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ObjectiveStenting is an established endoscopic therapy for malignant gastric outlet obstruction (mGOO). The choice of stent (covered vs uncovered) has been examined in prior randomised studies without clear results.DesignIn a multicentre randomised prospective study, we compared covered (CSEMS) with uncovered self-expandable metal stents (UCSEMS) in patients with mGOO; main outcomes were stent dysfunction and patient survival, with subgroup analyses of patients with extrinsic and intrinsic tumours.ResultsOverall survival was poor with no difference between groups (probability at 3 months 49.7% for covered vs 48.4% for uncovered stents; log-rank for overall survival p=0.26). Within that setting of short survival, the proportion of stent dysfunction was significantly higher for uncovered stents (35.2% vs 23.4%, p=0.01) with significantly shorter time to stent dysfunction. This was mainly relevant for patients with extrinsic tumours (stent dysfunction rates for uncovered stents 35.6% vs 17.5%, pConclusionsDue to poor patient survival, minor differences between covered and uncovered stents may be less relevant even if statistically significant; however, subgroup analysis would suggest to use covered stents for intrinsic and uncovered stents for extrinsic malignancies.

INTRODUCTION Muscle cramps are common comorbidities in chronic liver disease (CLD). Although the prevalence of these has been reported in patients with liver cirrhosis (LC), that of CLD is unknown. In this study, we aimed to clarify the prevalence and characteristics of muscle cramps in individual CLD. PATIENTS AND METHODS A total of 432 patients with CLD who visited our hospital were enrolled. The existence of muscle cramps, frequency, time zone, duration, and the degree of pain were investigated using a medical interview questionnaire. RESULTS The median age of the patients was 65 years and 48.6% of the patients were women. The prevalence of muscle cramps was 25.9%. Age, female sex, lower BMI, existence of comorbid diseases, and liver fibrosis were associated significantly with muscle cramps. In LC, muscle cramps were significantly frequent, and the severity and duration of these were significantly stronger and longer compared with chronic hepatitis. Female sex [odds ratio (OR): 2.26; P=0.014], diabetes (OR: 29.4; P

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging but essential for improving its poor prognosis. We established a multicenter study to clarify the clinicopathological features, and to propose new algorithm for early diagnosis of PDAC. Ninety-six patients with stage 0 and IA PDAC were enrolled from 13 high-volume centers. Overall, 70% of the patients were asymptomatic. The serum pancreatic enzyme levels were abnormal in half of the patients. The sensitivity of endoscopic ultrasonography (EUS) for detecting small PDAC was superior to computed tomography and magnetic resonance imaging (MRI) (82%, 58%, and 38%, respectively). Indirect imaging findings were useful to detect early-stage PDAC, especially, main pancreatic duct stenosis on MRI had the highest positive rate of 86% in stage 0 patients. For preoperative pathological diagnosis, the sensitivity of endoscopic retrograde cholangiopancreatography (ERCP)-associated pancreatic juice cytology was 84%. Among the stage IA patients, EUS-guided fine-needle aspiration revealed adenocarcinoma in 93% patients. For early diagnosis of PDAC, it is essential to identify asymptomatic patients and ensure close examinations of indirect imaging findings and standardization of preoperative pathological diagnosis. Therefore, a new diagnostic algorithm based on tumor size and imaging findings should be developed.

Steroids are the first-line drugs for induction of remission in patients with type 1 autoimmune pancreatitis (AIP), and the usefulness of steroid maintenance therapy to prevent relapse has recently been reported. However, even during steroid therapy, a relatively large percentage of patients relapse and the predictive factors for relapse have not yet been elucidated. The aim of this study was to clarify the predictive factors for relapse of AIP patients during steroid therapy.The medical records of 76 patients with type 1 AIP with continued steroid therapy after induction of remission were analyzed retrospectively. The relapse rate during steroid therapy was evaluated, and the risk factors for relapse were investigated by univariate and multivariate analysis of clinical factors.Relapse occurred in 28.9% (22/76) of the patients. The cumulative relapse rates were 10.5% at 1 year, 25.0% at 3 years, 34.9% at 5 years, and 43.0% at 10 years. In multivariate analysis, presence of sclerosing dacryoadenitis/sialadenitis at the time of initial diagnosis of AIP was an independent risk factor for relapse (HR 3.475, p = .009). The cumulative relapse rates of patients with sclerosing dacryoadenitis/sialadenitis reached 21.4% at 1 year, 56.0% at 3 years, and 78.0% at 5 years.Sclerosing dacryoadenitis/sialadenitis was a predictive factor for relapse in type 1 AIP during steroid therapy; in such cases, strict follow-up is necessary with relapse in mind.

Background and Aim. Endoscopic nasobiliary drainage (NBD) effects according to diameter remain unclear. We aimed to assess the drainage effects of the 4-Fr and 6-Fr NBD catheters. Methods. This prospective, multicenter, randomized, controlled study was conducted at Hiroshima University Hospital and related facilities within Hiroshima Prefecture. Endoscopic retrograde cholangiopancreatography (ERCP) in 246 patients revealed acute cholangitis, obstructive jaundice, and/or extrahepatic cholestasis; 4-Fr or 6-Fr NBD catheters were randomly allocated and placed in these patients. The primary endpoint was the efficacy of NBD based on the technical success rate and clinical success (rates of change in blood test and amount of bile output). Secondary endpoints included the spontaneous catheter displacement rate and nasal discomfort. Results. The technical success rate and clinical success did not differ significantly between groups. No spontaneous catheter displacement was noted in either group. Nasal discomfort due to catheter placement was significantly lower in the 4-Fr group versus the 6-Fr group (24 h after ERCP: 2.4 versus 3.5 cm, P=0.005; 48 h after ERCP: 2.2 versus 3.1 cm, P=0.01). Conclusion. The 4-Fr NBD catheter was not inferior to 6-Fr NBD catheter in terms of clinical success; the 4-Fr NBD catheter was useful to reduce nasal discomfort.

