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This study explores how changes in sibship composition associated with fertility decline may, in conjunction with entrenched family norms and expectations associated with specific sibship positions, impact marriage rates and further reduce fertility. We evaluate this possibility by focusing on Japan, a society characterized by half a century of below-replacement fertility and widely shared family norms that associate eldest (male) children with specific family obligations. Harmonic mean models allow us to quantify the contribution of changes in both marriage market composition with respect to sibship position and sibship-specific pairing propensities to the observed decline in marriage rates between 1980 and 2010. One important finding is that marriage propensities are lower for those pairings involving men and women whose sibship position signals a higher potential of caregiving obligations, especially only-children. Another is that changes in marriage propensities, rather than changing sibship composition, explain most of the observed decline in marriage rates. We also found that marriage propensity changes mitigate the impact of the changing sibship composition to some extent. However, the limited contribution of changing sibship composition to the decline in first-marriage rates provides little support for a self-reinforcing fertility decline via the relationship between changing sibship composition and marriage behavior., (Copyright © 2023 The Authors.)

Research on educational assortative mating has devoted much attention to educational expansion but has been less focused on a concurrent trend of importance: growing differentiation among higher education institutions. In this study, I examine whether the bifurcation between high- and low-tier institutions in the context of high participation in tertiary education may clarify the mixed evidence on educational homogamy trends across countries. I apply log-linear and log-multiplicative models to analyze trends in educational assortative mating in Japan, which is characterized by a clear, widely acknowledged hierarchy of institutional selectivity. I find that the odds of homogamy are higher among graduates of selective universities than among graduates of nonselective universities. Further, assortative mating trends among graduates of selective and nonselective universities have diverged in recent years. This latter finding perhaps reflects that with the more rapid increase in the share of female students enrolled in less selective institutions, their opportunities to "marry up" have decreased. Results point to the importance of the growing heterogeneity of institutional characteristics, which was obscured in earlier studies, for understanding the impact of educational assortative mating on economic inequality., (Copyright © 2022 The Author.)

There is much evidence to suggest that family background and the context of secondary education both contribute to the formation of educational inequalities. Meanwhile, our knowledge about the role of ability in generating class differences in educational outcomes is still limited. By deploying genetic data that allow us to measure at least part of "innate" ability inherited through biological mechanisms from parents, this study examines how such abilities are associated with educational tracking outcomes among U.S. high schoolers. This study also details our understanding of the role of nature and nurture in the educational attainment processes by testing for gene-environment interactions-that is, a joint, mutually moderating effect of one's genetic potential and one's environment (e.g., family background or school context) on phenotypic outcomes (educational tracking). Using the National Longitudinal Study of Adolescent to Adult Health that collects a unique set of demographic, educational, and genetic characteristics of students, we report the following results: First, a positive association between the genetic potential for educational attainment and taking advanced courses holds even after controlling for previous course tracking measures. Second, results provide suggestive evidence that parental SES amplifies the association between one's genetic potential for educational attainment and mathematics tracking. In contrast to the argument by some stratification scholars that places primary emphasis on the role of social background for the reproduction of educational stratification, the present findings imply that we need to fully consider the role of genetic inheritance for educational stratification in addition to social origin.

Background: Understanding the trend toward later and less marriage is particularly important in low-fertility societies where alternatives to marriage are limited and childbearing outside of marriage remains rare., Objective: Our goal in this paper is to advance our understanding of the wide variety of explanations offered for later and less marriage in Japan by focusing explicitly on marriage intentions and desires., Methods: Using two sources of nationally representative data, we describe the prevalence of positive, negative, and passive marriage intentions and desires among men and women who have never been married. We also examine socioeconomic differences in intentions, patterns of marriage desires across young adulthood, and relationships between marriage desires and outcomes. By linking three pathways to later and less marriage (rejection of marriage, failure to realize marriage desires, and unplanned drifting into singlehood) to specific theoretical frameworks, we generate indirect insights into explanations for later and less marriage., Conclusions: Although the large majority of unmarried men and women want to marry, less than half of respondents married across nine waves of the Japanese Life Course Panel Survey. Among those who remained unmarried, roughly two-thirds can be classified as 'drifting' into singlehood, about 30% as 'failing to realize marriage desires,' and no more than 5% as 'rejecting marriage.', Contribution: By extending the small body of research on marriage intentions and desires, this study provides a framework for thinking broadly about explanations for later and less marriage in Japan and highlights the importance of both failure to realize marriage desires and unplanned drifting into singlehood.

