Acute antibody-mediated rejection possibly due to anti-human leukocyte antigen DQB1 antibodies after renal transplantation - case report.

A 61-year-old Japanese woman, who had undergone hemodialysis because of chronic glomerulonephritis, received a living renal transplant from her ABO blood type-compatible spouse. HLA typing of A, B and DRB showed 3/6 mismatches. Complement-dependent cytotoxicity crossmatches, HLA antibody screening with the use of flow panel reactive antibody (PRA), and flow cytometry crossmatches (FCXM) were all negative. Tacrolimus, mycophenolate mofetil, methylprednisolone (MP), and basiliximab induction were used as the standard immunosuppressive therapy. After renal transplantation, her serum creatinine level favorably decreased, but urine output was not sufficiently obtained, contrary to our expectations. Doppler sonography revealed disappearance of diastolic arterial flow on postoperative day 2. The episode biopsy showed acute antibody-mediated rejection (AMR) based on the current Banff classification, although FCXM and flow PRA were still negative. To determine the cause of acute AMR, we expanded the HLA typing at high resolution levels to Cw, DQB1, and DPB1. Retrospective analysis of perioperative sera demonstrated the presence of low levels of donor-specific HLA IgG and moderate levels of IgM antibody against DQB1 before transplantation. There was an elevation of IgM antibody at the time of rejection, whereas IgG antibody showed no remarkable change. AMR was successfully treated with plasma exchange, low-dose intravenous immunoglobulin, high-dose intravenous MP pulse, and rituximab.

Strongly spin-orbit coupled two-dimensional electron gas emerging near the surface of polar semiconductors.

We investigate the two-dimensional highly spin-polarized electron accumulation layers commonly appearing near the surface of n-type polar semiconductors BiTeX (X=I, Br, and Cl) by angular-resolved photoemission spectroscopy. Because of the polarity and the strong spin-orbit interaction built in the bulk atomic configurations, the quantized conduction-band subbands show giant Rashba-type spin splitting. The characteristic 2D confinement effect is clearly observed also in the valence bands down to the binding energy of 4 eV. The X-dependent Rashba spin-orbit coupling is directly estimated from the observed spin-split subbands, which roughly scales with the inverse of the band-gap size in BiTeX.

Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy.

ABO-incompatible (ABOi) renal transplantation has been increasing, but malignant tumor is a troubling complication of kidney transplantation due to potent immunosuppression. Few previous studies, however, have demonstrated that potent immunosuppression for ABOi living-donor renal transplantation (LDRT) is a risk factor for malignancy. In the present research, data on 252 LDRT patients ftom 2003 to 2008 were retrospectively analyzed to clarify whether ABOi LDRT was associated with malignancy. A potent immunosuppressive regimen for ABOiLDRT consisted of splenectomy, cyclophosphamide, and double-filtration plasmapheresis to minimize the risk of antibody-mediated rejection, in addition to conventional immunosuppresssants including calcineurin inhibitor, prednisolone, and anti-CD25 monoclonal antibody. A total of 11 incidences of malignancy were observed during a median follow-up of 48 months. The incidence rates in ABO-compatible (ABOc; n = 189) and ABOi (n = 63) LDRT groups were 4.2 % (8/189) and 4.8 % (3/63), respectively. Kaplan-Meier survival analysis showed no statistical difference in event-free survival for malignancy between ABOc and ABOiLDRT groups (log-rank P = .73). Multivariable Cox regression analyses identified no associations of malignancy with ABOi LDRT or any immunosuppressant use. In conclusion, our investigation suggested that potent immunosuppression with splenectomy and cyclophosphamide for ABOi LDRT may not be a risk factor for malignancy.

Clinical characteristics and outcomes of renal transplantation in elderly recipients.

BACKGROUND: Elderly renal transplant candidates constitute one the fastest-growing populations among end-stage renal disease patients. Since the impacts of advanced recipient age have not yet been fully defined, we evaluated the clinical characteristics and outcomes of elderly renal transplant recipients. METHODS: Among 564 adult renal transplant recipients, at our center between 2000 and 2009, 64 were at least 60 years of age (Elderly group), and 500 were younger than 60 years (Young group) at the time of the procedure. We compared their clinical features and surgical management. RESULTS: There were significant differences in mean donor age (55.6 years vs. 53.2 years, P = .030) and gender mismatch (77.0% vs. 63.4%, P = .035). However, there were no significant differences between the two groups in patient and graft survivals (P = .177 and P = .365, respectively). Malignancy after transplantation was a significant risk factor upon univariate evaluation but only ABO incompatibility upon multivariate analysis of patient and graft survival. The main cause of graft loss among the Elderly group was death with a functioning graft due to heart failure. CONCLUSIONS: Renal transplantation is a feasible, safe option for the elderly and should be actively implemented. However, screening for cancer and heart disease should be mandatory to improve outcomes.

