Monoclonal Antibody Specific for TIRC7 Induces Donor-specific Anergy and Prevents Rejection of Cardiac Allografts in Mice

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.     

Motion‐induced disturbance of auditory–motor synchronization and its modulation by transcranial direct current stimulation

The timing of personal movement with respect to external events has previously been investigated using a synchronized finger‐tapping task with a sequence of auditory or visual stimuli. While visuomotor synchronization is more accurate with moving stimuli than with stationary stimuli, it remains unclear whether the same principle holds true in the auditory domain. Although the right inferior–superior parietal lobe (IPL/SPL), a center of auditory motion processing, is expected to be involved in auditory–motor synchronization with moving sounds, its functional relevance has not yet been investigated. The aim of the present study was thus to clarify whether horizontal auditory motion affects the accuracy of finger‐tapping synchronized with sounds, as well as whether the application of transcranial direct current stimulation (tDCS) to the right IPL/SPL affects this. Nineteen healthy right‐handed participants performed a task in which tapping was synchronized with both stationary sounds and sounds that created apparent horizontal motion. This task was performed before and during anodal, cathodal and sham tDCS application to the right IPL/SPL in separate sessions. The time difference between the onset of the sounds and tapping was larger with apparently moving sounds than with stationary sounds. Cathodal tDCS decreased this difference, anodal tDCS increased the variance of the difference and sham stimulation had no effect. These results supported the hypothesis that auditory motion disturbs efficient auditory–motor synchronization and that the right IPL/SPL plays an important role in tapping in synchrony with moving sounds via auditory motion processing.     

Post injury changes in the properties of mesenchymal stem cells derived from human anterior cruciate ligaments

Purpose

The anterior cruciate ligament (ACL) rarely heals spontaneously after rupture. Mesenchymal stem cells (MSCs) contribute to healing in various tissues, therefore, they may also have a key role in healing after ACL rupture. The purpose of this study was to investigate the properties of MSCs in ruptured ACLs.

Methods

Human ACL samples were harvested from patients undergoing primary ACL reconstruction, and samples were classified by the number of days post rupture (phase I <21 days; phase II 21–56 days; phase III 57–139 days phase IV ≥140 days). We evaluated the characteristics of MSCs, such as colony-forming capacity, differentiation potential and cell-surface markers.

Results

There was a tendency for high colony-forming capacity during phases I and II, which tended to decrease in phase III. Chondrogenic, adipogenic and osteogenic differentiation potential was maintained until phase II but decreased in phase III. Most surface-epitope expression was consistent from phase I to III: positive for CD44, CD73, CD90 and CD105; negative for CD11b, CD19, CD34, CD45 and human leukocyte antigen-D-related (HLA-DR). The presence of these surface markers proved the existence of MSCs in ruptured ACL tissue.

Conclusions

Our results suggest that colony-forming and differentiation potential decrease over time. It is important to consider changes in properties of MSCs and use ACL tissue in the acute phase of rupture when biological manipulation is required.     

Clinical effectiveness of measurement of serum total human chorionic gonadotropin for diagnosis and management of testicular seminomatous germ cell tumor

Serum free-beta human chorionic gonadotropin (fbhCG) has been used for the diagnosis and management of testicular tumors for many years in Japan, while the measurement of serum hCG is widely used in the world. There have been reports of false-positive cases with serum fbhCG and due care must be taken in order not to take the wrong treatment strategy. Serum hCG is said to be more useful in the diagnosis and management of non-seminoma than serum fbhGC. Because of the false-positive issue with serum fbhCG, however, we consider it appropriate to use serum hCG for measurement even in seminoma. We simultaneously measured serum hCG and serum fbhCG in 25 cases of seminoma in order to evaluate the usefulness of hCG assay in the diagnosis and management of seminoma. In the measurements, we found 5 false-positive cases (20%) with serum fbhCG. The diagnostic sensitivity of the 20 cases with the exception of the 5 false-positive cases was 16 cases (80%) and 14 cases (70%) with serum hCG and serum fbhCG, respectively. We conclude that serum hCG is more reliable and is a useful assay in the diagnosis and management of seminoma, but serum fbhCG is not useful in the diagnosis and management of testicular tumor and its independent measurement should not be used to avoid misleading results.     

Totally laparoscopic colectomy with intracorporeal anastomosis achieved using a laparoscopic linear stapler: experience of a single institute

Purpose  

Laparoscopic colonic surgery is now widely accepted. We assessed the safety and effectiveness of using a total intracorporeal surgical strategy to perform intracorporeal functional end-to-end anastomosis with an endoscopic linear stapler to treat colon cancer.     

Evaluation of complications related to therapeutic colonoscopy using the bipolar snare

Background

The complications with therapeutic colonoscopy reported to date have been associated with the monopolar snare, and the frequency of complications related to use of the bipolar snare is uncertain. This study aimed too investigate the incidence of bleeding and perforation associated with the bipolar snare and to identify the risk factors for bleeding.

Methods

Between October 2001 and December 2008, all patients with colorectal polyps treated using the bipolar snare were enrolled in this retrospective study. Clinical data were assembled from an electronic database. The incidence of bleeding and perforation was investigated, and the risk factors for bleeding also were determined using multivariate analysis.

