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ABSTRACT: Inappropriate host immunological reactions against unknown ligands via the Toll-like receptor (TLR) cascades may trigger progressive inflammatory biliary destruction that manifests as biliary atresia (BA) in newborns or infants. The aim of the study was to clarify the role of the innate immune system in the development of BA.
Liver tissue was obtained from 49 patients with pediatric hepatobiliary diseases: 19 with BA, 21 with choledochal cysts, and 9 with other hepatobiliary diseases. BA samples obtained during the initial portoenterostomy and reoperation or liver transplantation (LT) were classified as early and late BA groups, respectively. Of the early BA group, those requiring LT were designated as the LT group, and the others were designated as the non-LT group. The mRNA expression levels of TLRs 2, 3, 4, 7, and 8 were determined by real-time quantitative reverse transcription-polymerase chain reaction and were compared between groups. The correlation between TLR mRNA expression level and age at sampling was examined for each TLR in the patients with BA.
TLR8 mRNA, encoding the receptor for single-stranded RNA, was significantly higher in the early BA group, compared with non-BA groups (P = 0.008). Within the BA group, mRNA levels of TLRs 2 and 8 were significantly higher in the early group than in the late group (P = 0.02 and 0.006, respectively), despite there being no significant correlation between TLR mRNA expression and age at sampling, except for TLR7 (r = 0.77, P = 0.001). Compared with the non-LT group, the LT group demonstrated significantly higher mRNA expression of TLRs 3 and 7 (P = 0.02 and 0.01, respectively).
Innate immune responses may contribute to the initiation and progression of BA. Severe inflammation characteristic of BA around the time of the first operation may abate postoperatively, but determination of selected TLR mRNA expression levels in the liver at the time of Kasai portoenterostomy may assist in predicting the prognosis of patients with BA.
Journal of pediatric gastroenterology and nutrition 08/2011; 53(6):620-6. · 2.18 Impact Factor
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ABSTRACT: Biliary atresia (BA) is an idiopathic inflammatory obliterative cholangiopathy of neonates, leading to progressive biliary cirrhosis. Hepatoportoenterostomy (Kasai procedure) can cure jaundice in 30% to 80% of patients. Postoperative clearance of jaundice is one of the most important factors influencing long-term outcomes of BA patients. Multidrug resistance protein 2 (MRP2) is one of the canalicular export pumps located in hepatocytes; it exports organic anions and their conjugates (e.g., bilirubin) into bile canaliculus. Although MRP2 is an essential transporter for the excretion of bilirubin, its role in the clinical course of BA patients is unclear. The present study investigated the relationship between hepatic MRP2 expression and clinical course in BA patients, with particular emphasis in curing jaundice after hepatoportoenterostomy.
No significant differences in hepatic MRP2 expression level were observed between BA and controls groups. There was no correlation between MRP2 expression and age at time of surgery in BA and control groups. In BA patients, MRP2 expression level in the jaundice and jaundice-free group did not differ significantly (2.0 × 10-4 vs 3.1 × 10-4, p = 0.094). Although the serum level of total bilirubin just before surgery did not correlate with MRP2 expression level (rs = 0.031, p = 0.914), the serum level of total bilirubin measured at 2 weeks (rs = -0.569, p = 0.034) and 4 weeks after surgery (rs = -0.620, p = 0.018) were significantly correlated with MRP2 expression level. Furthermore, MRP2 expression level was inversely correlated with ratio of change in serum total bilirubin level over 4 weeks (rs = -0.676, p = 0.008), which represents the serum bilirubin level measured at 4 weeks after surgery divided by value just before surgery. There was no correlation between expression level of MRP2 and nuclear receptors, such as retinoid × receptor α, farnesoid × receptor, pregnane × receptor, or constitutive androstane receptor.
Hepatic MRP2 expression level was associated with postoperative clearance of jaundice in BA patients, at least within 1 month after hepatoportoenterostomy. This finding suggests that not only morphological appearance of the liver tissue but also the biological status of hepatocytes is important for BA pathophysiology.
