago-gastric varices and 2 patients who underwent adult living related donor liver transplantation (ALRDLT). The portal pressure remarkably decreased after shunting in all patients with esophago-gastric varices (388 +/- 42 mm H2O vs. 247 +/- 57 mm H2O; P < .05). It also decreased after a shunt operation in patients who had undergone liver transplantation. We report that the excessive shear stress by portal hypertension after small-for-size LRDLT induces a liver injury and the decompression of portal hypertension by splenic arterial ligation or splenectomy prevents postoperative liver injury following massive hepatectomy and small-for-size LRDLT. Our present studies suggested that IMV left renal vein shunting might prevent postoperative liver injury by partial decompression of excessive portal hypertension following small-for-size LRDLT.

Changes in serum LECT 2 levels during the early period of liver regeneration after adult living related donor liver transplantation.

We investigated changes in serum leukocyte cell-derived chemotaxin2 (LECT2) levels between donors and recipients in the early period during liver regeneration following adult living related donor liver transplantation (LRDLT). Five recipients (three women, two men; 37.0 +/- 15.8 years old), all of whom had end-stage liver failure, underwent LRDLT from healthy five donors (two women, three men; 41.6 +/- 14.3 years old) between June 2000 and February 2001. FK506 and methylprednisolone were used as immunosuppressants for recipients. Serum LECT2 levels decreased immediately after both the hepatectomy in all donors and the implantation of liver graft in all recipients. Donors showed a nadir at 3 to 12 hours, increasing at 24 to 48 hours. The nadir in recipients occurred several hours after the donors. The serum LECT2 levels of donors were significantly higher than those of recipients on day 5 (9.5 +/- 5.9 ng/mL vs 3.1 +/- 2.2 ng/mL, P = .04) and on day 7 (9.3 +/- 3.8 ng/mL vs 3.5 +/- 1.1 ng/mL, P = .04). Serum GPT and GOT levels were inversely proportionate to the serum LECT2 levels. The present studies suggest that LECT2 participates in liver regeneration and injury following hepatectomy.

Serum LECT2 level as a prognostic indicator in acute liver failure.

In the present study, we investigated the relationship between serum leukocyte cell-derived chemotaxin2 (LECT2) levels and liver function in patients with acute liver failure, and its use as a prognostic indicator. We studied six acute liver failure patients (two women, four men; 49.8 +/- 20.7 years old) admitted to our hospital in 2002. These patients had diagnoses of fulminant hepatitis due to acute liver failure (1) from congestive heart failure; (2) from portal venous gas, and (3) from postoperative disseminated intravascular coagulation (DIC). We measured serum LECT2, GOT, and GPT levels, the last two being inversely proportionate to the serum LECT2 levels. When the serum GPT levels peaked, the serum LECT2 levels were the lowest. When the liver function recovered, serum LECT2 levels increased. Three of four patients died due to liver failure, one to congestive heart failure. Maximum serum LECT2 levels among the expired group were significantly lower than those among the alive group (0.96 +/- 0.8 ng/mL vs 12.9 +/- 4.3 ng/mL). Serum LECT2 levels may be a prognostic indicator of recovery from liver failure. The present study suggests that in clinical medicine LECT2 participates in regeneration after injury of hepatocytes.

Gender-related difference, geographical variation and time trend in dietary cadmium intake in Japan.