This paper investigates the patterns and trends of educational assortative marriage in Japan. Using data from the Employment Status Survey and the Comprehensive Survey of Living Conditions of the People on Health and Welfare, we investigated the trends of association between husbands' and wives' educational attainment (481,144 couples) by applying log-linear, log-multiplicative layer effects, and regression-type models. The analysis revealed that, in general, educational assortative marriage has decreased continuously. In terms of the log-odds ratios, the association of educational attainment between spouses for women born between 1975 and 1979 decreased by about 25%, in comparison with that of women born between 1950 and 1954. The regressiontype models showed that the pattern of association was asymmetric while patterns of change were symmetric with respect to sex. We discuss what caused the decline in educational assortative marriage with a persistent gender asymmetric structure.

This study reports the treatment and local control of advanced breast cancer with a giant ulcer. A 53-year-old woman presented with a large left breast tumor and an associated giant ulcer, with massive exudates, bleeding, and an offensive odor. Histopathological examination revealed an invasive ductal carcinoma(Luminal B type). Computed tomography(CT) showed multiple metastases to the lymph nodes, lungs, liver and bones. The patient received chemotherapy with a combina- tion of paclitaxel(PTX 90mg/m / 2)and bevacizumab(BEV 10 mg/kg). After 4 courses of chemotherapy, there was a significant reduction in the tumor size, the discharge of exudates and bleeding as well as lumbago and femoral pain. High CEA and CA15-3 levels had been normalized and CT showed a remarkable decrease in metastases. Compared to the tumor itself, the ulcer associated with it had shown a smaller decrease in size, and there was the possibility of perforation in the thin chest wall. Suspecting these outcomes to the adverse events of BEV, its use was discontinued, and starting with course 5 of chemothera- py, we administrated only PTX(90mg/m2). Subsequently, the ulcer showed obvious granulation and was infected. CT of the chest prior to the second course of PTX revealed pleurisy, pneumonia and atelectasis. Following the administration of antibiotics, while infection in the ulcer had subsided, pleurisy and pneumonia continued, with increased right pleural effusion, which finally required drainage. We had to discontinue the administration of PTX. BEV, although effective as first-line therapy, has the adverse effect of slowing wound healing. Therefore, even though the combination therapy of BEV and PTX is markedly effective for systemic therapy, it should be altered for local wound healing as in this case.

A 58-year-old man who complained of an abdominal tumor was admitted to our hospital. Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomen and that there were ascites and liver metastases. A liver biopsy was performed. The liver biopsy showed a small cell carcinoma pattern, but no definitive origin of the tumor was determined. Considering the extensive peritoneal invasion and multiple liver metastases, he received 2 / courses of cisplatin/etoposide chemotherapy, but his tumor became larger with concomitant abdominal pain and nausea. The patient suddenly died due to multiple organ failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis of primary small cell carcinoma of the pancreas.

The patient was a 72-year-old male diagnosed with type III poorly-differentiated adenocarcinoma in the lesser curvature by gastric fiberscopy. An abdominal computed tomography (CT) scan showed the thickness of the gastric wall and the enlarged lymph node around the stomach and laparoscopic examination revealed peritoneal dissemination. The patient received neoadjuvant combined chemotherapy with S-1 and CDDP. S-1 (100 mg/day) was orally administered for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (100 mg/body) was administered by intravenous drip on day 8. After the third course, significant tumor reduction was obtained. Total gastrectomy, splenectomy and D2 nodal dissection were performed. Peritoneal dissemination disappeared, and the histological diagnosis revealed complete disappearance of cancer cells in the ascites and no metastasis in all lymph nodes. The patient has now been in good health with no recurrence for 22 months after surgery. The combined neoadjuvant chemotherapy with S-1 and CDDP can be an effective treatment of choice for advanced gastric carcinoma with peritoneal dissemination.

