Motoshi Wada

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.

Development of an implantable artificial anal sphincter by the use of the shape memory alloy.

In this study, we developed and assessed an artificial anal sphincter driven by an shape memory alloy actuator (AS-SMA). The performance characteristics of the device were analyzed with a measurement system. Assessment showed that the AS-SMA could generate a pressure of 55 mm Hg at an atmospheric temperature of 36°C, and displacement of the SMA actuator was 7.5 mm when the temperature of the SMA plate was 55°C. To evaluate opening and closing, we studied a piglet colostomy model, in which the AS-SMA was implanted around the colostomy in the extraperitoneal space. Flow control tests using living porcine intestine revealed that the AS-SMA could maintain fecal continence against an intestinal pressure of 75 mm Hg. The high pressure zone corresponding to the location of the device was demonstrated in a manometric examination. For 6 days after surgery, we activated the AS-SMA twice a day and observed the bowel movements. The animal experiment indicated that the AS-SMA is able to control the bowel movements of patients with fecal incontinence if several problems, such as burning of tissue around the device and compression injury of the intestine, are resolved.

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.

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.

OX40 and IL‐7 play synergistic roles in the homeostatic proliferation of effector memory CD4+ T cells

T‐cell homeostasis preserves the numbers, the diversity and functional competence of different T‐cell subsets that are required for adaptive immunity. Naïve CD4+ T (TN) cells are maintained in the periphery via the common γ‐chain family cytokine IL‐7 and weak antigenic signals. However, it is not clear how memory CD4+ T‐cell subsets are maintained in the periphery and which factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE‐labeled CD4+CD44highCD62Llow effector memory T (TEM) cells were transferred into sublethally‐irradiated syngeneic C57BL/6 mice, and the systemic cell proliferative responses, which can be divided distinctively into fast and slow proliferations, were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of TEM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL‐7. The simultaneous blockade of both OX40 and IL‐7 signaling completely inhibited the both fast and slow proliferation. The antigen‐ and OX40‐dependent fast proliferation preferentially expanded IL‐17‐producing helper T cells (Th17 cells). Thus, OX40 and IL‐7 play synergistic, but distinct roles in the homeostatic proliferation of CD4+ TEM cells.

Functional evaluation of an artificial anal sphincter using shape memory alloys.

This article describes an implantable artificial anal sphincter using shape memory alloys and its in vivo assessment in porcine models. The new design was developed as a low invasive prosthesis with a simple structure to solve the problem of severe fecal incontinence in patients with hypoplastic sphincters or without anal sphincters and especially for ostomates. The artificial anal sphincter consists of two shape memory alloy (SMA) plates as the main functional parts to perform two basic functions when the SMA artificial sphincter is fitted around intestines (i.e., an occlusion at body temperature and an opening function on heating). Our previous assessments with short-term animal experiments revealed promising properties with the occlusion function of the device, although some complications, such as overpressure induced ischemia, heat burn, and infections, remained. This article addresses the concerns related to the practical use of the device, the power supplement to drive the actuator, and overheating protection of the device inside bodies. Results of chronic animal experiments of up to 4 weeks suggested great potential for the improved device.

High trough levels of oral FK506 induced by loss of small intestine

Abstract: To establish a safe and effective usage of oral tacrolimus (FK506) in small bowel transplantation (SBTx) recipients, trough levels and area under the curve (AUC) values of FK506 were assessed using swine models of SBTx and short bowel. Thirty‐eight Landrace male piglets were divided into four groups as follows: Group 1, controls (n=13); Group 2, a one‐third small bowel model (n=5); Group 3, a short bowel model (n=10); and Group 4, a one‐third small bowel allograft model (n=10; five donors and five recipients). Piglets of Groups 1 and 3 were further divided into two sub‐groups, according to the route of drug administration: Groups 1a (n=10) and 3a (n=7) received FK506 orally, and Groups 1b (n=3) and 3b (n=3) received FK506 intravenously. Oral or intravenous FK506 was started on post‐operative day 3 and continued until day 7 in each group. On day 7, trough levels and AUC values were measured. In Groups 1a, 2, 3a and 4, trough levels of FK506 were 2.1±1.2 (p<0.01 vs. Group 2, 3a or 4), 11.2±2.1, 23.3±4.8 (p<0.05 vs. Group 2 or 4) and 14.6±3.0 ng/mL, and AUC values were 101±90 (p<0.01 vs. Group 3a or 4), 319&±155, 808±200, and 531±113 ng.h/mL, respectively. Both trough levels and AUC values were lowest in Group 1a and highest in Group 3a. Between Groups 1b and 3b, there was no significant difference in the blood levels of intravenous FK506. The shorter the functioning residual small intestine was, the higher the trough level of oral FK506 was, while the presence or absence of small intestine did not affect blood levels of intravenous FK506. These results suggest that oral FK506 is metabolized in the functioning small intestine during its absorption. Therefore, events which cause intestinal malfunction, such as graft rejection in SBTx, inflammation and loss of small intestine, may adversely raise the trough level of oral FK506.