Complementary DNA microarray analysis of human livers cannot exclude the influence of the immunological response. In this study, complementary DNA microarray analysis was performed under immunodeficient conditions with human hepatocyte chimeric mice, and gene expression profiles were analyzed by hepatitis B virus (HBV) infection and/or interferon treatment. The expression levels of 183 of 525 genes upregulated by interferon treatment were significantly suppressed in response to HBV infection. Suppressed genes were statistically significantly associated with the interferon signaling pathway and pattern recognition receptors in the bacteria/virus recognition pathway (P = 1.0 × 10(-8) and P = 1.2 × 10(-8), respectively). HBV infection attenuated virus recognition and interferon response in hepatocytes, which facilitated HBV escape from innate immunity.

We report preventive innominate artery division or ligation through a suprasternal approach for impending tracheo-innominate artery fistula (TIF) with recurrent airway oozing in patients with severe neuromuscular disease. Our approach is less invasive and a favorable procedure as preventive surgery for impending TIF.

Objective: Fontan completion in patients with atrial isomerism, in which the inferior vena cava (IVC) and the hepatic vein (HV) drain separately, is technicallychallenging.Herein,wereviewoursurgicalapproachto these patients.Methods:Themedical recordsof 50 consecutive patients with atrial isomerism who underwent Fontan completion between 1998 and 2008 were reviewed retrospectively. Results: Separate HV drainage was present in 17 patients. Patientswith interrupted IVC were excluded. Patient characteristics were as follows: median age, 26 months (range 15—149); median weight, 9.6 kg (range 8.1—47.2); right atrial isomerism, 16 patients; and left atrial isomerism, one. The IVC and the separate HVat the level of diaphragm were contralateral in 16 patients, and ipsilateral in one. The surgical procedures for directing blood flow from the IVC and the separate HV to the pulmonary arteries were as follows: en bloc resection of the IVC and the HVand anastomosing these veins to an extracardiac conduit in 10 patients; connecting the IVC to the HV in a side-to-side fashion before anastomosing them to an extracardiac conduit in one; and lateral tunnel in another. When the IVC and the HV were widely separated by the vertebrae, we chose an intra-extracardiac conduit (intra-atrial septation) in four patients and an extracardiac conduit for the IVC and the right HVand lateral tunnel for the separate left HV in one. There was no mortality. Five re-operations were performed (pacemaker in two patients; one each of fenestration, release of outflow obstruction and ligation of collateral arteries). Sixteen patients underwent follow-up catheterisation, which revealed central venous pressure of 12.0 2.0 mmHg and arterial oxygen saturation of 92% 6%. Conclusions: The mid-term results of the Fontan completion in patients with atrial isomerism and separate HV drainage were excellent. The distance between the IVC and the separate HVand the position of the vertebrae should be considered when choosing a surgical technique. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Background. The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like family of cytidine deaminases induce G-to-A hypermutation in hepatitis B virus (HBV) genomes and play a role in innate antiviral immunity. The clinical relevance of this protein family is unknown. Methods. We analyzed 33 instances in which 17 patients with chronic HBV infection experienced >2 increases of > 100 IU/L in alanine aminotransferase (ALT) level; we used a quantitative differential DNA denaturation polymerase chain reaction assay to quantify the hypermutated HBV genomes observed during 21 of these 33 increases in ALT level. Results. Of the 9 increases in ALT level that involved a > 5-fold increase (relative to basal levels) in the number of hypermutated genomes observed, 8 were associated with a >2-log reduction in plasma HBV DNA level. In contrast, a corresponding decrease in plasma HBV DNA level was observed for only 1 of the 12 increases in ALT level that did not involve an increase in the number of hypermutated genomes (P < .001). Hepatitis B e antigen clearance was often observed in patients who experienced an increase in the number of hypermutated genomes. Interferon treatment induced hypermutation in HBV genomes in an animal model. However, there was no apparent increase in the number of hypermutated genomes among the majority of patients who received interferon therapy, probably because the number of hypermutated genomes had already increased prior to the initiation of therapy. Conclusion. Our results suggest that a marked increase in the number of hypermutated genomes represents a strong immunological host response against the virus and is predictive of hepatitis B e antigen clearance and plasma HBV DNA level reduction.

Background & Aims This study aimed to identify host single nucleotide polymorphisms (SNPs) that are associated with the efficacy of interferon (IFN) therapy in patients with chronic hepatitis C. Methods We examined whether 116 tagging-SNPs from 13 genes that are involved in type I IFN signaling associate with the outcome of IFN therapy in Japanese case-control groups; the study included 468 sustained responders and 587 nonresponders. Results We identified 2 SNPs (rs3792323 [A/T] and rs616589 [G/A]), located in intron 2 of mitogen-activated protein kinase–activated protein kinase 3 (MAPKAPK3) that were associated with the outcome of IFN therapy in patients infected with hepatitis C virus (HCV) genotype 1b ( P = 4.6 × 10 −5 and 4.8 × 10 −5 , respectively). The 2 SNPs were in strong linkage disequilibrium and multivariate logistic regression analysis showed that rs3792323 is an independent factor associated with the IFN efficacy (genotype 1b; P = .0011). MAPKAPK3 is a kinase involved in the mitogen and stress responses, but the biological significance of MAPKAPK3 in IFN responses is poorly understood. By using an allele-specific transcript quantification assay in liver biopsy, we showed that allele-specific expression of MAPKAPK3 messenger RNA, corresponding to the risk allele for nonresponse, was significantly higher than that of the other allele. Luciferase reporter assay data indicated that overexpression of MAPKAPK3 inhibits IFN-alfa–induced gene transcription via IFN-stimulated response element and IFN-γ–activated site. Conclusions The SNP rs3792323 in MAPKAPK3 associates with the outcome of IFN therapy in patients with HCV genotype 1b. Our functional analyses indicate that MAPKAPK3 inhibits IFN-alfa–induced antiviral activity.