OBJECTIVES: The present analysis was initiated to examine possible gender-dependency, geographic variation, and time-dependent changes in dietary intake of cadmium (Cd-F) among general populations in Cd-non-polluted areas in Japan. The role of rice as Cd-F source was also within the scope. METHODS: Two databases on Cd and nutritional analyses were re-visited. Both databases were established through collection of 24-h food duplicate portion samples from residents in areas with no known Cd pollution, and contained information on Cd and energy contents in the duplicate portion, together with daily rice consumption, the gender, the age and the location of the residence of each sample donor. The first and the second databases were established through surveys in the years around 1980 on 564 cases and around 1995 on 702 cases, respectively. The two databases were combined for evaluation by multiple regression (MRA) and other analyses. RESULTS: The analyses showed that men tended to take more Cd than women, more clearly so in the 1980 survey than in the 1995 survey. When Cd-F in the 1995 survey was compared with that in the 1980 survey, a substantial decrease was observed, e.g. by 30% (from 37.5 to 26.2 microg/day) in case of women. Cd-F values varied subject to the survey sites in a wide range (e.g. from 20 to 86 microg/day among women in the 1980 survey). In MRA with Cd-F as a dependent variable and survey sites and food intake factors (e.g. rice and energy intakes) as independent variables, the survey sites could explain more than 53% and 35% of total variation in Cd-F in the 1980 and 1995 surveys, respectively. Rice consumption was also influential to Cd-F in both surveys with partial correlation coefficients of 0.36 and 0.21, respectively, the influence being stronger in the 1980 survey than in the 1995 survey. A significant correlation was detected between the 1980 and 1995 survey results both in Cd-F and in rice consumption. CONCLUSION: Geographic and gender-related differences, and time-dependent decrease in dietary Cd intake in Japan were detected through analyses of food duplicate-based databases. The leading role of rice as dietary Cd source was also observed.

Right ventricle of patients undergoing congenital cardiac surgery differentially expresses haem oxygenase-1 and heat shock protein 70 genes.

Reactive oxygen species are implicated in the pathogenesis of cardiac hypertrophy. Haem oxygenase-1 (HO-1), the rate-limiting enzyme in haem catabolism, is induced by oxidative stress and confers protection against oxidative tissue injuries. We used Northern blotting to examine expression of HO-1 and heat shock protein 70 (HSP70) in the hypertrophic cardiac muscle of eight patients (one infant and seven children) who underwent surgery for congenital heart disease. Levels of HO-1 and HSP70 mRNA were significantly increased in all specimens, but the orders of magnitude of the increases were different, suggesting that the genes expressing HO-1 and HSP70 are regulated separately.

Dietary taurine intake and serum taurine levels of women on Jeju Island.

The purpose of this study was to investigate the dietary taurine intake and serum taurine levels of women on Jeju Island in Korea. Sixty six married women aged 43.5 +/- 7.1 volunteered for this study: 34 from the city area and 32 from two fishing-farming areas. Diet samples were collected from the participants; the samples included three meals (breakfast, lunch and supper), including snacks, drinks and whatever else the participants had eaten for 24 hours. Taurine levels in the diet and serum were determined as the dabsyl derivative by HPLC with a Rf-detector. The intake of taurine ranged from 8.4 to 767.6 mg/day and its mean value was 163.9 +/- 150.2 mg/day (mean +/- SD). There was a significant difference between the two groups: 114.9 +/- 78.7 for the women from the city area and 215.9 +/- 187.9 mg/day for the women from the fishing-farming areas (p<0.001). The taurine intake of the total diet, including all snacks and drinks, was 2300 +/- 584 g/day for the city area and 2342 +/- 528 g/day for the fishing-farming areas. The daily protein intake was 58.8 +/- 16.4 g for the women of the city area and 65.5 +/- 17.1 g for the women of the fishing-farming areas. There was a significant correlation between the intake of fish/shellfish and taurine (p=0.001) while there was no correlation between the intake of protein and taurine (p=0.057). The taurine levels in serum ranged from 68.6 to 261.6 micromol/L and the mean value was 169.7 +/- 41.5 micromol/L. There was no significant difference between the women from the city area and the women from the fishing-farming areas in serum taurine levels. The correlations of serum taurine levels with serum retinol levels (p=0.016) and alpha-tocopherol (p=0.014) levels were significant. These results suggest that taurine intake is dependent on the fish/shellfish intake and that taurine may play an important role in the retention of antioxidative nutrients.