We report a case of liposarcoma of the spermatic cord associated with rectum cancer. A 78-year-old man visited our hospital with a complaint of painless left inguinal mass. He also showed constipation and bloody bowel discharge, rectum cancer was diagnosed by further evaluation. Ultrasonography, computed tomography and magnetic resonance imaging revealed a 2 x 4 x 6 cm mass in the left spermatic cord. Left high orchiectomy for the left inguinal tumor and Hartmann's procedure for rectum cancer was performed. Histologically, the mass in the left spermatic cord was well differentiated liposarcoma and rectum cancer was poorly differentiated adenocarcinoma. He died from rectum cancer with no evidence of recurrence of liposarcoma of the left spermatic cord after follow up for 6 months.

A 72-year-old male with advanced gastric cancer (cT3N2M0H0P0CY1, cStage IV) was treated with TS-1/CDDP as neoadjuvant chemotherapy. TS-1 (60 mg/m(2)/day) was orally administered for 3 weeks followed by 2 drug free weeks as a course, and CDDP (60 mg/m(2)) was administered by intravenous drip on day 8. After the fourth course,a significant tumor reduction was obtained. Total gastrectomy, splenectomy, and D 2 type nodal dissection were performed. The histological diagnosis revealed complete disappearance of cancer cells in the stomach and all of the lymph nodes, which is a so-called pathological complete response. The patient has now been in good health without a recurrence for 24 months after surgery. This case suggests that neoadjuvant chemotherapy with TS-1/CDDP is a potential regimen for advanced gastric cancer.

Pancreas transplantation (PTx) is the only therapy that can cure type 1 diabetes mellitus. With the recent advance of surgical procedures and immunosuppression, the outcome of PTx has become better than it used to be before, but some problems still remain. It is rather difficult to induce tolerance and to reverse rejection once it occurred because pancreas graft itself has a strong immunogenicity. Another important issue is regarding the recurrence of autoimmune disease in the pancreatic graft, therefore, some animal models are necessary to delineate and regulate those immune responses specific for PTx. Recently, PTx is also clinically applicable for type 2 diabetic patients with end-stage renal disease. It has been shown that insulin resistance was improved by PTx in type 2 diabetic recipients. In the current study, we have introduced some useful type 1 and type 2 diabetic models mainly based on our experimental experiences., (Copyright (c) 2007 Wiley-Liss, Inc. Microsurgery 2007.)

We report a 72-year-old man who was diagnosed by gastroscopy as having a type III poorly differentiated adenocarcinoma in the lesser curvature, with the longest diameter being 10 cm. An abdominal computed tomography (CT) scan revealed multiple liver metastases, thickening of the gastric wall, and an enlarged paraaortic lymph node. The serum carcinoembryonic antigen (CEA) level was 60 ng/ml and the carbohydrate antigen (CA) 19-9 level was 1355 U/ml. The patient received combined chemotherapy with doxifluridine (800 mg/body per day) and paclitaxel (one course comprised three weekly infusions at a dose of 70 mg/m(2) followed by 1-week rest). After the completion of three courses, the patient achieved a complete response (CR), with complete disappearance of the primary tumor, the metastatic foci in the liver, and the enlarged abdominal lymph nodes; as well, the tumor markers were normalized. Adverse effects included only mild anorexia that was limited to grade 1. He maintained a CR for 1 year and 2 months. Combination chemotherapy with paclitaxel and doxifluridine can be an effective treatment for unresectable advanced gastric carcinoma.

We conducted combined therapy of weekly paclitaxel and doxifluridine (5'-DFUR) for 23 cases of advanced and recurrent gastric carcinomas to investigate their efficacy and safety. Subjects included 7 unresectable cases, 5 noncurative resection cases, and 11 recurrent cases. Twenty of the 23 subjects had a history of prior treatment with another anticancer drug. The treatment regime consisted of one course comprising 70 mg/m(2)of paclitaxel weekly for three consecutive weeks followed by one week rest, combined with 800 mg/day of 5'-DFUR orally. Results revealed a response rate of 17.6% (3/17), with 2 cases of CR, 1 case of PR, 10 cases of NC, and 4 cases of PD. One of the CR cases was an unresectable case involving a primary tumor, liver metastasis, and abdominal lymph node metastasis, while the other was a recurrent case involving abdominal lymph node metastasis. The median survival period was 387 days. The one-and two-year survival rates were 52% and 24%, respectively. In terms of adverse effects, there were only single cases of grade 3 leukopenia and grade 3 neutropenia, with no cases of grade 4 hemotoxicity. Both patients could be treated as outpatients. Combination therapy of weekly paclitaxel and 5'-DFUR can be an effective and safe therapy for advanced and recurrent gastric carcinomas.