Results

This study collected 4,719 patients with 10,513 lesions. Perforation occurred for eight patients (0.17%) and bleeding in 66 patients (1.4%). Age younger than 60?years was a significant risk factor for bleeding (P?P?P?P?P?Conclusions The complication rates for the bipolar snare appear to be comparable with those for the monopolar snare based on comparison of the results reported in the literature. Age (<60?years), lesion size (??10?mm), macroscopic type (pedunculated), and lesion location (rectum) are independent risk factors for bleeding.     

Periductal infiltrating type of intrahepatic cholangiocarcinoma: a rare macroscopic type without any apparent mass

Purpose

This study was undertaken to elucidate the clinicopathological characteristics and surgical outcome of the periductal infiltrating (PI) type of intrahepatic cholangiocarcinoma (ICC), which is a distinct macroscopic type of ICC arising from the second-order of the intrahepatic bile ducts without apparent invasion of the surrounding liver parenchyma.

Methods

All patients with the PI type of ICC were identified from a database of patients with intrahepatic cholangiocellular carcinoma that underwent surgical resection between 1983 and 2009. The clinicopathological data of these patients were analyzed retrospectively.

Results

Sixteen of 203 patients (7.9%) had the PI type of ICC. The median survival was 7.7?years with 5-year survival rate of 62.1%. The PI type of ICC showed a significantly better survival than the mass-forming (MF) type (P?=?0.0293) or MF plus PI type of ICC (P?=?0.0001). Microscopic examinations showed intrahepatic metastasis to be absent in all the patients with PI type ICC. The incidence of intrahepatic metastases in patients with PI type was significantly lower in comparison to that of patients with MF type (P?=?0.0030) and MF plus PI type (P?=?0.0533), respectively.

Conclusion

Surgery could therefore provide a favorable outcome in patients with the PI type of ICC, probably due to its lower incidence of intrahepatic metastases.     

Simultaneous blockade of co-stimulatory signals, CD28 and ICOS, induced a stable tolerance in rat heart transplantation

An inducible co-stimulator (ICOS), a recently identified co-stimulatory receptor with a close structural homology of CD28 and CTLA4, is expressed on activated T cells. Anti-ICOS antibody was demonstrated to be effective on prolongation of graft survival after liver transplantation in rats. In this study, we investigated the potency of tolerance induction using the antibody combined with a recombinant adenovirus vector containing CTLA-4Ig cDNA (AdCTLA-4Ig) in rat heart transplantation model. Using a DA-to-Lewis rat heart transplantation model, an anti-rat ICOS antibody and AdCTLA-4Ig were simultaneously administered i.v. into recipients. The tissue specimens from the grafts were removed on various days after transplantation for histological evaluation. Donor-strain skin and heart grafts, and third-party heart allografts were challenged in the recipients with a long-term surviving graft. Splenocytes from the tolerance-induced recipients were used for adoptive transfer study. Anti-ICOS antibody alone did not prolong the survival of heart allograft. AdCTLA-4Ig monotherapy significantly prolonged the survival of heart allograft (Group 4). With a combination of Anti-ICOS antibody and AdCTLA-4Ig, all recipients were resulted in a long-term allograft acceptance for more than 200 days (Group 8). When challenged donor-strain skin grafts in the tolerant rats of Group 4, the skin was rejected, which also lead to a rejection of primary heart allografts. The recipients in Group 8 also rejected donor-strain skin grafts with no rejection of the primary heart grafts. These recipients accepted secondary heart grafts from donor-strain but not third-party. In Group 8 long-term survival recipients showed a high population of CD4+CD25+ regulatory T cell in peripheral blood, and in adoptive transfer study subtraction of these CD4+CD25+ T cells accelerate the rejection of heart graft in secondary irradiated recipients. The present results demonstrated that anti-ICOS antibody combined with AdCTLA-4Ig potently induces a stable immune tolerance after heart allografting in rat, which is mediated by the induction of CD4+CD25+ regulatory T cells. This strategy may be attractive for clinical employment to induce transplantation tolerance.     

Surgical repair of a common atrium in an adult.

We report a rare successful surgical repair of a common atrium (CA) with mild tricuspid valve (TV) regurgitation due to valvular annulus enlargement in a 39-year-old man, who had a complete atrial septum defect (ASD) without the characteristic of an endocardial cushion defect. The left-to-right shunt ratio was 85 percent and the Qp/Qs was 6.7 due to the CA. Left ventriculogram revealed no evidence of typical goose-neck deformity and no mitral valve regurgitation. The operation consisted of making a new atrial septum with an autologous pericardial patch and tricuspid annuloplasty (DeVega) using extracorporeal circulation. There was no evidence of a cleft on the anterior leaflet of the mitral valve or the septal leaflet of the TV. The postoperative echocardiogram showed no residual shunt flow through a new atrial septum and no TV regurgitation, and atrioventricular (AV) dissociation did not occur. We consider this procedure to be widely applicable in consideration of the favorable results obtained after surgical treatment.