Tumour suppressive microRNA-874 regulates novel cancer networks in maxillary sinus squamous cell carcinoma.

BACKGROUND: On the basis of the microRNA (miRNA) expression signature of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-874 was significantly reduced in cancer cells. We focused on the functional significance of miR-874 in cancer cells and identification of miR-874-regulated novel cancer networks in MSSCC. METHODS: We used PCR-based methods to investigate the downregulated miRNAs in clinical specimens of MSSCC. Our signature analyses identified 23 miRNAs that were significantly reduced in cancer cells, such as miR-874, miR-133a, miR-375, miR-204, and miR-1. We focused on miR-874 as the most downregulated novel miRNA in our analysis. RESULTS: We found potential tumour suppressive functions such as inhibition of cancer cell proliferation and invasion. A molecular target search of miR-874 revealed that PPP1CA was directly regulated by miR-874. Overexpression of PPP1CA was observed in MSSCC clinical specimens. Silencing of the PPP1CA gene significantly inhibited cancer cell proliferation and invasion. CONCLUSION: The downregulation of miR-874 was a frequent event in MSSCC, which suggests that miR-874 functions as a tumour suppressive miRNA, directly regulating PPP1CA that has a potential role of an oncogene. The identification of novel miR-874-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.

[Delayed traumatic diaphragmatic hernia with strangulated stomach; report of a case].

A 30-year-old male who had suffered from the left hemopneumothorax due to the traffic accident 13 years before was admitted to our hospital suffering from abdominal pain. Computed tomography revealed the stomach was incarcerated through the left central tendon of the left diaphragm. He was diagnosed as delayed traumatic diaphragmatic hernia and emergency operation was performed via thoracic approach. Stomach and omentum, densely adhered to the lung and the chest wall, were strangulated in the left pleural cavity and hardly reducible. Stomach and omentum were reduced through the enlarged hernia and necrotized stomach was totally resected under the subsequent laparotomy. Hernia was closed directly via thoracic approach. A prompt diagnosis is necessary for a case highly suspicious of delayed traumatic diaphragmatic hernias presenting with strangulation.

Changes in coagulation condition, cytokine, adhesion molecule after repair of type A aortic dissection.

OBJECTIVE: Because residual dissection often exists even after the repair of a type A dissection, we evaluated coagulation conditions, cytokine levels, and adhesion molecule levels in mid-term follow up after repair of type A dissections. METHODS: Thrombin-antithrombin III complex (TAT), D-dimer, soluble interleukin-2 receptor (sIL-2R), soluble intercellular adhesion molecule (sICAM)-1, and type III procollagen peptide (PIIIP) were measured in 12 patients (mean age=63 years) following the repair of a type A aortic dissection at 6-82 months after repair (median=33 months). RESULTS: In the chronic phase, TAT and D-dimer were significantly higher in patients following the repair of a type A dissection compared to healthy controls (TAT; 12+/-8 vs. 2.5+/-1.2 ng/ml, P = 0.0001, D-dimer; 779+/-1384 vs. 104+/-46 U/ml, P = 0.0001). Cytokine was significantly higher in the affected patients (sIL-2R; 556+/-205 vs. 398+/-132 U/ml, P = 0.003, sICAM-1; 255+/-131 vs. 211+/-48 ng/ml, P = 0.136). Collagen turnover (PIIIP) showed a significantly higher value in the affected patients (0.80+/-0.32, vs. 0.58+/-0.13 U/ml, P = 0.002). sIL-2R, sICAM-1 and PIIIP showed a negative correlation with the follow-up period (sIL-2R; r = -0.733, P = 0.0067, sICAM-1; r = -0.61, P = 0.035, PIIIP; r = -0.692, P = 0.0126). We found a positive correlation between aortic size and TAT (r = 0.644, P = 0.0238, n = 12) as well as with D-dimer (r = -0.7831, P = 0.0106, n = 12) and TAT showed significantly higher values in the residual dissection group compared to those without residual dissection (16.6+/-7.9 vs. 7.45+/-4.75 ng/ml, P = 0.035). CONCLUSION: Hypercoagulation conditions continued even after repair. Both TAT and D-dimer would be good indices for following up patients having repaired aortic dissections. Furthermore, cytokine, adhesion molecules, and collagen turnover would return to a stable state unless impairment and expansion of the vessel wall occurred.

