Single-Shot Ternary Readout of Two-Electron Spin States in a Quantum Dot Using Spin Filtering by Quantum Hall Edge States.

We report on the single-shot readout of three two-electron spin states-a singlet and two triplet substates-whose z components of spin angular momentum are 0 and +1, in a gate-defined GaAs single quantum dot. The three spin states are distinguished by detecting spin-dependent tunnel rates that arise from two mechanisms: spin filtering by spin-resolved edge states and spin-orbital correlation with orbital-dependent tunneling. The three states form one ground state and two excited states, and we observe the spin relaxation dynamics among the three spin states.

Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks.

The study of rare human syndromes characterized by radiosensitivity has been instrumental in identifying novel proteins and pathways involved in DNA damage responses to ionizing radiation. In the present study, a mutation in mitochondrial poly-A-polymerase (MTPAP), not previously recognized for its role in the DNA damage response, was identified by exome sequencing and subsequently associated with cellular radiosensitivity. Cell lines derived from two patients with the homozygous MTPAP missense mutation were radiosensitive, and this radiosensitivity could be abrogated by transfection of wild-type mtPAP cDNA into mtPAP-deficient cell lines. Further analysis of the cellular phenotype revealed delayed DNA repair, increased levels of DNA double-strand breaks, increased reactive oxygen species (ROS), and increased cell death after irradiation (IR). Pre-IR treatment of cells with the potent anti-oxidants, α-lipoic acid and n-acetylcysteine, was sufficient to abrogate the DNA repair and clonogenic survival defects. Our results firmly establish that mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation, suggesting a pathogenesis that involves the disruption of ROS homeostasis.

Efficacy and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in kidney transplant recipients.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia. In this study, we evaluated the efficacy and safety of febuxostat for the management of hyperuricemia in renal transplant recipients. PATIENTS AND METHODS: Between June 2012 and January 2013, a total of 22 renal transplant recipients (56 ± 10 years old) with hyperuricemia were enrolled in this study. All patients underwent de novo kidney transplantation, except for 1 patient, who received a second kidney transplant. Ten patients receiving allopurinol and 3 patients receiving benzbromarone were converted to febuxostat at doses of 10-20 mg/d. In the remaining 9 patients, who did not have a history of other urate-lowering medications, febuxostat was initiated at a dose of 10 mg/d. RESULTS: Uric acid levels after initiation of febuxostat were significantly lower than before treatment (5.7 ± 0.7 mg/mL vs 8.0 ± 0.8 mg/mL; P < .001). At last follow-up visit, 16 of the 22 patients (73%) achieved uric acid levels of ≤ 6.0 mg/dL, despite the low dosage of febuxostat. All patients were maintained on febuxostat without serious adverse events, except for 1 patient, who discontinued febuxostat because of numbness in the arms. CONCLUSIONS: Low-dose febuxostat is a promising alternative to allopurinol or benzbromarone for the treatment of hyperuricemia in kidney transplant recipients. The long-term urate-lowering efficacy and safety of febuxostat with regard to renal function in kidney transplant recipients with hyperuricemia requires further investigation.

Nondestructive real-time measurement of charge and spin dynamics of photoelectrons in a double quantum dot.

We demonstrate one and two photoelectron trapping and the subsequent dynamics associated with interdot transfer in double quantum dots over a time scale much shorter than the typical spin lifetime. Identification of photoelectron trapping is achieved via resonant interdot tunneling of the photoelectrons in the excited states. The interdot transfer enables detection of single photoelectrons in a nondestructive manner. When two photoelectrons are trapped at almost the same time we observed that the interdot resonant tunneling is strongly affected by the Coulomb interaction between the electrons. Finally the influence of the two-electron singlet-triplet state hybridization has been detected using the interdot tunneling of a photoelectron.

Two- and three-electron Pauli spin blockade in series-coupled triple quantum dots.

We investigate two- and three-electron spin blockade in three vertical quantum dots (QDs) coupled in series. Two-electron spin blockade is found in a region where sequential tunneling through all QDs is forbidden but tunneling involving virtual hopping through an empty QD is allowed. It is observed only for the hole cycle with a distinct bias threshold for access to the triplet state. Three-electron spin blockade involving the quadruplet state is observed for nonequibilium conditions where sequential tunneling is allowed and the triplet state is accessible. Our results shine light on the importance of the nonequibilium conditions to obtain sufficient population of triplet and quadruplet states necessary for spin blockade.

Evolution of registry and tracking system for organ transplantation in Japan.