The functional roles of porcine CD80 molecule and its ability to stimulate and regulate human anti-pig cellular response.

Background. The pig is currently considered to be the most likely candidate for a xenogenic-organ source. Anti-pig human T-cell response via co-stimulatory molecules has been studied with great interest. The soluble form of porcine CD80 has recently been cloned and characterized, but the sequence of the transmembrane form has not been determined. The purpose of this study was to investigate the functional interaction between porcine CD80 and human T cells using the full-length clone of porcine CD80. Materials and Methods. Specific complementary DNA (cDNA) clones encoding porcine CD80 were isolated and sequenced using rapid amplification of cDNA ends-polymerase chain reaction. Polymerase chain reaction-amplified cDNA coding for the open reading frame of the porcine CD80 transmembrane form was subcloned into an expression vector and then transfected into Chinese hamster ovary (CHO) cells. CHO cells transfected with porcine CD80 (CHO-pCD80) were co-cultured with human CD4+ T cells and then interleukin-2 secretion was measured and transferred pCD80 expression in these human T cells was detected by flow cytometry. Results. We cloned and determined the complete nucleotide sequence for the transmembrane form of porcine CD80. Results from our T-cell co-stimulatory assay showed significant interleukin-2 production when co-stimulated with CHO-pCD80. Human naïve CD4+ T cells acquired xenogenic pCD80 molecules in the process of T-cell activation. Conclusions. Findings from this study seem to suggest that pCD80 has the functional ability to regulate human anti-pig cellular response. In addition, genetic manipulation of porcine co-stimulatory molecules offers a potentially new therapeutic strategy to prevent xenogeneic rejection across species.

A National Survey of Patients With Intestinal Motility Disorders Who Are Potential Candidates for Intestinal Transplantation in Japan

Intestinal motility disorders are a major cause of intestinal failure. Severe cases such as idiopathic pseudo-obstruction represent life-threatening illnessed. Intestinal transplantation is a treatment for severe motility disorders with irreversible intestinal failure. However, the prevalence of severe motility disorders is unknown. We performed a national survey to identify patients with intestinal motility disorders who require an intestinal transplant. The national survey of 302 institutions treating intestinal motility disorders identified 147 patients treated from 2006 to 2011 at 46 institutions. The mean patient age was 12.1 years (range, 0.3-77.5). The mean age of onset was 3.0 years (range, 0.0-68.8). Diagnoses included chronic idiopathic intestinal pseudo-obstruction (n = 96), Hirschsprung disease (n = 29), megacystis microcolon intestinal hypoperistalsis syndrome (n = 18), and other (n = 6). There were 126 survivors and 21 patients who died during the last 5 years. The mortality rate was 14.3%. Eighty-five percent of patients required parenteral nutrition for more than 6 months, which was defined as irreversible intestinal failure. Among surviving patients with irreversible intestinal failure, 8 (9.4 %) developed hepatic failure with jaundice and 27 (31.8%) 2 or more central vein thromboses. In all, at least 35 patients (41%) with irreversible failure due to intestinal motility disorders may be candidates for transplantation. The prevalence of severe intestinal motility disorders was elucidated in Japan. Severe cases should be referred to transplant centers.

Current status of intestinal transplantation in Japan.

The development of total parenteral nutrition (TPN) has dramatically improved the prognosis of patients afflicted with intestinal failure. However, TPN-related complications, which remain a problem for patients with intestinal failure can be addressed by intestinal transplantation, which can significantly improve their prognosis and quality of life. The first intestinal transplantation in Japan occurred in 1996. Of the 17 intestinal transplantations performed to date, six were obtained from deceased donors and 11 from living donors. The primary indications were: short gut syndrome (n = 8), intestinal function disorder (n = 7), and retransplantation (n = 2). In our experience, the 1-year and 5-year patient survival rates are 87% and 69%. All nine patients receiving transplants in the last 7 years have survived, which seem to be acceptable results for the treatment of intestinal failure. Relatively few intestinal transplantations have been performed to date, mainly due to the lack of national health insurance coverage for the procedure and the ban of the use of donors below 15 years of age. Liver failure patients are also ineligible because liver-intestine or multiorgan transplants are not allowed by current guidelines. Case numbers may increase in the future as the result of allowing for pediatric donors in the new Act on Organ Transplantation, which went into effect in July 2010. We continue to work on reforming national insurance coverage to cover multiorgan transplantations.