無脾症候群は多種多様な心奇形を合併し,重症度の高い疾患群である.今回,1987～2006年10月末の過去約20年間に当院で初回より手術介入を行った無脾症候群連続71例(1987～1996年:前期群34例,1997～2006年10月末:後期群37例)を検討した.前期群に有意に肺動脈弁狭窄(p=0.010)が多く,後期群で新生児(p=0.010),体重3kg未満例(p=0.037),肺動脈弁閉鎖(p=0.013)が多かった.全例Fontan手術対象で,二心室治療対象例はいなかった.前期群の累積生存率は1年52.9%,5年32.4%と不良であり,原因として,1)右心バイパス到達までの期間が長く,房室弁逆流や長期のチアノーゼによる側副血行路増生などの問題も絡んで,容量負荷による心機能低下を起こしたこと,また,2)肺動脈縮窄を中心とする肺動脈系の問題,総肺静脈還流異常症(TAPVC)を中心とする肺静脈系の問題が絡み合って十分な肺区域の確保が困難であったことが考えられた.そこで後期群で手術方針を変更し,容量負荷を回避して心機能を保護するため,1)早期の右心バイパス手術到達,2)積極的な房室弁形成を行い,また,有効肺区域を可能なかぎり確保するため,3)中心肺動脈領域での肺動脈形成を伴う肺血流路確保(central pulmonary artery strategy),4)TAPVC修復時の吻合手技の改良を行った.また,それらにもかかわらず肺血流が左右不均衡でFontan手術到達困難とされた症例には,5)新しい中間手術:intrapulmonary-artery septationを導入した.結果としては,後期群の累積生存率は1年66.8%,5年53.1%と,前期群に比して改善傾向を認めた(p=0.102).生存における術前りスク因子の検討で,単変量解析で有意であったのは,前期群では,新生児(p=0.036),心外型TAPVC(p=0.049),術前肺静脈狭窄(PVO)(p=0.001),後期群ではTAPVC IV型(p=0.001)であり,多変量解析で有意であったのは,前期群では術前PVO(p=0.038),後期群ではTAPVC IV型(p=0.007)であった.上記の心機能保護と有効肺区域の確保を重要視した治療方針の変更により,より重症度の高い後期群においても成績が改善し,新生児や心外型TAPVC,術前PVOが有意リスクから外れ,TAPVC IV型は今後の課題となった.

We present the first reported case of truncus arteriosus, interrupted aortic arch with hypoplastic tricuspid valve and right ventricle and anomalous left coronary artery orifice in a neonate in whom successful palliation was performed using two-staged procedure. The first-stage palliation was the bilateral pulmonary artery band at age 2 days. The second-stage palliation was a Norwood procedure concomitant with ASD creation and patch augmentation of the pulmonary artery confluence at 22 days. The patient is doing well, with unobstructed aortic arch and mild truncal valve regurgitation.

It is difficult to manage patients with single ventricular physiology and unbalanced pulmonary arteries. Since 1998, we started a novel approach [Intrapulmonary-artery Septation (IPAS)] to improve the result for those with severe unbalanced pulmonary arteries consisting of a well-grown pulmonary artery and an inadequately-grown pulmonary artery. The inadequately-grown pulmonary artery includes severe pulmonary arterial hypoplasia and pulmonary venous obstruction. This approach is based on the following concepts: (1) A reliable blood source should be secured to recover the inadequately-grown pulmonary artery; (2) Wasteful volume-load should be prevented for the heart; (3) Long stenosis or non-confluence of pulmonary artery should be avoided. IPAS primarily consists of (A) a Glenn shunt; (B) a systemic-pulmonary artery shunt; and (C) a septation-patch. Both (A) and (B) are adjoined on a well-grown pulmonary artery, and (C) is placed between (A) and (B). PAS brings two separate blood flows of a Glenn shunt to the well-grown side and SPS on the inadequately-grown side. IPAS was performed in 20 patients. Seventeen reached the Fontan operation. Eleven underwent postoperative catheterization and seven had acceptable-balanced pulmonary blood flow distribution. IPAS can pilot more complicated cases having severe unbalanced pulmonary arteries to the Fontan circulation.

Lamivudine is a major drug approved for treatment of chronic hepatitis B virus (HBV) infection. Emergence of drug-resistant mutants with amino acid substitutions in the YMDD motif is a well-documented problem during long-term lamivudine therapy. Here we report a novel lamivudine-resistant strain of HBV with an intact YMDD motif, which included an amino acid substitution, rtA181T, in the reverse transcriptase (RT) domain of HBV polymerase. The substitution also induced a unique amino acid substitution (W172L) in the overlapping hepatitis B surface (HBs) protein. The YMDD mutant strains were not detected even by using the sensitive peptide nucleic acid-mediated PCR clamping method. The detected nucleotide substitution was accompanied by the emergence of an additional nucleotide substitution that induced amino acid change (S331C) in the spacer domain. The rtA181T mutant strain displayed a threefold decrease in susceptibility to lamivudine in in vitro experiments in comparison with the wild type. In vivo analysis using human hepatocyte-chimeric mice confirmed the resistance of this mutant strain to lamivudine. We developed a method to detect this novel rtA181T mutation and a previously reported rtA181T mutation with the HBs stop codon using restriction fragment length polymorphism PCR and identified one patient with the latter pattern among 40 patients with lamivudine resistance. In conclusion, although the incidence is not high, we have to be careful regarding the emergence of lamivudine-resistant mutant strains with intact YMDD motif.