Background: Transanal intersphincteric resection (ISR) was introduced and has been increasingly performed as an ultimate surgical treatment for extremely low rectal cancer. We considered that high quality and less invasive surgery could be achieved if ISR and laparoscopic surgery were combined., Methods: Between December 2003 and June 2004, we performed laparoscope-assisted ISR for two patients with very low rectal cancer and total colectomy for two patients with ulcerative colitis complicated by colorectal cancer. In all patients, the transanal procedure was preceded by trans-abdominal laparoscopic rectal excision., Results: Preceding transanal dissection facilitated muscle layer-oriented curative dissection, and more importantly, made subsequent laparoscopic rectal excision effortless as a result of penetrating to the dissected pelvic cavity. All patients showed favorable recovery including postoperative anal function with no complication or recurrent disease., Conclusions: This procedure is feasible and has favorable short-term results for radical treatment of very low rectal disease, while preserving anal function.

Background: The mechanism involved in the spontaneous acceptance of liver allografts in some rat strain combinations remains unclear. Immunoregulatory NKR-P1TCRalphabetaT (NKT) cells primarily produce IL-4 and IFN-gamma, and enhance the polarization of immune responses to Th2 and Th1, respectively. The aim of this study was to clarify the role of graft-derived NKT cells in inducing the spontaneous acceptance of rat orthotopic liver transplantation (OLTx), Methods: The experimental groups were divided as follows: Group 1, BN to LEW "low responder (acceptor)" combination; Group 2, DA to LEW "high responder (rejector)" combination; naïve BN (Group 3) or LEW recipients (Group 4) with liver allografts from irradiated BN donors. The recipients had liver allografts from irradiated donors reconstituted from the following cell populations 24 hr before harvesting, spleen cells (SPCs, Group 5), IgSPCs (Group 6), IgNKR-P1SPCs (Group 7), and IgTCRabSPCs (Group 8), Results: In Group 1, the percent of graft-derived NKT cells harvested on day 7 posttransplant were significantly higher than in Group 2. In the case of BN liver allografts that had been irradiated and reconstituted with cell populations including NKT cells (Groups 5 and 6), the mean graft survival (MST) was extended to 39.2+/-5.7 and 38.8+/-8.0 days, respectively. In contrast, when NKT cells were excluded (Groups 7 and 8), the grafts were acutely rejected within MST of 17.8+/-4.0 and 18.8+/-7.7 days, respectively. The concentrations of IL-10 and TGF-beta, but not IL-4 in IgGICs culture supernatants were predominant in the acceptor, whereas those with IFN-gamma predominated in the rejector., Conclusions: Graft-derived NKT cells might be responsible for spontaneous acceptance in the rat OLTx.

The principal barrier to the use of pigs as donors to humans is hyperacute rejection mediated by the interaction of alpha-gal abundantly expressed on pig cells and the natural anti-Gal antibody, abundantly produced in humans. This antibody-mediated hyperacute rejection may be overcome by an alpha1, 3 galactosyltransferase gene-knockout pig. However, xenograft cells could be rejected by T cells, especially CD8+ cytotoxic T lymphocytes (CTL)-mediated response, because these elements show great cytotoxicity against xenografted cells. We previously demonstrated that the Fas/FasL pathway is a major contributor to CD8+ CTL function. Furthermore, we sought to prevent this cytotoxicity by overexpression of membrane-bound FasL carrying the deletion at the metalloproteinase cleavage site or by decoy Fas antigen that does not contain the death domain in its cytoplasmic region. To investigate the effects of coexpression of these molecules, we cotransfected both genes into swine endothelial cells (SEC). The double-overexpression effectively prevented CD8+ CTL-mediated killing. Although cotransfectants and single transfectants of either membrane-bound FasL or decoy Fas gene showed similar inhibition of cytotoxicity, the expression levels of decoy Fas in SEC cotransfectants were much lower than those of decoy Fas single transfectants. These data suggest that beneficial effects for prevention of CTL-mediated xenocytotoxicity may be produced by the double expression of these molecules. The overexpression of both molecules on xenografted cells may decrease the innate cellular response to xenografts creating a window of opportunity to facilitate xenograft survival.