Comparative Hepatology 08/2011; 10:6. · 1.88 Impact Factor
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Takeshi Saito,
Tomoro Hishiki,
Keita Terui,
Yoshiharu Sato, Tetsuya Mitsunaga,
Elena Terui,
Mitsuyuki Nakata,
Ayako Takenouchi,
Gen Matsuura,
Eriko Yahata,
Sachie Ohno,
Hirotaka Sato,
Noriyuki Yanagawa,
Yoshitada Masuda,
Hideo Yoshida
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ABSTRACT: Standard choledochal cyst (CC) operations involve dilated extrahepatic bile duct excision followed by biloenterostomy. However, biliary variants and associated intrahepatic bile duct (IHBD) stenoses or dilatations triggering postoperative sequelae require additional procedures. The usefulness of preoperative 3-dimensional magnetic resonance cholangiopancreatography (3D MRCP) and virtual cholangioscopy (VES) for observing biliary morphology and pancreaticobiliary maljunction (PBM) was evaluated.
In 16 pediatric CC patients (age range, 4 months to 9 years; median, 3 years), visualization of PBM and aberrant bile duct anatomy and IHBD morphology at the hepatic hilum (HH), umbilical portion (UP), and posterior branch (POST) were compared between 3D-MRCP and intraoperative cholangiography (IOC). VES and intraoperative cholangioscopy (IOS) findings were compared.
HH, UP, and POST visualization rates were 100%, 94%, and 94%, respectively, by 3D-MRCP, and 100%, 69%, and 69%, respectively, by IOC. IHBD stenosis detection rates at each region were 38%, 13%, and 13%, respectively, by 3D-MRCP, and 25%, 0%, and 9%, respectively, by IOC. IHBD dilatation detection rates at each part were 75%, 47%, and 60%, respectively, by 3D-MRCP, and 88%, 82%, and 91%, respectively, by IOC. PBM was confirmed in 56% and 93% of cases on 3D-MRCP and IOC, respectively. Both 3D-MRCP and IOC showed biliary variants in 5 cases (31%). VES showed membranous strictures at HH, UP, and POST in 6, 2, and 2 cases, respectively, whereas IOS did so at HH in 4 cases and POST in 2.
Preoperative 3D-MRCP and VES accurately depict biliary morphology, allowing concrete operative planning in pediatric CC patients, complementing IOC and IOS.
Surgery 01/2011; 149(4):569-75. · 3.10 Impact Factor
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ABSTRACT: Fetal stabilization (FS) is a way to decrease stresses to the fetus during the perinatal period to control persistent pulmonary hypertension in neonates (PPHN). Although FS in congenital diaphragmatic hernia (CDH) patients has been reported, the effect of FS has not been evaluated sufficiently. The present study retrospectively evaluated influences of FS on the postnatal status of CDH patients.
Twenty-three cases of prenatally diagnosed CDH which were treated after birth in our institution from April 1998 to March 2010 were reviewed. From April 1998 to May 2007, FS was performed by administration of fentanyl and midazolam to the mother before subsequent cesarean section (FS group, n = 10). Beginning from June 2007, FS was discontinued (non-FS, n = 13).
At the first postnatal estimation, flow pattern of the ductus arteriosus had no difference between two groups. The oxygenation index of the FS group was significantly higher than that in the non-FS group (p = 0.045). Only the non-FS group had correlations between estimated standardized lung volume (% lung volume) and alveolar-arterial oxygen tension difference (p = 0.022), and between % lung volume and the oxygenation index (p = 0.0037).
During the period immediately after birth, FS had no obvious therapeutic effect on PPHN, and had a negative impact on respiratory status.
Pediatric Surgery International 01/2011; 27(1):29-33. · 1.25 Impact Factor
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Tomoro Hishiki,
Takeshi Saito,
Yoshiharu Sato, Tetsuya Mitsunaga,
Elena Terui,
Gen Matsuura,
Eriko Saito,
Ryohei Shibata,
Naoko Mise,
Yukiko Yokoyama,
Hideo Yoshida
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ABSTRACT: Neuroblastoma (NB) is one of the most common extracranial solid tumors in children and is known for its clinical and biological heterogeneity. The aim of this study is to reveal the functional role of src family kinases in the biological behavior of NB by inhibiting their kinase activities with a specific inhibitor, PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine).
