Hiromu Tanaka

Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6

B lymphocyte-induced maturation protein 1 (Blimp-1) is a key regulator for plasma cell differentiation. Prior to the terminal differentiation into plasma cells, Blimp-1 expression is suppressed in B cells by transcription repressors BTB and CNC homology 2 (Bach2) and B cell lymphoma 6 (Bcl6). Bach2 binds to the Maf recognition element (MARE) of the promoter upstream region of the Blimp-1 gene (Prdm1) by forming a heterodimer with MafK. Bach2 and Bcl6 were found to interact with each other in B cells. While both Bach2 and Bcl6 possess the BTB domain which mediates protein-protein interactions, they interacted in a BTB-independent manner. Bcl6 is known to repress Prdm1 through a Bcl6 recognition element 1 in the intron 5, in which a putative, evolutionarily conserved MARE was identified. Both repressed the expression of a reporter gene containing the intron 5 region depending on the presence of the respective binding sites in 18-81 pre-B cells. Co-expression of Bach2 and Bcl6 resulted in further repression of the reporter plasmid. Chromatin immunoprecipitation assays showed MafK to bind to the intron MARE in various B cell lines, thus suggesting that it binds as a heterodimer with Bach2. Therefore, the interaction between Bach2 and Bcl6 might be crucial for the proper repression of Prdm1 in B cells.

Impact of age at Kasai operation on short- and long–term outcomes of type III biliary atresia at a single institution

PURPOSE We reevaluated the impact of age at Kasai operation on the short- and long-term outcomes of type III biliary atresia (BA). PATIENTS AND METHODS From 1953 to 2009, 242 patients with type III BA underwent Kasai operation at ages ranging between 12 and 421 days (average, 79.7 days). The relationship between age at Kasai operation and jaundice disappearance rates (JDRs), and 10-, 20-, and 30-year native liver survival rates (NLSRs) were assessed retrospectively (JDR [%] = the number of patients in whom jaundice disappeared/the number of patients in each group × 100). RESULTS Age at Kasai operation had a significant impact on the JDRs (P < .001). However, there was no statistical relationship between long-term NLSR of the patients in whom jaundice disappeared after Kasai operation and operative age. From the results of the cumulative NLSRs estimated by Kaplan-Meier method, each survival rate was quite dependent on the age at operation until 30 years after Kasai operation, but the difference became much smaller in the later period provided age at operation was 4 months or younger. CONCLUSION The operative age as a prognostic factor might be less significant in the long-term outcome than in the short-term outcome.

Effects of age at Kasai portoenterostomy on the surgical outcome: a review of the literature

The efficacy of early Kasai portoenterostomy has been repeatedly reported. However, the optimal age for performing this procedure remains controversial. This article reviews the literature on the age of patients at the time of Kasai portoenterostomy and its utility as a prognostic indicator. The age at the time of surgery is a known predictor of outcome; however, its exact predictive value in this context is unclear. Multicenter studies involving large volumes of data have tended to show advantages of early Kasai portoenterostomy, and there is no clear evidence to recommend any delay in the timing of surgery. At present, a reasonable strategy would be to perform a Kasai portoenterostomy as early as possible. The stool color card system has recently been implemented in Japan as part of a nationwide screening program, and it is expected to work well based on the early reports. However, efforts to identify an optimal screening system for ensuring the earliest diagnosis of biliary atresia should continue. An early diagnosis of biliary atresia is difficult, and global efforts are required to improve the early diagnosis rates.

Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3

B lymphocyte-induced maturation protein 1 (Blimp-1) encoded by Prdm1 is a master regulator of plasma cell differentiation. The transcription factor Bach2 represses Blimp-1 expression in B cells to stall terminal differentiation, by which it supports reactions such as class switch recombination of the antibody genes. We found that histones H3 and H4 around the Prdm1 intron 5 Maf recognition element were acetylated at higher levels in X63/0 plasma cells expressing Blimp-1 than in BAL17 mature B cells lacking its expression. Conversely, methylation of H3-K9 was lower in X63/0 cells than BAL17 cells. Purification of the Bach2 complex in BAL17 cells revealed its interaction with histone deacetylase 3 (HDAC3), nuclear co-repressors NCoR1 and NCoR2, transducin β-like 1X-linked (Tbl1x), and RAP1-interacting factor homolog (Rif1). Chromatin immunoprecipitation confirmed the binding of HDAC3 and Rif1 to the Prdm1 locus. Reduction of HDAC3 or NCoR1 expression by RNA interference in B cells resulted in an increased Prdm1 mRNA expression. Bach2 is suggested to cooperate with HDAC3-containing co-repressor complexes in B cells to regulate the stage-specific expression of Prdm1 by writing epigenetic modifications at the Prdm1 locus.