Pancreas transplantation (PTx) has evolved as a clinical therapy to achieve sustained euglycemia. However, it remains unclear if naive diseased islets of the pancreas benefit from the avoidance of glucose toxicity by PTx. In the present study, using an animal model of type 2 diabetes, the Spontaneously Diabetic Torii (SDT; RT1a) rat, we syngeneically transplanted nondiabetic 10-week-old pancreaticduodenal grafts into diabetic 25-week-old recipients. In the control SDT rats that received no treatment, hyperglycemia developed with a mean onset time of 25 +/- 3.9 weeks of age. Few normal islet cells were found from 25 weeks and none at 40 weeks. However, in the PTx rats, the onset age (graft age) of diabetes was significantly prolonged (47 +/- 18.2 weeks). Moreover, we found that the beta-cell mass was significantly increased in the naive pancreases of 40-week-old PTx recipients (PTx40-naive). Interestingly, islet-like cell clusters of varying size were found close to ductal structures of PTx40-naive pancreases, suggesting that these cells are derived from ductal cells. Furthermore, pancreatic and duodenal homeobox factor-1 (PDX-1) was more clearly expressed in the nuclei of PTx40-naive pancreatic islet-like cell clusters. Our results demonstrate the development of duct-derived beta cells in the pancreas of type 2 diabetic recipients after PTx.

A simple surgical technique that facilitates circular-stapled Billroth I gastroduodenostomy in laparoscopic distal gastrectomy is described. After standard laparoscopic mobilization of the distal stomach, a small duodenotomy is made just distal to the pyloric ring. The anvil of a circular-stapling device, secured with a Vicryl suture, is introduced via the duodenotomy. The Vicryl suture is advanced anteriorly so that a center rod penetrates the anterior duodenal wall. The duodenum is staple-transected at this point, and the center rod is wrapped with the stapled duodenal stump by approximation of both edges using a suturing device. The circular-stapled gastroduodenostomy then is completed in a standard fashion. The authors have used this technique for three patients, and their early outcomes are promising.

Aims: Type 2 diabetes is characterized by a combination of insulin resistance and pancreatic beta-cell dysfunction. Although pancreas transplantation (PTx) is mainly performed in patients with type 1 disease, both clinical and experimental data have demonstrated that PTx improves insulin sensitivity in type 2 diabetic recipients. However, it remains unclear whether PTx has the potential to induce islet neogenesis in a recipient's native pancreas., Methods: Nondiabetic 10-week-old and diabetic (defined as blood glucose level >250 mg/dL) 25-week-old (average onset age of diabetes) male spontaneously diabetic Torii (SDT; RT1(a)) rats served as donors and recipients, respectively., Results: In nontreated control SDT rats, beta-cell mass gradually decreased and blood glucose levels progressively increased (>600 mg/dL after 40 weeks of age). In PTx rats, however, the onset of diabetes was significantly delayed (>47.5 +/- 18.2 [graft age] versus 25.2 +/- 3.9 weeks in control rats). On immunohistochemical staining, insulin-secreting islets were observed in the naive pancreata of 40-week-old recipients with PTx (PTx40w), whereas no islets were found in 40-week-old control SDT rats. Moreover, the islets in the native pancreata of PTx40w recipients were located close to ductal structures, and PDX-1 (pancreatic duodenal homeobox-1)-positive cells were more clearly visible. These results indicate the possibility of beta-cell regeneration in the recipient native pancreas by avoiding glucose toxicity under normoglycemic condition achieved by PTx., Conclusions: Pancreas transplantation has beneficial effects on impaired islet, inducing regeneration in the spontaneously diabetic Torii rat.

Although the birth of homozygous alpha1, 3 galactosyltransferase gene-knockout pigs raised hopes for an imminent breakthrough in the prevention in the antibody-mediated rejection of pig to human discordant xenotransplants, human CD8(+) cytotoxic T lymphocyte (CTL)-mediated killing may represent a new immunological barrier to long-term survival in xenograft recipients. In this study, we demonstrated that the cytotoxicity of human CD8(+) CTL against swine endothelial cells (SEC) is highly detrimental and mediated at least in part by the Fas/FasL pathway. To prevent this CTL-mediated xenocytotoxicity, we overexpressed the human decoy Fas antigen, which does not contain a death domain in its cytoplasmic region, by means of binding competition with endogenous pig Fas antigen on SEC for the common ligand, human FasL. Furthermore, we generated a membrane-bound form of human FasL that cannot be cleaved by a putative metalloproteinase to produce a soluble form, which was assessed as an inhibitor of CTL cytotoxicity. Both human decoy Fas and membrane-bound FasL were effective to prevent CTL-mediated killing, suggesting that these novel molecules may represent a step forward toward preventing CD8(+) CTL-mediated xenograft rejection. The combined expression of both molecules may be more beneficial to protect xenograft cells.