NB cell lines (SH-SY5Y, IMR32, RT-BM-1, CHP134, NLF, and LA-N-5) were treated with 0.1-10 µM of PP2. Morphological changes, cell growth, and cell death were assessed, as well as all-trans retinoic acid (ATRA)-induced neuronal differentiation and epidermal growth factor (EGF)-induced proliferation.
At 24 h after PP2 treatment, NB cell lines showed drastic cell aggregation. PP2 also inhibited cell growth of NB in a dose-dependent manner. Apoptosis was detected in these cells. ATRA-induced neuronal differentiation of RT-BM-1 was not affected by PP2. PP2 reduced the proliferative effect of EGF. EGF-induced rapid activation of Akt, which was not blocked by PP2 treatment, suggesting that the cellular events triggered by PP2 were independent to PI3 kinase/Akt signaling pathway.
Our data suggests that src family kinases promote cell survival/proliferation and reduces cell aggregation of NBs. Src family kinase inhibitors may be good candidates for a novel molecular target therapy.
Pediatric Surgery International 11/2010; 27(2):225-30. · 1.25 Impact Factor
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Takeshi Saito,
Tomoro Hishiki,
Keita Terui,
Yoshiharu Sato, Tetsuya Mitsunaga,
Elena Terui,
Mitsuyuki Nakata,
Ayako Takenouchi,
Gen Matsuura,
Shugo Komatsu,
Eriko Yahata,
Sachie Ono,
Hirotaka Sato,
Noriyuki Yanagawa,
Hideo Yoshida
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ABSTRACT: To evaluate the usefulness of multi-detector row computed tomography (MDCT) in the postoperative long-term follow-up of biliary atresia (BA) patients for detection of esophagogastric varices due to portal hypertension and intrahepatic bile duct (IHBD) dilatations. Well-developed esophagogastric varices can cause unexpected life-threatening rupture and contribute to the progression of hepatopulmonary vascular diseases. Dilated IHBDs can trigger cholangitis.
After corrective surgery, 29 BA patients (median age 14 years, range 6 months to 27 years) with suspected long-term sequelae underwent 16-slice MDCT. Esophagogastric varices and IHBD dilatations were evaluated using reconstructed images. Detection rates for esophagogastric varices were compared between MDCT and endoscopic findings. Differences in detection rates for IHBD dilatations between MDCT and ultrasonography (US) were also investigated.
Detection rates for esophageal varices did not differ significantly between MDCT and endoscopy, while three cases positive only on MDCT, including one with hepatopulmonary syndrome, showed conspicuous peri-esophageal varices deep in the esophageal wall. MDCT showed a significantly higher detection rate than endoscopy (p = 0.03) for gastric fundal varices. MDCT with the maximum intensity projection disclosed IHBD dilatations in 17 postoperative BA cases, 15 out of which had past history of cholangitis, while US detected them in 6 cases (p = 0.003). In addition, MDCT was more advantageous for detecting IHBD dilatations, particularly those located in the posterior lobe.
Among postoperative BA patients, compared to endoscopy, MDCT had comparable and superior detection rates for esophageal and gastric fundal varices, respectively. MDCT also precisely demonstrated the location and extent of IHBD dilatations. In long-term follow-up of BA patients, MDCT can help determine follow-up strategies.
Pediatric Surgery International 10/2010; 27(3):309-14. · 1.25 Impact Factor
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ABSTRACT: A boy with a history of esophageal atresia repair received an esophagoesophagostomy at 14 months for a severe refractory anastomotic stricture, which had already required repeated balloon dilation with intralesional dexamethasone injection. Anastomotic leakage and stricture was again evident after the second surgery, and the patient underwent five procedures of balloon dilations with intralesional dexamethasone injection. Dysphagia was persistent and the patient required dilation every 2-3 weeks. After the sixth dilation, the patient was given 1 mg/kg per day of dexamethasone i.v. for 3 days. Dexamethasone i.v. was tapered during the following 3 days and finished at day 6. A week later, endoscopic findings showed an apparent improvement in the stricture. Another dilation was followed by 1 mg/kg per day dexamethasone i.v. for 7 days, and 0.75 kg/mg per day oral dexamethasone for another 7 days. The stricture improved completely and the anastomosis was patent after the second dilation. The patient is doing well without dysphagia and has not required additional dilation for over 18 months after the last dilation. Balloon dilation in combination with systemic dexamethasone administration may be an effective treatment that could substitute invasive techniques including surgical manipulation for severe refractory strictures.