Previously, the renal and liver transplantation registry in Japan was enforced yearly using registration and tracking papers only on recipients. The input of all patient data and announcement of statistical analysis to the public required a long time. Following The Declaration of Istanbul 2008, the committees planned to establish new registry and tracking systems for renal and liver transplantations on both recipients and donors. As the first step, for renal transplantation, we established a new registry and tracking system, JARTRE (JApan Renal Transplantation REgistry), using flash (USB) memory in 2009. The recipient and donor data were inputted into the USB memory in the transplantation centers. The memory was collected once a year by the committees with performed at 3 months at 1 year and every year after, the operation. As the second step, for liver transplantation, we established an online registry and tracking system, LITRE-J (LIver Transplantation REgistry in Japan), using the Internet in 2011. The recipient and donor data are inputted online in the centers just after transplantation. The tracking is performed at 3 months, at 1 year and every year after the operation. In 2012, we will convert the JARTRE system to an online registration and tracking system using the Internet like LITRE-J. The advantages of these system are the ease of input, scope of the data, and rapidly for statistical processing. Herein we have reported the details of JARTRE and LITRE-J, as well as the evaluation of the registry and tracking systems for renal and liver transplantation in Japan.

Aharonov-Bohm oscillations changed by indirect interdot tunneling via electrodes in parallel-coupled vertical double quantum dots.

Aharonov-Bohm (AB) oscillations are studied for a parallel-coupled vertical double quantum dot with a common source and drain electrode. We observe AB oscillations of current via a one-electron bonding state as the ground state and an antibonding state as the excited state. As the center gate voltage becomes more negative, the oscillation period is clearly halved for both the bonding and antibonding states, and the phase changes by half a period for the antibonding state. This result can be explained by a calculation that takes account of the indirect interdot coupling via the two electrodes.

New registry and tracking system for renal transplantation in Japan.

Following The Declaration of Istanbul 2008, a registration committees of The Japan Society for Transplantation and The Japanese Society for Clinical Renal Transplantation planned to establish a new registry and tracking system for renal transplant recipients and donors supported by a Health Labor Sciences Research Grant by The Ministry of Health Labour and Welfare. In place of the previous paper-based system, we established the new registry and tracking system, JARTRE (Japan Renal Transplantation Registry), using USB memory in 2009. Recipient and donor data were inputted into the USB memory at the transplantation centers. The memory was reviewed a yearly by committees. The recipient and donor registration included details from both. The tracking is performed centrally 3 months, 1 year, and every year after the operation. The advantages of this system are the ease of input, adequacy of the data, and rapid statistical processing. In 2009, we registered 97.9% of new renal transplantation recipients and donors; in 2008 it was more than 81.9% of all past renal transplantation recipients in Japan.

Actions of the Japanese Pancreas and Islet Transplantation Association regarding transplanted human islets isolated using Liberase HI.

PURPOSE: The potential for introducing transmissible spongiform encephalopathy (TSE) into islet cells was indicated by recognizing that Liberase HI is isolated from Clostridium histolyticum grown in media containing brain-heart infusion broth. A national team within the Japanese Pancreas and Islet Transplantation Association implemented an islet transplantation program in Japan using Liberase HI. The program comprised 65 islet isolations from non-heart-beating donors and 34 transplants into 18 patients. Herein, we have summarized how the Association followed these recipients over the long term. PROCEDURES: We established an ad hoc committee to follow recipients transplanted with islets isolated using Liberase HI after becoming informed of the associated dangers of using this enzyme. We also stopped islet transplantations using Liberase. The committee addressed the major concerns of the risk of the collagenase being contaminated with TSE and of the recipient follow-up. All recipients were examined by diffusion MRI and EEG and then scheduled for evaluation and follow-up by specialists in Creutzfeldt-Jakob disease (CJD). Bioassays of bovine spongiform encephalopathy prions in the enzyme proceeded using knock-in mice expressing bovine prion protein. These assays could detect contaminating prions at a dilution of 1 × 10(4). After inactivating its collagenase activity, Liberase HI was injected into the abdominal cavities of knock-in mice. Four months later, prion infectivity in Liberase HI was evaluated by immunohistochemical staining and Western blotting of spleen homogenates using anti-prion protein antibodies. MAIN FINDINGS: Western blotting and immunohistochemical staining did not detect prions in Liberase HI. Diffusion MRI and EEG evaluations performed by CJD specialists confirmed that none of the transplanted recipients had CJD. CONCLUSIONS: Three years of follow-up revealed that none of the Japanese recipients of islet transplants developed CJD. Prion bioassays showed that the Liberase HI used to isolate islets for transplantation was free of infectious TSE prions.