Background: Laparoscopic surgery has been applied to patients with primary Crohn's disease, and its beneficial outcomes have been already investigated. However, there is no systematic study of laparoscopic surgery for patients with recurrent diseases., Methods: We performed reoperation for 43 patients with recurrent Crohn's disease, including 23 patients who underwent laparoscope-assisted surgery., Results: For all the patients, laparoscope-assisted surgery could be performed safely, even if the patients had been treated previously by open surgery or had undergone multiple abdominal procedures. Conversion to open or hand-assisted laparoscopic surgery was necessary for 16 patients (69.6%) because of dense adhesions (11 cases) or bulky tumor (5 cases). Importantly, even if the procedure was converted, the skin incision was significantly shorter than with open surgery, and postoperative recovery was faster, especially for the patients who underwent conversion to hand-assisted laparoscopic surgery., Conclusions: Laparoscope-assisted surgery is feasible and advantageous in reoperation for patients with recurrent Crohn's disease.

Background: CTLA4Ig gene transfer directly to graft tissue might have the potential to avoid the need for systemic immunosuppression. In our previous studies of bio-breeding (BB) rats, local adenovirus-mediated CTLA4Ig gene transfer protected the pancreas from autoimmune and alloimmune responses. This study investigated the potency of local CD28/B7 costimulatory blockade for induction of donor-specific tolerance and further examined the existing mechanisms., Methods: Brown Norway (BN; RT1)-pancreaticoduodenal grafts transfected with Ad.CTLA4Ig via intraarterial ex vivo perfusion were transplanted into streptozotocin-induced diabetic Lewis (LEW; RT1) rats., Results: Ad.CTLA4Ig transduced grafts combined with a short course of FK506 resulted in indefinitely prolonged survival (>156 days vs. 19.5 days with FK506 alone). CTLA4Ig was predominantly expressed in grafts on day 4. The expression was gradually diminished and was only slightly detectable at day >100. The proliferative responses against BN antigen were remarkably enhanced among recipients with rejected grafts, but the T-cells from tolerant recipients (>100 days) showed poor cytotoxic responses. On adoptive transfer assay, the splenic T-cells of tolerant recipients were able to suppress the rejection of BN, but not third-party Wistar Furth (WF; RT1) hearts in irradiated (480 cGy) LEW recipients. The percentage of CD4CD25 splenic T-cells was significantly increased in tolerant recipients (13.53 +/- 4.06% vs. 6.06 +/- 0.56% in naive rats)., Conclusion: CTLA4Ig gene transfer to the pancreaticoduodenal allograft combined with a short course of FK506 induces donor-specific tolerance. The mechanism of maintaining tolerance could be explained by development of splenic T suppressor cells.

Background: In terms of the temporal relationship between pancreas transplantation (PTx) and reversal of diabetic ocular complications, it has been difficult but important to determine a "point of no return." Thus, it is of great clinical interest to evaluate the efficacy of PTx on diabetic ocular complications., Methods: A spontaneous type 2 diabetic model of Spontaneously Diabetic Torii (SDT; RT1) rats was used in the present study, and syngeneic PTx was performed., Results: In the control SDT rats that received no treatment, hyperglycemia (>250 mg/dL) was developed from 25.2+/-3.9 weeks of age. Lens opacity was observed in all rats at 15 weeks after the onset of diabetes. Fluorescein angiography and immunohistochemistry detected the nonperfusion area and neovascularization in the retina at 5 weeks of diabetes. Daily insulin treatment could not prevent or reverse the ocular changes in our experiment. Fluorescein filling defect of the retinal vessels was observed at 10 weeks of diabetes. However, in the PTx rats, normoglycemia was achieved at all experimental time points. Diabetic cataract and retinopathy could have been prevented and improved if PTx had been performed at 5 weeks, but not at 10 weeks after the onset of diabetes. With PTx treatment, an inhibition of angiogenesis in the retina at 5 weeks after the onset of diabetes was demonstrated by immunohistochemistry., Conclusions: Our results indicate that the potential use of the SDT rat for diabetes study and the positive effect of PTx performed before the "point of no return" could prevent and cure diabetic ocular complications.