Pediatric Surgery International 06/2009; 25(6):531-3. · 1.25 Impact Factor
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ABSTRACT: We report herein a case of prenatally detected neonatal adrenocortical tumor (ACT). The patient was an otherwise healthy newborn girl. No signs of Beckwith-Wiedemann syndrome were identified, and her family medical history did not suggest predisposition to cancer. Computed tomography and ultrasonography after birth revealed a round solid tumor 40 mm in diameter in the right suprarenal area. The precise diagnosis of ACT was unexpectedly obtained based on results from the Japanese neonatal mass screening program. Blood 17-hydroxyprogesterone is routinely measured as a part of this program for early detection of congenital adrenal hyperplasia in Japan. Abnormally elevated level of 17-hydroxyprogesterone was reported in the patient and, thus, led to the diagnosis of ACT. Surgical resection was safely performed with perioperative steroid replacement. Adrenocortical tumors are extremely rare in childhood, particularly in the neonatal period. Some of these tumors secrete abnormally high levels of cortisol, suppressing function of the contralateral adrenal gland and, thus, leading to life-threatening postoperative adrenal insufficiency. Scheduled steroid replacement enables safe perioperative management in such cases. Adrenocortical tumor should always be considered among the differential diagnoses for neonatal suprarenal mass because precise diagnosis will enable the physician to develop appropriate treatment strategies.
Journal of Pediatric Surgery 11/2008; 43(10):e19-22. · 1.45 Impact Factor
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ABSTRACT: A rare case of gastric duplication of childhood is reported. A 1-month-old boy underwent pyloromyotomy for infantile hypertrophic pyloric stenosis. At laparotomy, a protruding lesion was identified in the anterior wall of the pylorus. The pylorus was hypertrophic as indicated preoperatively, and a normal pyloromyotomy was performed. Wedge biopsy of the protruding lesion revealed an intestinal structure, and gastric duplication was diagnosed. The child remained asymptomatic thereafter, but considering the risk of the duplication becoming symptomatic, a second laparotomy was performed at 1 year of age. The duplication cyst shared part of the wall with the pylorus, and the cyst was removed by cystectomy, leaving the pyloric muscle intact. The cyst was found to be communicating with the pancreatic duct. The child is doing well without any symptoms as of 18 months after second laparotomy. To the best of our knowledge, this is the youngest case of gastroduodenal duplication with pancreatic duct communication yet reported.
Journal of Pediatric Surgery 10/2008; 43(9):e1-3. · 1.45 Impact Factor
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ABSTRACT: Pancreatitis associated with pancreaticobiliary maljunction (PBM) is commonly treated nonoperatively before surgery. It is, however, sometimes uncontrollable, and little has been reported about the management.
Focusing on the preoperative management, we reviewed clinical courses of 4 PBM cases (ages 1 to 7 years old). Each had pancreatitis that was totally resistant to medical treatment and was applied endoscopic sphincterotomy (ES).
The first case underwent percutaneous transhepatic catheter drainage (PTCD) primarily. In spite of daily lavage using the drainage tube for a week, plugs located in the common channel were not removed, and clinical findings were not improved. Therefore, ES followed by removal of protein plugs was performed to improve pancreatitis dramatically. Through this experience, 3 subsequent cases with refractory pancreatitis all underwent successful ES primarily soon after the medical treatments turned out to be ineffective. In all 4 cases, protein plugs were impacted in common channels, and ES could successfully remove the plugs that were impossible to remove by using PTCD. Improved preoperative pancreaticobiliary decompression by ES shortens the duration of recalcitrant acute pancreatitis associated with PBM allowing for a subsequent safe operation.