Early humoral-mediated graft injuries in ABO-incompatible kidney transplantation in human beings.

INTRODUCTION: Acute humoral rejection is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) renal transplantation (RTx) and is present from the early period after RTx. However, the characteristics of early humoral-mediated graft injury are pathologically uncertain. OBJECTIVE: To analyze tissue from 10 protocol graft biopsies performed in 10 patients within 30 days post-RTx to clarify the pathologic features of early humoral-mediated graft injuries in ABO-i RTx. METHODS: Pathologic findings were examined using light and electron microscopy and immunofluorescence studies for C4d. Protocol biopsies were performed within 30 days after RTx in the absence of an episode of dysfunction (creatinine concentration 1.21-1.81 mg/dL). RESULTS: The immunofluorescence study demonstrated C4d deposition in peritubular and glomerular capillaries. Acute glomerulitis with infiltration of mononuclear cells and neutrophils was observed in 3 patients. Furthermore, glomerulitis was accompanied by endothelial cell injuries, widening of subendothelial spaces with a double-contoured glomerular basement membrane, and mesangiolysis. CONCLUSION: In ABO-i RTx, early humoral-mediated graft injuries were observed in approximately 30% of patients despite normal graft function. They were characterized by C4d deposition and glomerular capillary injury. These findings suggest that renal glomeruli are the first site of graft injury by anti-A or anti-B blood type antibody with complement activation in ABO-i RTx.

Persistent glomerular hematuria in living kidney donors confers a risk of progressive kidney disease in donors after heminephrectomy.

Although glomerular hematuria is likely a sign of chronic kidney disease that will develop into overt nephropathy after donation, it remains unclear whether prospective donors with hematuria should be excluded. We reviewed the medical records of 242 donors who donated at our institution from 2001 to 2007 and surveyed the prevalence of hematuria pre- and postdonation. We then investigated the association of hematuria with proteinuria postdonation and trends in glomerular filtration rate. Before donation, 8.3% of 242 donors presented with persistent hematuria, a finding that was significantly associated with dysmorphic hematuria before donation. Most cases of predonation persistent hematuria persisted after donation, and the overall prevalence increased to 15.3%. During a median follow-up period of 2.3 years after donation, 8.3% developed persistent proteinuria, with incidence being significantly higher in donors having persistent hematuria with dysmorphic red blood cells (d-RBC) both before and after donation. Postdonation persistent hematuria with d-RBC was also associated with a progressive decline in renal function. These results indicate that persistent glomerular hematuria is strongly associated with a higher incidence of postdonation progressive kidney disease. Potential donors with persistent glomerular hematuria should be excluded, while those with isolated hematuria need to be evaluated with heightened caution.

How do living kidney donors develop end-stage renal disease?

The clinical course and risk factors for developing end-stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case-control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow-up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long-term (more than 10 years) follow-up of donors with special attention on the risk factors of CKD.

Caveolin-1 expression is a distinct feature of chronic rejection-induced transplant capillaropathy.

Peritubular capillary basement membrane multilayering (PTCBMML) is a pathological landmark of chronic rejection-induced transplant capillaropathy (TC), but its cellular mechanisms are not fully understood. We observed de novo caveolae formation in endothelial cells in TC under electron microscopy. To examine the role of caveolae and their structural components in TC, biopsy samples from cases of chronic rejection were double-immunostained for Caveolin-1 (Cav-1) and Pathologische Anatomie Leiden-endothelium (PAL-E; a marker of peritubular capillary [PC]). Thirty-two cases of chronic rejection (group I) were compared with 18 cases of interstitial fibrosis and tubular atrophy with no evidence of any specific etiology (IF/TA; group II) and eight cases of peritubular capillaritis (group III). The Cav-1/PAL-E immunoreactivities in groups I-III (%Cav-1/PAL-E) were 41.8+/-23.1%, 8.1+/-7.3% (p < 0.01 vs. group I) and 12.7+/-7.4% (p < 0.01 vs. group I), respectively. Furthermore, multiple linear regression models demonstrated that %Cav-1/PAL-E was independently associated with the PTCBMML grade and reduced PC number. No correlation was observed between %Cav-1/PAL-E and PC C4d deposition in group I. We conclude that de novo caveolae formation in PC endothelia is involved in TC in chronic rejection.

Hand-assisted laparoscopic splenectomy in ABO-incompatible kidney transplant recipients.