We performed laparoscopic intragastric surgery (LIGS) for gastric stromal tumors located at the esophago-cardiac junction (ECJ) in 7 patients. The tumors measured 27 to 75 mm in diameters. Histologically, there were 4 cases of gastrointestinal stromal tumors, 2 leiomyomas, and 1 schwannoma. LIGS was performed with 1 camera port (10 mm) inserted by the open method and two 5-mm working ports inserted by puncturing the stomach. Tumors were enucleated or resected with appropriate margins confirming the muscle layer of the stomach wall and retrieved orally by gastrofiberscope. The mean surgical duration was 141.4 minutes. Recent patients took their first meal on day 3 postoperatively and were discharged within a week. There were no complications including stenosis or gastroesophageal reflux in any patient to date. LIGS is a feasible surgical option for gastric stromal tumors located at ECJ.

Pancreas and islet transplantation is the only treatment that can cure type 1 diabetes mellitus (DM). With the recent advances of operative procedure and immunosuppression, pancreas graft survivals have become better than before, but some problems still remain. It is extremely difficult to establish tolerance and to reverse rejection once it has been initiated because the pancreas graft itself has a strong immunogenicity. It is also known that pancreatic graft failure is sometimes due to autoimmune recurrence. In the clinical situation, however, these immunologic events actually coexist within the pancreatic graft. Thus, it is rather difficult to analyze each of them independently, but possible to delineate each of these immunologic mechanisms with using animal models of type 1 DM such as BB (BioBreeding) rats or NOD (nonobese diabetic) mice. In the current study, we reviewed the immunological characteristics in pancreas transplantation (PTx) based on our experimental experiences together with that of others and investigated the possibility of tolerance induction in PTx.

Adenovirus-mediated CTLA4Ig gene transfer has been reported to enhance graft survival in several rodent transplantation models. In this study, we investigated the efficacy of ex vivo and systemic transfer of the CTLA4Ig gene by adenoviral vectors in pancreatic islet allo-transplantation. Islet grafts from BN rats were transplanted to chemically induced diabetic LEW rats. First, ex vivo CTLA4Ig gene transfer into isolated islets was performed prior to transplantation. Survival of transduced grafts under the kidney capsule was slightly prolonged (8.6+/-1.3 days) compared with survival of untransduced grafts (6.7+/-1.2 days); when combined with a short course of FK506, graft survival was further extended (32.6+/-10.7 days vs. 13.7+/-1.0 days with FK506 alone). Secondly, systemic gene transfer was accomplished by intravenous administration immediately after the transplantation procedure. In these animals, islet grafts under the kidney capsule survived longer (15.2+/-3.3 days) than in controls (6.7+/-1.2 days), and when FK506 was administered perioperatively, all the islet grafts survived for more than 100 days. In systemically transduced recipients, the survival of islet grafts transplanted into the liver was not significantly different from that of the grafts placed under the kidney capsule. In order to examine organ-specific immunogenicity, heterotopic BN cardiac grafts were transplanted to LEW rats intra-abdominally, with the virus transferred systemically as in the islet model. In contrast to the islet grafts, all the cardiac grafts were accepted for longer than 100 days, even without FK506 therapy. Finally, the LEW recipients with long-surviving islet or cardiac grafts were re-transplanted with islet grafts from the same donor strain (BN) on day 100. The second islet grafts survived longer than 100 days in half of the cardiac recipients, but consistently failed in the islet recipients. We conclude that in this transplant model, CTLA4Ig gene transfer and FK506 treatment synergistically improved islet graft survival, systemic transfer of the gene was more effective than ex vivo transfer to the islets, and donor-specific tolerance could not be achieved for islet transplantation but was achieved for cardiac transplantation.

