Osteoprotegerin is secreted into the coronary circulation: a possible association with the renin-angiotensin system and cardiac hypertrophy.

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor.

The mitotic apparatus plays a pivotal role in dividing cells to ensure each daughter cell receives a full set of chromosomes and complement of cytoplasm during mitosis. A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus. We have identified an interaction of h-warts/LATS1 with zyxin, a regulator of actin filament assembly. Zyxin is a component of focal adhesion, however, during mitosis a fraction of cytoplasmic-dispersed zyxin becomes associated with h-warts/LATS1 on the mitotic apparatus. We found that zyxin is phosphorylated specifically during mitosis, most likely by Cdc2 kinase, and that the phosphorylation regulates association with h-warts/LATS1. Furthermore, microinjection of truncated h-warts/LATS1 protein, including the zyxin-binding portion, interfered with localization of zyxin to mitotic apparatus, and the duration of mitosis of these injected cells was significantly longer than that of control cells. These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus.

Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity.

Guanosine triphosphate (GTP) cyclohydrolase I, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), is subject to feedback inhibition by BH4, a cofactor for phenylalanine hydroxylase. Inhibition was found to depend specifically on BH4 and the presence of another protein (p35). The inhibition occurred through BH4-dependent complex formation between p35 protein and GTP cyclohydrolase I. Furthermore, the inhibition was specifically reversed by phenylalanine, and, in conjunction with p35, phenylalanine reduced the cooperativity of GTP cyclohydrolase I. These findings also provide a molecular basis for high plasma BH4 concentrations observed in patients with hyperphenylalaninemia caused by phenylalanine hydroxylase deficiency.

Schwannoma of the esophagus: a case exhibiting high 18F-fluorodeoxyglucose uptake in positron emission tomography imaging.

Esophageal schwannoma is rare and it is difficult preoperatively to confirm a definitive diagnosis, even using current imaging techniques. We present a case of a benign esophageal schwannoma that was surgically excised and confirmed by immunohistochemical staining. Conventional radiological studies, including barium meal, computed tomography and endoscopic examination had shown a solid submucosal tumor of the upper thoracic esophagus but had been unable to confirm the diagnosis. Positron emission tomography was carried out to evaluate the malignant potential and showed a high uptake of 18F-fluorodeoxyglucose (FDG) into the tumor in both the early and delayed phase, suggesting that the tumor was a potentially malignant tumor such as a gastrointestinal stromal tumor. This is the first reported case of esophageal schwannoma that indicated a high FDG uptake. Although consensus has not been reached regarding the precise mechanism of FDG accumulation in schwannomas, we discuss our clinicopathological findings and review other studies of the subject.

De novo autoimmune hepatitis after living donor liver transplantation in a 25-day-old newborn baby: a case report.

De novo autoimmune hepatitis (AIH) has been described recently as a new type of graft dysfunction in pediatric patients receiving liver transplantation. Herein we have reported the case of a boy, diagnosed as neonatal hemochromatosis, who received a reduced left lateral graft 25 days after birth. Pretransplantation autoantibodies and serological tests were negative. The postoperative course was smooth. No episode of vascular or biliary complication or acute cellular rejection was observed. The maintenance immunosuppressant was tacrolimus only. Liver dysfunction occurred 13 months after living donor liver transplantation. Liver biopsies showed no acute cellular rejection, but severe apoptosis and regeneration of liver cells at the centrolobular area. At that time, various autoantibodies including anti-nuclear, anti-double-stranded DNA, and anti-smooth muscle antibodies were positive. In addition, serum immunoglobulin G (IgG) was elevated. Based on these findings, he was diagnosed as de novo AIH. The treatment consisted of reducing the tacrolimus dose and reintroduction of steroids. After 12 months of treatment, liver dysfunction improved, serum autoantibodies became negative, and serum IgG level normalized. Currently his immunosuppressive therapy consists of low-dose tacrolimus and prednisolone. In conclusion, the present case demonstrated that de novo AIH can appear in living donor liver transplant patients despite appropriate immunosuppression. Reducing the tacrolimus dose and reintroduction of prednisolone sustained the graft and prevented retransplantation.

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

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

Feasibility of auxiliary partial living donor liver transplantation for fulminant hepatic failure as an aid for small-for-size graft: single center experience.

Auxiliary partial orthotopic liver transplantation (APOLT) or heterotopic auxiliary partial liver transplantation (HAPLT) was initially indicated for potentially reversible fulminant hepatic failure (FHF). We started auxiliary partial living donor liver transplantation (LDLT) for FHF in February 2002. Since then, 5 FHF patients (3 females and 2 males) underwent auxiliary partial LDLT: 3 cases of APOLT and 2 cases of HAPLT. All of them received a small-for-size graft: graft-to-recipient weight ratio (GRWR) < or = 1.0%. The etiologies of FHF were hepatitis B virus (HBV) in 1, Wilson's disease in 1, and unknown origin in 3 cases. Three were the acute type and 2 the subacute type of FHF. Median age was 45 years (range, 14-54 years). Blood type was identical in all cases. A left lobe graft was used in 4 instances and a right lobe graft in 1 case. Median GRWR was 0.74 (range, 0.42-0.85). Median follow-up was 42 months (range, 3 days to 70 months). Three of 5 patients (60%) were alive (at 42, 67, and 70 months) and 1 was free of immunosuppression after sufficient recovery of the native liver. Two cases succumbed: 1 at postoperative day 3 because of cytomegalovirus pneumonia and 1 at 10 months after APOLT because of sepsis. Complications were seen in all 5 patients: Relaparotomy for hemostasis in 3, decompression surgery of the abdominal cavity in 1, rehepaticojejunostomy in 1, and biliary strictures in 2 cases. Auxiliary partial LDLT may be a choice as an aid for a small-for-size graft in FHF.