OBJECTIVE: We perform living-related ABO-incompatible kidney transplantations to alleviate the organ shortage in our country. Splenectomy has been performed routinely in these recipients, although its clinical significance remains controversial. In this study, we have reported our experience with a hand-assisted laparoscopic splenectomy (HALS) technique. METHODS: Between April 2000 and December 2006, 50 patients (23 males) underwent ABO-incompatible kidney transplantation with HALS. The mean age and weight of the recipients were 44 +/- 13 years and 56 +/- 12 kg, respectively. All patients underwent preoperative plasmapheresis to reduce isoagglutinin (A and/or B antibody). In 6/50 patients, a hand-assisted device was placed through a peritoneal window in the right lower abdominal skin incision for kidney engraftment. In the remaining 44 patients, a 6-cm upper midline or periumbilical midline incision was made for the hand-assisted device in the lateral position. RESULTS: An ABO-incompatible procedure was completed successfully in all cases. The average HALS time was 118 +/- 42 minutes, with an average pneumoperitoneum time of 79 +/- 40 minutes and average blood loss of 48 +/- 81 g. There were two conversions to open splenectomy because of intraoperative bleeding and suspected pneumothorax. Two other cases required relaparotomy because of hematoma and perforation of the ileum. Successfully operations were achieved through the previous periumbilical incision. CONCLUSIONS: Although meticulous, rigorous surgical technique is essential, HALS is safe and feasible for recipients of ABO-incompatible grafts with tissue weakness and a bleeding tendency because of renal failure and preoperative plasmapheresis.

Effects of immunosuppressants on the progression of hepatitis C in hepatitis C virus-positive renal transplantation and the usefulness of interferon therapy.

OBJECTIVE: The purpose of this study was to analyze the effects of immunosuppressants on hepatitis C virus (HCV) replication to establish optimal immunosuppressive therapy in HCV-positive renal transplantation. MATERIALS AND METHODS: Cyclosporine (CsA), tacrolimus (Tac), mycophenolate acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and methylprednisolone (MP) were administered to HCV replicon cells alone or in combination with interferon (IFN). HCV RNA was quantitatively determined. Of our 2064 recipients of renal transplantations between 1980 and 2005, 153 were HCV-positive. We analyzed changes in hepatic function and the efficacy of IFN therapy in these patients. RESULTS: Only CsA strongly inhibited the growth of HCV RNA (13.1% at 1.0 microg/mL). MPA enhanced the inhibition of the growth of HCV RNA in the presence of IFN. Tac and MP reduced, rather than enhanced, the efficacy of IFN. Progression to chronic hepatitis occurred in a significantly smaller number of patients in the CsA than the Tac group (6 vs 19; P = .04). Serum alanine aminotransferase (ALT) levels were comparable pretransplantation and posttransplantation in the CsA group (24.8 +/- 20.5 vs 28.9 +/- 28.3 IU/L, respectively, while a significant elevation was noted in the Tac group (22.2 +/- 21.5 vs 32.6 +/- 30.8 IU/L, respectively; P = .024). Two of 4 patients who underwent combination therapy with IFN and ribavirin during treatment with CsA and MMF obtained an HCV-negative status for over 24 weeks. CONCLUSIONS: CsA effectively prevents the progression of chronic hepatitis in HCV-positive renal transplant patients. A greater response rate can be expected by concurrent administration of CsA and MMF under IFN therapy.

Successful third kidney transplantation with intensive immunosuppression in a highly sensitized recipient.

HLA sensitization associated with previous kidney transplantation is a major drawback to retransplantation. Recently we successfully performed a third graft using intensive immunosuppression for a highly sensitized recipient. The patient was a 31-year-old man who had previously undergone a living donor graft from his father at our institute in 1999. His kidney graft function had deteriorated due to chronic allograft nephropathy, returning to hemodialysis therapy in 2005. He received a second graft from a deceased donor in another country on August 14, 2006. It rejected on postoperative day 3 possibly due to acute accelerated rejection. He was offered a third kidney from his brother. Panel-reactive antibody (PRA) tested before the third procedure revealed positive class I (88%) and class II (96%) PRAs. Mycophenolate mofetil (MMF) was started 3 weeks before the third transplantation, and preoperative plasmapheresis performed thrice. He underwent the living donor graft on March 9, 2007. Immunosuppression consisted of tacrolimus, MMF, methylprednisolone, and basiliximab. Immediately afterward there was a sudden decrease in allograft blood flow and urine output, implying hyperacute rejection. Following treatment with plasmapheresis and a single dose of rituximab (200 mg), the kidney allograft function recovered, although the PRA at 3 weeks was still positive. Six months posttransplantation, he is well with a creatinine of 0.9 mg/dL. Our protocol may reduce the risk for graft loss in a highly sensitized transplant recipient.