Risk factors affecting late-presenting liver failure in adult patients with biliary atresia

PURPOSE Following the Kasai operation, a number of patients have developed liver failure, even after long-term postoperative courses. We assessed the clinical parameters to clarify the early risk factors affecting late-presenting liver failure in biliary atresia. MATERIALS AND METHODS From 1955 to 1991, 277 patients underwent a Kasai operation. Among those patients, 92 survived with their native liver for more than 20 years, and 72 continue to survive with their native liver in good condition (Group 1). In 20 patients, persistent jaundice recurred after the age of 20 years (Group 2). The postoperative courses of these patients were assessed retrospectively, and the clinical parameters, including age at the time of the Kasai operation (AGE, days), the period required for jaundice to disappear (PJD, days), and the association with early cholangitis (CG), were compared between the 2 groups. RESULTS Of the 20 patients in Group 2, 8 survived after a liver transplantation (LTx). Eight patients had recurrent jaundice, including 4 on the waiting list for anLTx. Additionally, 2 patients died after anLTx at the ages of 22 and 39. Another patient died of liver failure at the age of 28. One patient died of massive esophageal variceal bleeding at the age of 29. Significant differences were confirmed with respect to AGE (Group 1<Group 2, p<.001), PJD (Group 1<Group 2, p<.001), and CG (Group 1: Group 2=47 %: 75 %, p=.028). CONCLUSIONS A considerable number of adult patients developed liver failure, even after the age of 20 years. AGE, PJD, and CG were found to be risk factors affecting late-presenting liver failure. Therefore, close patient follow-up is essential, especially for long-term survivors with a late operative age and early postoperative complications.

Postnatal management of prenatally diagnosed biliary cystic malformation

PURPOSE Recent advances in ultrasonography have increased prenatal diagnosis of biliary atresia (BA) and choledochal cyst (CC). These conditions are not easy to distinguish before or just after birth. This study investigated diagnostic and therapeutic problems in prenatal diagnosis of BA and CC. METHODS We retrospectively studied clinical characteristics and progression of hepatobiliary cysts in 10 patients (4 cases of BA, 6 cases of CC) from the time of diagnosis. Chronological changes in cyst size and gallbladder morphology were assessed and measured sequentially by ultrasonography. RESULTS Three cases of BA were type I cyst and 1 case was type III-d. All cases of CC were type Ia. Cyst size decreased between birth and surgery in BA but increased in CC. The gallbladder appeared atrophic in BA. There was no significant difference in gestational age or cyst size at prenatal diagnosis, changes in cyst size between birth and surgery, and degree of liver fibrosis. CONCLUSIONS BA should be suspected if cyst size decreases before and after birth and the gallbladder atrophies after birth. Cholangiography is the only reliable method to differentiate BA from CC. Neonatal surgery is indicated for CC with icterus and liver dysfunction.

Preclinical development of SMA artificial anal sphincters

This article presents some progress in the development for preclinical trials of an artificial anal sphincter using shape memory alloys. The novel device has been proposed and developed by the authors group at Tohoku University. It has two dominant features different from other systems, which are either clinically available or still under development. One is that a solid driving element, a combination of shape memory alloy (SMA) ribbons and silicone elastomer sheets with a layered structure, is adopted for the opening and closing functions of the artificial sphincter. The other is a sandwich mechanism for the closing of bowel to reduce the risk of buckling induced ischemia which has been reported in hydraulically driven artificial sphincters with a radial squeezing mechanism. The device has fewer parts inside the body and therefore be implanted more easily. A new design eliminating the risk of heat burns enables long‐term implantation and brings the device closer to practical use. Functionality and safety of the device have been proved in three‐month animal experiments.