Long-term follow-up study of biliary reconstructions and complications after adult living donor liver transplantation: feasibility of duct-to-duct reconstruction with a T-tube stent.

The aim of this study was to analyze the feasibility of duct-to-duct biliary reconstruction (hepaticohepaticostomy) with a T-tube stent (HH-T) after adult living donor liver transplantation (LDLT) based on long-term follow-up. We retrospectively evaluated 63 primary adult LDLTs who had survived >1 month from March 1999 to January 2008. We compared the incidence of bile leaks and biliary strictures (BS) in 3 groups of patients: Roux-en-Y hepaticojejunostomy (HJ; n = 18); duct-to-duct hepaticohepaticostomy with external stents except a T-tube (HH; n = 26); and HH-T (n = 19). Median follow-up was longer among the HJ (63 months) than the other groups (32 months in HH and 25 months in HH-T; P = .04). Bile leaks developed in 8 of the HJ cases (44%); 9 of the HH cases (33%); and 1 of the HH-T cases (5%; P = .02). All cases with bile leaks (n = 18) were treated using continuous drainage, 15 of them (83%) successfully. BS developed in 4 HJ cases (22%); 12 HH cases (46%), and 4 HH-T cases (21%; P = .12). Intervention for BS (n = 20) was successful in 10 cases (50%) via an endoscopic approach and 6 cases (30%) via a percutaneous transhepatic approach. Operative management for BS was required in 4 cases (20%). Biliary reconstruction using HH-T may be effective to prevent bile leaks after LDLT. However, HH-T may not decrease the incidence of BS after adult LDLT.

Early regular examination of biliary strictures by endoscopic retrograde cholangiography for duct-to-duct biliary reconstruction after adult living donor liver transplantation.

In September 2006, we initiated regular screening of biliary strictures (BS) by endoscopic retrograde cholangiography (ERC) within 6 months after removal of external stents among duct-to-duct biliary reconstructed adult living donor liver transplantations (LDLT). From March 2000 to January 2008, we retrospectively evaluated 45 primary adult LDLTs who had survived >1 month. We separated the cases into 2 groups-the early cases (March 2000 to August 2006: n = 34) and the late cases (September 2006 to January 2008: n = 11)-to compare the incidences of BS and the success rates of endoscopic treatments. Median follow-up of the late cases (8.0 months) was shorter than that of the early cases (38.5 months; P = .0003). The overall incidence of BS was 36% (16/45), with 32% (11/34) among the early and 45% (5/11) among the late cases (P = .18). BS was successfully treated by endoscopic management in 4/5 (80%) late cases and 3/11 (27%) early cases (P = .049). Two early patients required operative biliary reconstructions. Endoscopic procedure-related complications developed in 2 patients among the early cases. Early postoperative regular screening of BS by ERC for duct-to-duct biliary reconstructions may be effective to avoid surgical interventions after adult LDLT. However, repeat ERCs have a risk for pancreatitis and other complications. Further investigations and longer follow-up are needed to confirm the efficacy and safety of a regular examination by ERC for duct-to-duct biliary reconstructions in LDLT.

Optimization of acoustic coupling for bottom actuated scattering based subsurface scanning probe microscopy.

The characterization of buried nanoscale structures nondestructively is an important challenge in a number of applications, such as defect detection and metrology in the semiconductor industry. A promising technique is Subsurface Scanning Probe Microscopy (SSPM), which combines ultrasound with Atomic Force Microscopy (AFM). Initially, SSPM was used to measure the viscoelastic contrast between a subsurface feature and its surrounding medium. However, by increasing the ultrasonic frequency to >1 GHz, it has been shown that SSPM can also measure acoustic impedance based contrasts. At these frequencies, it becomes difficult to reliably couple the sound into the sample such that the AFM is able to pick up the scattered sound field. The cause is the existence of strong acoustic resonances in the sample, the transducer, and the coupling layer-the liquid layer used to couple the sound energy from the transducer into the sample-in combination with the nonlinearity of the tip-sample interaction. Thus, it is essential to control and measure the thickness of the coupling layer with nanometer accuracy. Here, we present the design of a mechanical clamp to ensure a stable acoustic coupling. Moreover, an acoustic method is presented to measure the coupling layer thickness in real-time. Stable coupling layers with thicknesses of 700 ± 2 nm were achieved over periods of 2-4 h. Measurements of the downmixed AFM signals showed stable signal intensities for >1 h. The clamp and monitoring method introduced here makes scattering based SSPM practical, robust, and reliable and enables measurement periods of hours.