Present status of pancreas transplantation in Japan--donation predominantly from marginal donors and modified surgical technique: report of Japan pancreas transplantation registry.

In Japan, organ donation has been still limited because of the strict donor criteria. The aim of this study was to show the effectiveness of pancreas transplantation (PTx) by analyzing the outcomes even under poor donor conditions. Thirty-six cases of PTx (32 simultaneous pancreas and kidney transplantations [SPK], 4 pancreas after kidney transplantations) performed during the last 8 years were examined especially for donor characteristics. Mean donor age of 41.4 +/- 11.9 years was considerably older compared with that in the United States and Europe; donors aged over 40 years comprised 67% of the total. According to the criteria described by Kapur, 29 cases (81%) in our series would be considered marginal. Thus, to increase blood supply into the pancreatic head, the gastroduodenal artery (GDA) was anastomosed using donor artery to common hepatic artery or iliac Y graft. These procedures were performed in 16 of the 24 cases in which there was liver procurement. Eventually, 34 cases (94%) preserved GDA continuity. Mean total cold ischemic time of pancreatic grafts was 12 hours 15 minutes. Of 214 registrants, 17 patients on the waiting list for SPK died of diabetic complications. To date, patient survival remains 100% with a mean follow-up period of 33 months. Pancreas graft survivals at 1, 3, and 5 years posttransplantation were 92%, 80%, and 80%, respectively. In contrast, kidney survivals were 91%, 91%, and 91%, respectively. The integrity of the pancreas head and duodenum by preservation of the GDA continuity might have decreased the risk associated with the marginal donors.

Glomerular expression of plasmalemmal vesicle-associated protein-1 in patients with transplant glomerulopathy.

Transplant glomerulopathy (TG) is a prominent feature of chronic rejection that is characterized by double contours of the glomerular capillaries (GC). In this report, we demonstrate that one of the histopathological features of TG is a phenotypic change of glomerular endothelial cells which is illustrated by increased caveolae formation. To verify the endothelial changes in this disease, we examined the expression of plasmalemmal vesicle-associated protein-1 (PV-1), a glycoprotein associated with plasmalemmal vesicles (caveolae), in the glomeruli of TG patients using pathologische anatomie Leiden-endothelium (PAL-E) antibody. Twenty-six cases of chronic allograft nephropathy (CAN) with TG were examined, compared with 16 cases of CAN without TG, type I MPGN (4 cases), and transplant glomerulitis (8 cases). Overall, 24 of 26 (92.3%), 4 of 16 (25%), 0 of 4, 0 of 8 cases were PAL-E-positive for GC, respectively. Further, the extent of glomerular PAL-E expression was positively correlated with both the grade of TG (rs= 0.72, p = 0.0003) and proteinuria (g/day) (rs= 0.51, p = 0.02). A correlation was not observed between glomerular PAL-E positivity and peritubular capillary C4d deposits (Yetes chi = 0.23, p = 0.89). In summary, the present study demonstrates expression of PV-1 in the GC of TG which is correlated with the grade of TG and proteinuria.

Thickening of the peritubular capillary basement membrane is a useful diagnostic marker of chronic rejection in renal allografts.

In kidney transplantation, the multilayering of the peritubular capillary basement membrane (MLPTC) in electron microscopy (EM) has been recognized as a feature of chronic rejection (CR). In this study, thickening of the peritubular capillary (PTC) basement membrane was evaluated by light microscopy (LM) to determine whether it corresponds to the MLPTC in EM and whether it can be used as a diagnostic marker of CR. Forty-eight patients with late renal allograft were divided into chronic allograft nephropathy (CAN) with CR (Group 1, n = 23), CAN without CR (Group 2, n = 19) and CAN-free (Group 3, n = 6). The thickening of the PTC basement membrane (ptcbm) was scored from grades 0 to 2 (ptcbm score), and the MLPTC thickness was measured in EM. Interobserver agreement on ptcbm scores was statistically significant (Kappa coefficient = 0.63). LM and EM lesions corresponded very well. The ptcbm score was highest in Group 1, and ptcbm2 corresponded closely with CR. Group 1 showed significantly thicker MLPTC than Groups 2 and 3. The results validated the usefulness of the ptcbm score and suggested that the thickening of the PTC basement membrane can be a novel diagnostic marker of CR.