The aim of this study was to examine and clarify the preoperative markers that are useful for differentiating between benign and malignant lesions of intraductal papillary-mucinous neoplasms (IPMN) of the pancreas, grouped according to morphologic classification.There are various stages of pathology in IPMN, ranging from benign to malignant lesions. Although the determination of appropriate treatment guidelines to deal with IPMN is a critical issue, no such guidelines have been established.One hundred twenty cases of IPMN were classified morphologically into either main or branch duct types. We compared the morphologic classification with histopathologic diagnosis using indicators of malignancy detected by imaging such as main duct diameter, the number and diameter of cysts, and the presence or absence of mural nodules. We also examined the usefulness of pancreatic juice cytology and measurement of telomerase activity as indicators of malignancy. Finally, we performed a survival analysis on the basis of morphologic classification to determine prognosis of IPMN.Whereas a high incidence (64%) of malignant lesions was seen in main duct type IPMN, benign lesions were dominant (80.5%) in branch duct type IPMN. Survival analysis showed that the prognosis was significantly worse in main duct type than in branch duct type IPMN. The lesions were aggravated in all patients with main duct type who did not undergo resection, resulting in death due to progression of the pancreatic lesion. The incidence of mural nodules was a useful indicator in main duct type, whereas main duct diameter and incidence of mural nodules were useful indicators in branch duct type. Although pancreatic juice cytology showed a high accuracy rate with low sensitivity for determining malignancy, measurement of telomerase activity in this juice was very effective for differentiating between benign and malignant lesions.The incidence of malignant lesions was extremely high in main duct type IPMN, indicating that surgery is required in all these patients. However, to determine whether surgery is indicated in branch duct type IPMN it is necessary to obtain an appropriate image diagnosis focusing on main duct diameter and mural nodules and also to carry out cytology and measurement of telomerase activity in samples of pancreatic juice.

We report a case of a Senning operation for very low birth weight infant weighing 1,168 g with transposition of the great arteries. The patient underwent a Senning operation on 62 days, 1,700 g after the first palliation. In this case, the orifice of the left anterior descending artery was located in sinus 1 (left posterior facing sinus), but we could not find orifices of both right coronary artery and left circumflex artery before the Senning operation. The surgical procedure of the Senning operation is typical one, but we used flesh autopericardial patch to cover the roof of the new pulmonary vein chamber to get an enough size. The patient recovered with no cardiac events after the repair.

BACKGROUND It has been reported that, in patients with intraductal papillary-mucinous tumor (IPMT) of the pancreas, it is difficult to distinguish adenoma from carcinoma preoperatively. Recently, it has also been reported that telomerase activity was detected in many patients with carcinoma. In this report, the authors used the method of telomerase repeat amplification protocol (TRAP) assay on pancreatic juice retrieved by endoscopic retrograde pancreatic juice aspiration (ERP aspiration). METHODS Pancreatic juice was collected from 28 patients (13 with intraductal carcinoma and 15 with adenoma) using ERP aspiration at either Hiroshima University Hospital or its affiliated hospitals. Two samples of pancreatic juice were collected from each patient. Each sample was examined by cytology for Papanicolaou staining and TRAP assay. RESULTS Four of 13 IPMT patients (31%) with intraductal carcinoma were diagnosed accurately by cytology. Seven of nine patients who were classified with benign tumors by cytologic assessment had tumors that expressed telomerase activity. Overall, 11 of 13 IPMT patients (85%) with intraductal carcinoma were diagnosed correctly by cytology associated with telomerase activity. All of the IPMT patients with adenoma were classified with benign tumors by cytologic assessment, and telomerase activity was not expressed. CONCLUSIONS In this study, the authors found that telomerase activity was expressed with a comparatively high probability in intraductal carcinoma. These results suggest that telomerase activity in pancreatic juices may be used as an adjunct to cytologic diagnosis and may aid further in distinguishing between benign IPMT and malignant IPMT of the pancreas preoperatively. Cancer 2001;91:35–41. © 2001 American Cancer Society.

We describe the case of 6-day-old baby girl with congenitally corrected transposition of the great arteries, Ebstein anomaly with severe tricuspid valve regurgitation, aortic atresia, hypoplastic aortic arch, and patent ductus arteriosus. She underwent Starnes procedure combined with the Norwood procedure. Postoperative echocardiography demonstrated good left ventricular function, reduced size of the right ventricle, and an unobstructed aortic arch. She was discharged and is currently awaiting a bidirectional Glenn operation.

A 31-day-old girl with right atrial isomerism, a single atrium, a single right ventricle, pulmonary atresia, patent ductus arteriosus, coarctation of the pulmonary artery, infracardiac total anomalous pulmonary venous connection, and a large hiatal hernia was referred to our institution. We successfully performed a first-stage open palliation comprising the creation of a systemic-to-pulmonary arterial shunt, pulmonary artery angioplasty, and correction of the total anomalous pulmonary venous connection. During cardiopulmonary bypass, the hiatal hernia was also repaired through the median sternotomy itself without another laparotomy. The postoperative course was uneventful, and we avoided the potential complications of pulmonary venous obstruction and enteral feeding. She underwent a bidirectional Glenn operation and Fontan completion at 5 and 19 months of age, respectively.