Clinical success of Neoral absorption profile.

We investigated the clinical benefits of cyclosporine microemulsion preconcentrate (CyA-MEPC; Neoral) in 16 de novo renal transplant recipients. The dose of CyA-MEPC was managed from AUC(0-4h), with serial target values of AUC(0-4h) at 5000-->4000-->3000-->2000 ng. hr/mL. The frequency of acute rejection episodes was 25%. The decreased renal function reached a low value of 12.5%, and creatinine was stable. Therefore, setting the target AUC(0-4h) value in the early phase at 5000 ng.hr/mL is an effective strategy to prevent acute rejection episodes. The single dose of Neoral given immediately after the renal transplant was 6 mg/kg (making a daily dose of 12 mg/kg). Thereafter, the dose-normalized AUC(0-4h) was set at a constant value to 4 weeks posttransplant. At week 4, the single dose was decreased to 4 mg/kg twice daily (a daily dose of 8 mg/kg). From these studies a daily dose of 12 mg/kg is suggested to be the appropriate amount for the first dose immediately after transplant. The renal biopsy performed at 6 months posttransplant showed neither cyclosporine-induced renal impairments, nor findings of chronic rejection, suggesting that 2000 ng.hr/mL is an appropriate target AUC(0-4h) value in the maintenance phase. These results suggest that it is possible to set the target value of C2 monitoring in the maintenance phase to a value slightly lower than that proposed from other studies.

More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism.

Between March 1981 and December 2000, we performed 1,053 total parathyroidectomies with forearm autograft for advanced renal hyperparathyroidism (HPT). Based on histopathologic and pathophysiologic investigations, surgical treatment should be considered when parathyroid glands show nodular hyperplasia. Measuring parathyroid volume by ultrasonography was useful to detect nodular glands and to determine surgical indications. The clinical effect of parathyroidectomy on the symptoms and biochemical variables was striking. Skeletal deformity, progressive bone loss, and vessel calcification leading to high mortality risk could not be alleviated by even successful surgery, however. To prevent cardiovascular complications, parathyroidectomy should be performed in the relatively early stage of renal HPT. Total parathyroidectomy with forearm autograft is a suitable procedure for renal HPT, especially in patients who require long-term hemodialysis. For surgeons, it is important to remove all parathyroid glands, including supernumerary glands, at the initial operation and to choose adequate parathyroid tissue for the autograft to prevent persistent and recurrent HPT. Although the risk of graft-dependent recurrent HPT is not negligible, enlarged transplanted parathyroid tissue can be removed easily and noninvasively from the forearm under local anesthesia. There is no risk of hypofunction of the autograft.

Osteoprotegerin levels before and after renal transplantation.

Osteoprotegerin (OPG) is a newly identified glycoprotein that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. The regulatory mechanism of OPG is still unclear after successful renal transplantation (RTX), however, resulting in resolution of uremia. The present study was designed to clarify the potential role of OPG in uremia and after RTX under immunosuppressive therapy. We evaluated circulating OPG levels by measuring them before and after RTX (postoperative days 2, 14, and 28). Our protocol of immunosuppressive drugs was dual therapy using cyclosporine and steroids. Serum OPG was quantitated using enzyme-linked immunosorbent assay. After successful RTX, serum OPG levels decreased significantly on day 14 and day 28 compared with the baseline level (P < 0.05). Creatinine clearance dramatically increased until day 14 and decreased thereafter. Serum OPG declines for the first 2 weeks after RTX owing to functioning allograft and decreases again for the next 2 weeks because of steroids and possible immunosuppressive agents.

Comparative analysis of host responses related to immunosuppression between measles patients and vaccine recipients with live attenuated measles vaccines.