Endoscopic sphincterotomy is one of the useful preoperative managements for refractory pancreatitis associated with PBM.
Journal of Pediatric Surgery 04/2008; 43(3):495-9. · 1.45 Impact Factor
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Tetsuya Mitsunaga,
Hideo Yoshida,
Katsunori Kouchi,
Tomoro Hishiki,
Takeshi Saito,
Shin-ichi Yamada,
Yoshiharu Sato,
Keita Terui,
Mitsuyuki Nakata,
Ayako Takenouchi,
Naomi Ohnuma
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ABSTRACT: There are various treatment strategies for gastroesophageal varices in children. We studied the therapeutic value of endoscopic variceal clipping (EVC) and ligation (EVL).
Four hundred ninety-nine endoscopic examinations performed between 1991 and 2005 were retrospectively analyzed. F2 and F3 varices with red color signs on follow-up endoscopy were treated with prophylactic EVC. In variceal rupture cases, EVC and EVL were used in combination.
Eighty-two prophylactic EVCs were done, and variceal progression was prevented in 89.9%. However, some patients had persistent red color signs and required frequent EVC. Ten emergent procedures were done for variceal rupture, and, in 4 cases, EVL was used to arrest massive variceal bleeding. Five patients developed bleeding during follow-up cause by rupture of gastric fundal varices, which probably had been aggravated by prior treatment for esophageal varices.
The control of gastroesophageal varices by routine EVC was satisfactory. However, ruptures during follow-up suggested the importance of controlling gastric fundal varices. Endoscopic variceal ligation is a simple, effective, and safe treatment tool, particularly for ruptured varices. However, it is difficult to treat gastric fundal varices with EVL; this disadvantage of EVL can be overcome by the concomitant use of EVC.
Journal of Pediatric Surgery 01/2007; 41(12):1980-3. · 1.45 Impact Factor
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ABSTRACT: Toxoplasma gondii-derived heat shock protein 70 (T.g.HSP70) induced maturation of bone marrow-derived dendritic cells (DCs) of wild-type (WT) C57BL/6 mice as evidenced by an increase in surface expression of MHC class I and II molecules and costimulatory molecules such as CD40, CD80, and CD86. Functionally, decreased phagocytic ability and increased alloreactive T cell stimulatory ability were observed in T.g.HSP70-stimulated DCs. These phenotypic and functional changes of T.g.HSP70-stimulated DCs were demonstrated in Toll-like receptor (TLR) 2- and myeloid differentiation factor 88 (MyD88)-deficient but not TLR4-deficient C57BL/6 mice. DCs from WT and TLR2-deficient but not TLR4-deficient mice produced IL-12 after T.g.HSP70 stimulation. T.g.HSP70-stimulated DCs from WT, TLR2-deficient, and MyD88-deficient, but not TLR4-deficient mice expressed IFN-beta mRNA. Thus, T.g.HSP70 stimulates murine DC maturation via TLR4 through the MyD88-independent signal transduction cascade.
Cell Stress and Chaperones 02/2006; 11(1):13-22. · 3.01 Impact Factor
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Katsunori Kouchi,
Hideo Yoshida,
Tadashi Matsunaga,
Yasuhiro Ohtsuka,
Erena Nagatake,
Yoshiharu Satoh,
Keita Terui, Tetsuya Mitsunaga,
Takenori Ochiai,
Miwako Arima,
Naomi Ohnuma
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ABSTRACT: The authors report the successful use of endoscopic ultrasonography (EUS) for finding the etiology and subsequent treatment strategy for esophageal stenosis in 2 children. In case 1, EUS showed anterior wall thickening and multiple low echoic regions in the mp layer. These regions were believed to be cartilage. Esophageal resection therefore was performed. In case 2, EUS showed disruption of the sm and mp layers at the stenosis, leading us to speculate that the stenosis was caused by gastroesophageal reflux. After balloon dilatation, he underwent antireflux surgery of Nissen's fundoplication. EUS was useful for determining the etiology of esophageal stenosis and, thus, the appropriate treatment strategy.
Journal of Pediatric Surgery 07/2002; 37(6):934-6. · 1.45 Impact Factor