Our aim of this study was to evaluate prospectively in patients with pancreatic cancer the effects of respiratory- gating during PET/CT acquisition on the determination of lesion volume and to measure tracer uptake. Our research included 36 patients diagnosed with pancreatic cancer. They underwent conventional whole-body PET/CT and subsequently respiratory-gated PET/CT of the upper abdomen. Based on list-mode PET acquisition data, respiratory-gated and non-gated images were created. Maximum standardized uptake values (SUVmax) and lesion volumes were compared between gated and non-gated images and also the rate of increase in SUVmax based on lesion size. Results showed that respiratory gating was successful in 34/36 patients. The median non-gated SUVmax was 6.2±2.1 and was 8.1±2.5 for respiratory- gated (P0.01). Lesion volumes could be calculated in 27/34 patients. The median non-gated lesion volume was 5.82±5.57cm(3) and 4.31±4.56cm(3) for respiratory-gated (P0.01). Furthermore, small lesions of ≤2cm had a significantly higher proportion of increased SUVmax compared to large lesions of2cm (P=0.016). In conclusion, respiratory-gated PET/CT for patients with pancreatic cancer reduced respiratory motion artifacts and allowed significantly higher SUVmax to be obtained. In addition, the rate of increase in SUVmax tended to be higher in patients with pancreatic cancers of less or equal to 2cm diameter.

Background Infants with a single ventricle who require a modified Blalock-Taussig shunt can have stenosis at the ductal insertion site on the pulmonary artery (PA). We hypothesized that primary PA plasty in the first palliation would limit PA stenosis and unbalanced pulmonary perfusion, and thereby facilitate safe accomplishment of the next operation. Methods From 1998 to 2012, functional single-ventricle patients with pulmonary atresia were managed as follows: initial operative strategy based on midline approach, using cardiopulmonary bypass, and central PA plasty (resection of all ductal tissue). All patients underwent catheter study and lung perfusion test before bidirectional cavopulmonary shunt (BCPS). Results Forty consecutive patients (heterotaxy, n = 27; others, n = 13) were enrolled in this study. Seven patients (17.5%) had repair of obstructed total anomalous pulmonary venous drainage, and 4 (10%) had repair of common atrioventricular valve at the first palliative operation. Fifteen patients (37.5%) underwent first palliation in the neonatal period. The mean PA index (mm 2 /m 2 ) before BCPS was 230.7 ± 101.7. No pulmonary stenosis was detected before BCPS. Pulmonary artery diameter ratio (nonshunt side/shunt side) was 0.93 ± 0.25; pulmonary lung perfusion ratio (nonshunt side/shunt side) was 0.9 ± 0.2. A multivariate analysis identified persistent total anomalous pulmonary venous drainage (extracardiac type; p = 0.002) as a factor associated with unbalanced branch pulmonary arteries at BCPS. Thirty-five patients underwent BCPS, and 31 underwent Fontan procedures. There were 4 early deaths and 4 late deaths. Conclusions The strategies we have employed facilitate safe accomplishment of the next-stage operation in diverse anatomic groups, with avoidance of unbalanced pulmonary vascular bed.

Although the Fontan procedure is now being performed in younger patients, the influence of the early timing of Fontan on midterm to long-term results remains unclear. We investigated whether the timing of Fontan completion affects subsequent hemodynamics in patients with functional single ventricle followed for more than 3 years.Between January 1997 and December 2008, 163 patients with functional single ventricle underwent extracardiac total cavopulmonary connection (TCPC) at a single institution. The survivors routinely underwent postoperative catheterization at 1 year and then every 5 years after TCPC and were divided into group A (weight10 kg; n = 65) and group B (weight10 kg; n = 97), and retrospectively reviewed.Mean follow-up was 6.6 ± 3.7 years. Mean weight and conduit size were 8.5 ± 0.8 kg and 17.1 ± 1.2 mm for group A versus 20.2 ± 13.1 kg and 18.8 ± 1.9 mm for group B, respectively (p0.001). There were 3 hospital deaths (group A, n = 1; group B, n = 2) and 5 late deaths (group A, n = 3; group B, n = 2). No TCPC was taken down. There were no thromboembolic events in either group. The end-diastolic volume of ventricle (eDV) (% of normal) was (232.7 ± 91.4 before TCPC versus 139.3 ± 57.2 5 years after TCPC; p0.001) in group A and (209.6 ± 77.7 before TCPC versus 136.7 ± 61.4 5 years after TCPC; p0.001) in group B. Ventricular ejection fraction and cardiac index at 5 years were similar in both groups. The end-diastolic pressure of ventricle (eDP) (mm Hg) at 1 year (p = 0.0037) and at 5 years (p = 0.047) was significantly lower in group A compared with group B.TCPC can be performed earlier with good intermediate results. Earlier unloading of a univentricular heart by means of TCPC might be advantageous for preservation of future ventricular function.

Asplenia syndrome (AS) is a complex disorder that includes a variety of cardiovascular and gastrointestinal malformations (GMs), and its prognosis remains poor. We treated 40 AS patients between 2000 and 2010, 10 of whom underwent surgery to correct GMs. These comprised 7 hiatus hernias (HH), 1 intestinal malrotation (IM), 1 stomach volvulus, and 1 ompalocele. In this review, we consider the optimal surgical timing and methods of management, especially for HH and IM. Surgery was performed in 6 of 7 HH patients. Four of those underwent laparotomy, 1 thoracotomy, and 1 laparoscopy. The Toupet method or fixation of the His angle or hiatus closure was selected in each case. Because the stomach intruding into the mediastinum may cause pulmonary venous obstruction and respiratory impairment, surgical repair is preferably performed prior to Glenn surgery. Among the 9 IMs, 8 were nonrotational and required no treatment, and only 1 required surgical treatment. GMs in AS are difficult to manage because of the unique anatomy, meaning there are no fixed surgical techniques. Each patient must be carefully examined preoperatively, and the optimum surgical method selected. Close collaboration with cardiovascular surgeons is vital when determining the timing and method of surgery.