Technical standardization of Kasai portoenterostomy for biliary atresia

BACKGROUND The purpose of this study was to assess the clinical outcome of patients treated with the current technique of Kasai procedure compared with that of those treated with previous procedures. METHODS We retrospectively assessed the outcomes of 256 patients with biliary atresia who underwent Kasai portoenterostomy at our hospital between 1972 and 2014. Patients were divided into four groups: group 1 (1972-1981, double Roux-en Y, n=91), group 2 (1982-1991, Suruga II, n=80), group 3 (1992-2000, double-valve Roux-en Y, n=46), and group 4 (2001-2014, total removal of the extrahepatic biliary remnants at hepatic capsule and Roux-en Y reconstruction with a spur valve, n=39). Clinical outcomes were compared between the four groups. RESULTS In groups 1, 2, 3, and 4, the rate of jaundice clearance was 65.9%, 77.5%, 63.0%, and 87.2%, respectively; incidence of early cholangitis was 60.4%, 53.8%, 37.0%, and 23.1%, respectively; requirement for redo Kasai surgery was 15.4%, 37.5%, 17.4%, and 5.1%, respectively; 10-year native liver survival rate was 53.8%, 60.1%, 44.1%, and 73.7%, respectively; and 10-year overall survival rate was 55.0%, 72.3%, 86.7%, and 97.3%, respectively. CONCLUSION The standardized Kasai procedure was associated with favorable outcomes. Long-term outcomes remain to be evaluated. LEVEL OF EVIDENCE Case-control/treatment study, level III.

Long-term outcomes of biliary atresia with splenic malformation

BACKGROUND We assessed the long-term outcomes of patients with biliary atresia with splenic malformation (BASM). METHODS We retrospectively assessed outcomes of 255 patients who underwent the Kasai procedure (KP) at our hospital between 1972 and 2014. Clinical outcomes of 11 patients with BASM (group A: nine with polysplenia, two with asplenia) and 244 patients with isolated BA (group B) were compared. RESULTS The incidence of early cholangitis and hepatopulmonary syndrome (HPS) was significantly higher in group A than in group B. Of the 11 group A patients, three died of severe cardiac defects during early infancy. Seven became jaundice free following KP, with three patients subsequently requiring liver transplantation (LTx). Four survived with their native livers for 2, 5, 22, and 23years, respectively. Overall 20-year survival rates were 63.6% and 66.5% and 20-year native liver survival rates were 29.0% and 47.3% in groups A and B, respectively. No significant difference in cumulative survival rates was observed between both groups. CONCLUSIONS Long-term outcomes in BASM patients without lethal cardiac defects were comparable to patients with isolated BA. Careful follow-up may be required in patients with BASM because of a potentially higher risk of secondary complications such as HPS.

Using 99mTc-DTPA galactosyl human serum albumin liver scintigraphy as a prognostic indicator in jaundice-free patients with biliary atresia

BACKGROUND We evaluated the clinical significance of follow-up data, including 99mTc-DTPA galactosyl human serum albumin (99mTc-GSA) liver scintigraphy data, as prognostic indicators for jaundice-free patients with biliary atresia (BA). METHODS Of 87 patients who underwent Kasai portoenterostomy (KP) between 1991 and 2012, 45 jaundice-free patients aged 1-2 years underwent 99mTc-GSA scintigraphy and were classified into 2 groups: those who survived with a native liver (Group A, n = 34) and those who required liver transplantation (LTx) (Group B, n = 11). We compared 99mTc-GSA scintigraphy data (HH15, LHL15, and HH15/LHL15 [H/L15]) and liver function test (LFT) results between the groups. The patients underwent a second 99mTc-GSA scintigraphy at approximately 5 years of age. RESULTS All patients survived. HH15, H/L15, total bilirubin, direct bilirubin, gamma-glutamyl transpeptidase, and alanine transaminase levels were higher in Group B than in Group A (p<0.05). Total and direct bilirubin levels were associated with H/L15 (p<0.05). There were no significant changes in results between the first and second 99mTc-GSA scintigraphy in Group A. CONCLUSIONS Mid- and long-term prognoses may be predicted using 99mTc-GSA scintigraphy data and LFTs in patients aged 1-2 years. We recommend regular monitoring of postoperative data following KP, even in jaundice-free patients. LEVEL OF EVIDENCE III.