Measles virus infection induces a profound immunosuppression. We analyzed in a time-dependent manner peripheral bloods of one to two-year-old children immunized with live attenuated measles vaccines, compared with age-matched measles patients, for immunosuppression. In contrast to transient severe lymphopenia with measles patients, primarily due to extensive apoptosis of a broad spectrum of uninfected lymphocytes, neither apoptosis nor lymphopenia occurred with measles vaccine recipients. Increase in number and activation of NK cells, which might compensate for the lymphopenia in measles patients, were not found with the vaccinees. While cell surface expression of apoptosis-related molecules such as TNF-related apoptosis-inducing ligand (TRAIL), TRAIL-receptors, CD95(Fas) and Fas-ligand, and plasma interferon-gamma were increased for measles patients, they remained unchanged after vaccination. Plasma interleukin (IL)-18, which is responsible for inducing apoptosis in several infectious diseases, was increased predominantly with measles patients, whereas the increase remained marginal with the vaccinees. IL-10 was elevated transiently in both measles patients and vaccinees. Decrease in plasma IL-12, which is often correlated with T cell suppression, was not found for both cases. Serum IgM and IgG antibodies to measles virus were induced at lower titers in the vaccinees than measles patients. These results indicate that in contrast to wild-type measles virus, live measles vaccines hardly provoked host cytokine responses that lead to apoptotic cytolysis of uninfected lymphocytes, lymphopenia and immunosuppression, and thereby induced weaker immune responses to the virus.

Chronic cyclosporin nephropathy: long-term effects of cyclosporin on renal allografts.

Cyclosporin (CSA) has significantly reduced both incidence and severity of acute rejection, and brought excellent graft survival rates. Chronic CSA nephrotoxicity seems to be the second most important diagnosis responsible for the late graft failure. CSA-associated arteriolopathy (CAA) is well known as a characteristic lesion of chronic CSA nephrotoxicity by graft biopsies. There are few reports on the long-term outcome of renal transplant patients with biopsy-proven chronic CSA nephrotoxicity after diagnosis of CAA. We conducted two studies, the long-term outcome of the patients with CAA, and the FGS lesion related to CAA. Seventy-four CAA patients continued on CSA therapy after diagnosis of CAA were classified into two groups by outcome of the graft after follow-up: the functioning graft group (n = 30) and the graft-loss group (n = 44). There was no significant difference in severity of CAA grade between the functioning and graft-loss groups. Concomitant lesion of chronic rejection but not severity of CAA was the most important risk factor of graft loss for CAA patients in our study. Of a total of 54 recipients with FGS lesion, 32 patients (59%) were diagnosed as CAA-associated glomerulopathy (CAG) accompanied with severe CAA. Eighteen of 32 CAG patients lost their grafts after follow-up. Their serum creatinine level at biopsy was higher than that of the functioning group; however, there was no significant difference in daily proteinuria at biopsy between two groups. We have tried to reduce CSA dosage to maintain lower blood levels than the usual optimal target levels, but did not discontinue CSA after diagnosis of severe CAA and FGS lesion. In 15 isolated pure CAG patients, those with increasing daily proteinuria exceeding 2 g lost their graft function even after reducing CSA administration. The change in daily proteinuria seems to be a useful indicator for late graft loss in the patients of FGS lesion with severe CAA. CAA is not specific for chronic CSA nephrotoxicity, and FGS lesion is also a non-specific lesion often developed in renal allografts. Our study revealed clinicopathological characteristics of chronic CSA nephrotoxicity. Isolated chronic CSA arteriolopathy of severe degree has a fairly good prognosis under controlled CSA therapy. FGS lesion accompanied by CAA is considered as a new concept of CAG, and increasing proteinuria in patients with CAG is a good indicator for poor outcome. These results will contribute towards an appropriate therapeutic plan for renal transplant patients undergoing long-term CSA treatment.

Does infiltration of neutrophils in peritubular capillaries indicate humoral rejection? A case displaying a characteristic lesion of a significantly high amount of neutrophils in peritubular capillaries at 1-h graft biopsy during transplant operation.

We present a case report of a 50-yr-old Japanese woman with a significant accumulation of neutrophils in the peritubular capillaries (PTC) and severe acute tubular necrosis (ATN) at 1-h allograft biopsy during transplant operation from cadaver donor after a cardiac death. Significant accumulation of neutrophils in the PTC is usually valuable diagnostically for acute humoral rejection. However, the patient showed no clinical signs of acute rejection. A second graft biopsy performed on the fifth postoperative day (POD) revealed that both infiltration of neutrophils in PTC and ATN lesions were more aggravated. Neither clinical course nor other morphological findings were compatible with humoral rejection. After the third biopsy of POD 27 revealing acute vascular rejection of moderate degree, acute rejection therapy using methylprednisolone pulse therapy and OKT-3 therapy was performed. Consequently, after a period of delayed graft function requiring haemodialysis for approximately 4 wk, graft function was restored and serum creatinine decreased to 2 mg/dL. Later, we were able obtain information from a paired graft from the same donor. Significant accumulation of neutrophils in the PTC similar to our recipient was also noted in a 1-h biopsy specimen of the paired kidney. This confirmed that the accumulation of neutrophils in the PTC noted in two recipients was transmitted from the donor kidney. The pathogenesis and clinical significance of neutrophils in the PTC has been shrouded in mystery.