Background Patients with right atrial isomerism (RAI) have several cardiac malformations historically resulting in significant morbidity and mortality. We sought to assess whether current surgical strategies have improved the outcomes of patients with RAI. Methods A retrospective review of our database from 1997 to 2010 identified 60 consecutive patients with RAI who underwent initial palliation at Mt. Fuji Shizuoka Children's Hospital. All of the patients had a functional single ventricle. Of the 60 patients, 33 patients (51.7%) had obstructed total anomalous pulmonary venous drainage (TAPVD), 23 patients (40.3%) had significant (more than moderate) atrioventricular valvular regurgitation (AVVR), 7 patients (12.3%) had hiatus hernia, and 4 patients (6.7%) had major aortopulmonary collateral arteries. Pulmonary outflow atresia was present in 39 of the patients (65%), and 46 patients had systemic-to-pulmonary artery shunts. Of the 33 patients with TAPVD, 18 underwent repair of the condition at initial palliation, 9 others at the time of a Glenn operation, 2 more through a Fontan operation, and 4 at the interstage between palliative surgeries. Eight of the 23 patients with significant AVVR underwent atrioventricular valve repair at initial palliation, 8 others at the time of Glenn operation, 4 others at the time of Fontan operation, and 3 during the interstage between operations. An initial neonatal surgical procedure was performed in 30 patients (50%). The mean follow-up period for patients in the study was 53.1 months. Results Operative mortality after initial palliation was 15.4% (4 of 26 patients) before 2003 and 17.6% (6 of 34 patients) after 2004 ( p = NS). Five-year survival was 53.8% before 2003 and 81.7% after 2004 ( p = 0.035, log-rank test). A multivariate analysis identified persistent AVVR of more than moderate degree ( p = 0.04) as a factor associated with late mortality. Conclusions The outcomes of surgery for RAI are improving. Neonatal palliative surgery for RAI carries a high operative risk of early mortality, and persistent significant AVVR remains a risk factor for late mortality.

ObjectivesHeterotaxy syndrome, which is often associated with atrioventricular valvar regurgitation, has been considered a risk factor for the surgical repair for Fontan candidates. The results of atrioventricular valve repair in this challenging patient population remain largely unknown.MethodsFrom July, 1994 to January, 2007, 25 patients with the heterotaxy syndrome consisting of 22 right isomerism and three left isomerism presented to the Shizuoka Children’s Hospital Japan with significant (3–4+) atrioventricular valvar regurgitation necessitating atrioventricular valve repair. The clinical and Doppler/echocardiographic data were retrospectively reviewed to determine the efficacy of the repair and patient outcome.ResultsPatients were divided into two groups on the basis of atrioventricular valvar regurgitation at the most recent follow-up: those with a successful late outcome, (0–2) and those with a poor outcome (3–4). There were 17 (67%) patients with a successful outcome and 8 (33%) with a poor outcome. The repair technique including leaflet apposition was predictive of a successful outcome (p = 0.003). Overall survival was 64% (16/25). Survival was 88.2% (15/17) for patients with a successful result versus 12.5% (1/8) for those with a poor outcome (p = 0.0007). Of the 15 survivors, 13 have reached final completion of the Fontan circulation, and two currently remain at the bi-directional Glenn shunt stage.ConclusionAtrioventricular valve repair can be accomplished in this challenging patient population with excellent results. The combination of the leaflet apposition technique and the Kay suture can be performed with an excellent outcome in the majority of patients with heterotaxy syndrome, even with significant atrioventricular valvar regurgitation.

Aim: Human APOBEC3 deaminases induce G to A hypermutation in nascent DNA strand of hepatitis B virus (HBV) genomes and seem to operate as part of the innate antiviral immune system. We analyzed the importance of APOBEC3A (A3A) and APOBEC3B (A3B) proteins, which are potent inhibitors of adeno-associated-virus and long terminal repeat (LTR)-retrotransposons, in chronic HBV infection. Methods: We focused on the common deletion polymorphism that spans from the 3′ part of A3A gene to the 3′ portion of A3B gene. An association study was carried out in 724 HBV carriers and 469 healthy control subjects. We also analyzed hypermutated genomes detected in deletion and insertion (non-deletion) homozygous patients to determine the effect of APOBEC3 gene deletion. Further, we performed functional analysis of A3A gene by transient transfection experiments. Results: The association study showed no significant association between deletion polymorphism and chronic HBV carrier state. Context analysis also showed a negligible effect for the deletion. Rather, mild liver fibrosis was associated with APOBEC gene deletion homozygosity, suggesting that A3B deletion is not responsible for chronic HBV infection. Functional analysis of A3A showed that overexpression of A3A induced hypermutation in HBV genome, although the levels of hypermutants were less than those introduced by A3G. However, overexpression of A3A did not decrease replicative intermediates of HBV. Conclusion: These results suggest that A3A and A3B play little role in HBV elimination through anti-viral defense mechanisms. The significance of hypermutation induced by A3A should be investigated further.

ObjectiveWe aimed to evaluate surgical repair of atrioventricular valve regurgitation in patients with functional single ventricle.MethodsThe medical records of 65 consecutive patients with functional single ventricle who underwent atrioventricular valve repair between January 1999 and October 2008 were reviewed retrospectively. Their characteristics were as follows: median age, 9.5 months; median weight, 6.0 kg; atrial isomerism, 31 patients; and hypoplastic left heart syndrome, 12 patients. Regurgitation was repaired at the palliative, Glenn, and Fontan stage in 21, 29, and 15 patients, respectively.ResultsThe overall survival was 79% and 70% at 1 and 5 years, respectively. The risk factors for mortality were age less than 3 months (P

The establishment of clonal infection of hepatitis C virus (HCV) in a small-animal model is important for the analysis of HCV virology. A previous study developed models of molecularly cloned genotype 1a and 2a HCV infection using human hepatocyte-transplanted chimeric mice. This study developed a new model of molecularly cloned genotype 1b HCV infection. A full-length genotype 1b HCV genome, HCV-KT9, was cloned from a serum sample from a patient with severe acute hepatitis. The chimeric mice were inoculated intrahepatically with in vitro-transcribed HCV-KT9 RNA. Inoculated mice developed viraemia at 2 weeks post-infection, and this persisted for more than 6 weeks. Passage experiments indicated that the sera of these mice contained infectious HCV. Interestingly, a similar clone, HCV-KT1, in which the poly(U/UC) tract was 29 nt shorter than in HCV-KT9, showed poorer in vivo infectivity and replication ability. An in vitro study showed that no virus was produced in the culture medium from HCV-KT9-transfected cells. In conclusion, this study developed a genetically engineered genotype 1b HCV-infected mouse. This mouse model will be useful for the study of HCV virology, particularly the mechanism underlying the variable resistance of HCV genotypes to interferon therapy.

Objective: The purpose of this study is to evaluate the surgical repair of functional single ventricle and extracardiac total anomalous pulmonary venous connection (TAPVC). Methods: Between January 1998 and December 2007, 26 consecutive patients underwent surgical repair of extracardiac TAPVC. Their characteristics were as follows: median age, 34 (range 0—744) days; median weight 3.2 (range 2.0—9.6) kg; supracardiac TAPVC, 11 patients; infracardiac, 5; mixed, 10; right atrial isomerism, 24; pulmonary atresia, 16; and obstructed TAPVC, 17. Concomitant procedures includedsystemic-to-pulmonary shunt in 9 patients,pulmonaryartery bandingin 5, ventricle-to-pulmonaryarteryshunt in 1, Norwood procedure in 1, bidirectional Glenn in 9, and Fontan procedure in 1. Results: The overall survival after the repair of TAPVC was 58% (95% confidence interval [CI], 39—77%) and 54% (95% CI, 34—73%) at 1 and 5 years, respectively. Of the 14 survivors (supracardiac, 9; infracardiac, 4; and mixed, 1), 12 underwent Fontan completion; 1, bidirectional Glenn; and 1 is awaiting bidirectional Glenn. Anastomotic stenosis did not occur, but recurrent pulmonary venous ostial stenosis (PVS) was observed in nine patients. Freedom from recurrent PVS was 56% (95% CI, 34—78%) at both 1 and 5 years. Reoperation for recurrent PVS was performed in six patients; of these patients, two underwent Fontan completion, but three with bilateral and multiple PVS declined. By Cox multivariate regression analysis, mixed TAPVC (p = 0.001, hazard ratio, 13.4; 95% CI, 2.8— 64.4) was a risk factor for mortality, and atrioventricular valve regurgitation, which required surgical intervention at the palliative stage (p = 0.024, hazard ratio, 23.4; 95% CI, 1.5—363.4) was a risk factor for recurrent PVS. Conclusions: The mid-term results of the surgical repair of functionalsingleventriclewith supracardiac orinfracardiacTAPVC areacceptable. The surgicaltreatmentof patientswith mixedTAPVC andwith severe atrioventricular valve regurgitation is not promising, but can be improved. # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Objective The extracardiac conduit Fontan procedure has led to improved outcomes. We performed the procedure in patients weighing less than 10 kg and evaluated its feasibility. Methods Since January 1999, 72 patients weighing less than 20 kg underwent extracardiac conduit Fontan procedure with polytetrafluoroethylene conduits. The patients were divided into 2 groups: 36 patients weighing less than 10 kg in group S and 36 weighing more than 10 kg in group L. Mean weight, median age, and median follow-up period in groups S and L were 8.5 ± 1.1 and 14.0 ± 3.0 kg, 18.9 and 42.0 months, and 29.2 (1.7–79.7) and 42.1 (2.8–94.2) months, respectively. Postoperatively, most patients received peritoneal drainage catheters. We reviewed data precatheterization and postcatheterization and postoperative course. Results Conduit sizes in groups S and L were 17.0 ± 1.3 and 17.9 ± 1.9 mm, respectively ( P = .03). Five patients required fenestrations. There were 2 hospital deaths, 1 in each group, and 2 late deaths in group S. The postoperative course was identical in both groups, except for median length of stay in the intensive care unit and peritoneal drainage volume. Group S versus L: ventilator support, 11 versus 7 hours; pleural drainage, 9 days each; pleural drainage greater than 14 days, 6 versus 5 cases; peritoneal drainage, 8 versus 7 days; intensive care unit stay, 7 versus 4 days ( P = .01), peritoneal drainage volume, 26.1 versus 14.1 mL · kg · d −1 ( P = .0007). Conclusions The early outcome of the extracardiac conduit Fontan procedure was satisfactory in patients weighing less than 10 kg. However, the required size of the conduit remains debatable.

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n=7) and LAM (n=36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n=6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n=12, 0.456 log copies/ml, P=0.0125) or in whom the YMDD mutant never emerged (n=18, 0.688 log copies/ml, P=0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy.

We developed a reverse genetics system of hepatitis C virus (HCV) genotypes 1a and 2a using infectious clones and human hepatocyte chimeric mice. We inoculated cell culture-produced genotype 2a (JFH-1) HCV intravenously. We also injected genotype 1a CV-H77C clone RNA intrahepatically. Mice inoculated with HCV by both procedures developed measurable and transmissible viremia. Interferon (IFN) alpha treatment resulted in greater reduction of genotype 2a HCV levels than genotype 1a, as seen in clinical practice. Genetically engineered HCV infection system should be useful for analysis of the mechanisms of resistance of HCV to IFN and other drugs.