Adrenalectomy for solitary adrenal metastasis from colorectal carcinoma.

A 60-year-old man underwent anterior resection for advanced rectal carcinoma. Seven years and 2 months later, right lower pneumonectomy was performed for a metastatic lung tumor. Two years and 2 months thereafter, left adrenalectomy was performed for solitary adrenal metastasis. The patient remained disease-free for 10 months postoperatively, until multiple lung metastases appeared. The patient is alive and well, under mild chemotherapy with oral doxifluridine, 3 years and 5 months after left adrenalectomy. We conclude that patients with solitary adrenal metastasis may benefit from surgical resection and that resection could be considered as a therapy for solitary adrenal metastasis from colorectal carcinoma.

Serum progesterone and estradiol-17beta concentrations in captive and free-ranging adult female japanese black bears (Ursus thibetanus japonicus).

Progesterone (P4) and estradiol-17beta (E2) concentrations were measured in serum samples obtained from 23 captive and 23 free-ranging adult female Japanese black bears. We then determined the relationship between changes in these sex steroid hormones and pregnancy. In all captive bears, which included animals of both known and unknown reproductive status, serum P4 concentrations were low from April to July, then tended to become higher after August. The levels then became much higher still in November and December, but returned to low levels in March. Serum P4 concentrations in eight captive pregnant bears, which had parturitions the following spring, increased gradually from August (0.5-2.4 ng/ml) to October (0.9-3.6 ng/ml), and achieved significantly higher maximum levels in December (7.2-18.0 ng/ml). Thereafter, serum P4 concentrations tended to decrease (3.5-6.4 ng/ml in January and 0.3-0.7 ng/ml in March). In all captive bears, serum E2 concentrations varied from April to October but showed low levels in November and December, and became high in January. Serum E2 concentrations in the eight pregnant bears were high in May (95.6-191.4 pg/ml) and varied from August to October (35.6-143.3 pg/ml). Subsequently, serum E2 concentrations in December dropped to significantly lower minimum levels (5.3-11.9 pg/ml) and increased again in January (67.6-153.1 pg/ml). Among the free-ranging bears, the data on serum P4 concentrations in eight bears led to expectations of pregnancy, whereas serum E2 concentrations showed no distinct evidence related to pregnancy. These results, particularly in captive pregnant bears, indicate that a marked increase of P4 in December might be accompanied by reactivation of the corpus luteum preceding implantation. Furthermore, changes in E2 concentrations suggested the possibility that a decline in December and an increase in January are associated with implantation and parturition, respectively.

Non-polypoid colorectal neoplasias: a multicentric study.

A total of 781 non-polypoid colorectal neoplasias harvested at 4 main Hospitals in Tokyo, Japan (n = 420) and at 4 different time-intervals at the Karolinska Hospital, Stockholm, Sweden (n = 361) were reviewed. By applying strict histologic definitions, the lesions were classified into adenomas with low grade dysplasia (LGD), with high grade dysplasia (HGD), intramucosal carcinomas (IMC) or submucosal carcinomas (SMC). Of the non-polypoid neoplastic lesions reviewed in Sweden, 82.8% (n = 299) had LGD. In Japanese patients only 42.6% (n = 179) had LGD (p < or = 0.001). On the other hand, as many as 42.4% (n = 178) of the non-polypoid lesions in Japanese patients had HGD, but only 14.1% (n = 51) of those in Swedish patients (p < or = 0.001). Whereas 15.0% (n = 63) of the non-polypoid neoplasias seen in Japan were IMC or SMC, only 3.0% (n = 11) of those seen in Sweden were IMC or SMC (p < or = 0.001). The cause(s) for these differences remains unclear. In Japan, however, a marked increased incidence of colonic cancer has been recorded in later years. Whether the "catching up phenomenon" by the Japanese with western colonic cancer incidence includes increased histologic aggressiveness of non-polypoid neoplastic polyps--as found in this survey--remains to be elucidated.