G to A hypermutation of Hepatitis B virus (HBV) and retroviruses appears as a result of deamination activities of host APOBEC proteins and is thought to play a role in innate antiviral immunity. Alpha and gamma interferons (IFN-α and -γ) have been reported to upregulate the transcription of APOBEC3G, which is known to reduce the replication of HBV. We investigated the number of hypermutated genomes under various conditions by developing a quantitative measurement. The level of hypermutated HBV in a HepG2 cell line, which is semi-permissive for retrovirus, was 2.3 in 104 HBV genomes, but only 0.5 in 104 in permissive Huh7 cells. The level of APOBEC3G mRNA was about ten times greater in HepG2 cells than in Huh7 cells. Treatment of HepG2 cells with either IFN-α or -γ increased the transcription of APOBEC3G and hypermutation of HBV. These mRNAs and hypermutation of HBV genomes were induced more prominently by IFN-γ than by IFN-α. Both IFNs decreased the number of replicative intermediate of HBV. Overexpression of APOBEC3G reduced the number of replicative intermediate of HBV and increased hypermutated genomes 334 times, reaching 968 in 104 genomes. Deamination-inactive APOBEC3G did not induce hypermutation, but reduced the virus equally. Our results suggest that APOBEC3G, upregulated by IFNs, has a dual effect on HBV: induction of hypermutation and reduction of virus synthesis. The effect of hypermutation on infectivity should be investigated further.

Studies of hepatitis B virus (HBV) mutants have been hampered by the lack of a small animal model with long-term infection of cloned HBV. Using a mouse model in which liver cells were highly replaced with human hepatocytes that survived over a long time with mature human hepatocyte function, we performed transmission experiments of HBV. Human serum containing HBV and the virus produced in HepG2 cell lines that transiently or stably transfected with 1.4 genome length HBV DNA were inoculated. Genetically modified e-antigen–negative mutant strain also was produced and inoculated into the mouse model. A high-level (≈1010 copies/mL) viremia was observed in mice inoculated with HBV-positive human serum samples. The level of viremia tended to be high in mice with a continuously high human hepatocyte replacement index. High levels and long-lasting viremia also were observed in mice injected with the in vitro generated HBV. The viremia continued up to 22 weeks until death or killing. Passage experiments showed that the serum of these mice contained infectious HBV. Genetically engineered hepatitis B e antigen–negative mutant clone also was shown to be infectious. Lamivudine effectively reduced the level of viremia in these infected mice. In conclusion, this mouse model of HBV infection is a useful tool for the study of HBV virology and evaluation of anti-HBV drugs. Our results indicate that HBeAg is dispensable for active viral production and transmission. (HEPATOLOGY 2005;42:1046–1054.)

G to A hypermutation of the human immunodeficiency virus type 1 (HIV-1) is induced by a deaminase APOBEC3G and is related to host antiviral defense. APOBEC3G has also been found to reduce the replication of HIV-1 by an unknown mechanism. This enzyme also reduces the production of hepatitis B virus, although the mechanism for this action has not been clearly elucidated. The hypermutated hepatitis B virus (HBV) is rarely found in usual sequencing analyses. Using peptide nucleic acid mediated by polymerase chain reaction clamping, we detected the hypermutated HBV DNA in 1 of 8 patients with acute HBV infection and 4 of 10 with chronic HBV infection. In the latter group, hypermutated genomes were found only in eAb-positive patients. As much as 72.5% of G residues were mutated in the hypermutated clones. G to A substitutions were predominant in almost all clones sequenced compared with other substitutions. G to A mutated viral genomes also were found in HepG2–derived cell lines that continuously produced HBV into the supernatant. Both alpha and gamma interferon reduced virus production in these cell lines, but they did not alter the frequency of the hypermutation. Transcripts of APOBEC3G, as well as some other deaminases, were found in these cell lines. In conclusion, our results show that part of the minus strand DNA of HBV is hypermutated both in vitro (HepG2 cell lines) and in vivo. The role and mechanism of hypermutation in reducing HBV replication should be further investigated to understand the anti-HBV defense system. (HEPATOLOGY 2005;41:626–633.)

Objective: In the present study, we examined the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in human pancreatic cancer and the possible effects of its ligand engagement on cell growth. Methods: Seven human pancreatic cancer cell lines and 7 surgically resected human pancreatic cancer tissues were used as samples. The expression of PPARγ was analyzed with reverse transcription-polymerase chain reaction and immunoblotting. The interaction between PPARγ and PPAR-responsive element (PPRE) was examined by gel shift assay. Growth inhibition by thiazolidinediones was confirmed with anchorage-dependent and anchorage-independent growth assays. Results: PPARγ was detected in all cell lines tested and in 5 out of 7 cancer tissues (71%), but was not found in adjacent normal pancreatic tissues. Gel shift analysis revealed that the proteins in nuclear extracts of the pancreatic cancer cell line PANC-1 specifically bind to the PPRE. Cell growth was significantly inhibited by treatment with troglitazone and rosiglitazone in a dose- and time-dependent manner (p < 0.01). In contrast, a nonfunctional metabolic analog of troglitazone did not affect cell growth. Conclusion: These observations suggest that PPARγ plays an important role in human pancreatic cancer growth and that ligand-induced activation of PPARγ would be a useful strategy for treatment of human pancreatic cancer.

We investigated the expression of angiotensin II type 1 receptor (AT1) in pancreatic cancer. Both AT1 mRNA and protein were expressed in human pancreatic cancer tissues and cell lines. Binding assays showed that pancreatic cancer cells have specific binding sites for angiotensin II and that binding could be eliminated by treatment with a selective AT1 antagonist in a dose-dependent fashion. Surprisingly, the growth of cancer cells was significantly suppressed by treatment with antagonist, also in a dose-dependent manner. These observations suggest AT1 plays an important role in pancreatic cancer growth. Furthermore, ligand-induced inhibition of AT1 may be a useful therapeutic strategy.