Background and Purpose: Since the establishment of laparoscopic cholecystectomy (LC) for benign gallbladder lesions, the four-trocar method has been the standard procedure. However, the fourth trocar generally is used just for fundic retraction of the gallbladder. We have developed a three-trocar method for LC and performed it in 132 patients., Patients and Methods: After the creation of the pneumoperitoneum, the first 10-mm trocar sheath was inserted in the subumbilicus for the endoscope, the second 5-mm trocar in the epigastric paramedian point for the working port, and the third 5-mm trocar in the subcostal area for grasping forceps. Monofilament nylon with a straight needle was inserted through the right 7th intercostal space in the anterior axillary line, and the seromuscular layer of the gallbladder fundus was punctured and retracted toward the anterior abdominal wall. After that, usual cholecystectomy was performed., Results: Among the 132 patients who underwent the three-trocar method, 10 cases (8%) needed a fourth trocar. No patient was converted to open cholecystectomy. There were no significant differences in the operating time, the length of hospital stay after the operation, or the use of analgesics between the three-trocar and the four-trocar methods. No major complication was recognized., Conclusion: This method also has cosmetic advantages. Therefore, we believe this method might be recommended for LC.

Type 1 diabetes is the result of a selective destruction of pancreatic islets by autoreactive T-cells. Therefore, in the context of islet or pancreas transplantation, newly transplanted beta-cells are threatened by both recurrent autoimmune and alloimmune responses in recipients with type 1 diabetes. In the present study, using spontaneously diabetic BB rats, we demonstrate that whereas isolated islets are susceptible to autoimmune recurrence and rejection, pancreaticoduodenal grafts are resistant to these biological processes. This resistance is mediated by lymphohematopoietic cells transplanted with the graft, since inactivation of these passenger cells by irradiation uniformly rendered the pancreaticoduodenal grafts susceptible to recurrent autoimmunity. We further studied the impact of local immunomodulation on autoimmune recurrence and rejection by ex vivo adenovirus-mediated CTLA4Ig gene transfer to pancreaticoduodenal grafts. Syngeneic DR-BB pancreaticoduodenal grafts transduced with AdmCTLA4Ig were rescued from recurrent autoimmunity. In fully histoincompatible LEW-->BB transplants, in which rejection and recurrence should be able to act synergistically, AdmCTLA4Ig transduced LEW-pancreaticoduodenal allografts enjoyed markedly prolonged survival in diabetic BB recipients. In situ reverse transcription-polymerase chain reaction revealed that transferred CTLA4Ig gene was strongly expressed in both endocrine and exocrine tissues on day 3. These results indicate the potential utility of local CD28-B7 costimulatory blockade for prevention of alloimmune and autoimmune destruction of pancreatic grafts in type 1 diabetic hosts.

Background: Many strategies of tolerance induction by intrathymic (IT) injection of donor alloantigens have been reported to date; however, the timing of IT injection is usually 1-3 weeks before transplantation., Methods: To apply IT injection to cadaveric organ transplantation, 1 x 10(8) fully allogeneic bone marrow cells (BMC) of Buffalo (BUF; RT1b) rats were intrathymically injected into Wistar Furth (WF; RT1u) rats at the time of BUF cardiac allografting with short-course therapy of antilymphocyte serum (ALS) and FK506 in our experimental model., Results: Allogeneic IT injection of BUF BMC with ALS and FK506 indefinitely prolonged graft survival (mean survival time > 210 days) in all WF rats. On day 130 after grafting, tolerant WF rats accepted donor BUF skin grafts (> 120 days) but not third-party Lewis skin grafts. In control groups, syngeneic IT injection of WF BMC or intravenous injection of donor BUF BMC in combination with ALS/FK506 therapy failed to induce tolerance. In vivo testing was performed during induction (1 month) or during maintenance (6 months of tolerance. In the mixed lymphocyte reaction (MLR), spleen T cells of tolerant rats at 1 month after grafting displayed hyporesponsiveness after stimulation with donor cells. The addition of interleukin (IL)-2 to MLR culture did not restore T-cell responsiveness. Tolerant rats had a significantly decreased frequency of T cytotoxic cell precursors (fTcp) of 1:4,926, and frequency of IL-2-producing T helper cell precursors (fThp) of 1:23,925, compared with naive rats (1: 2,158 and 1:4,266, respectively). By 6 months after grafting, however, the anti-donor MLR proliferative responses of tolerant rats had been restored to the levels of naive splenic T cells. These tolerant rats displayed restoration of the (fTcp) of 1:2,842 and of the (fThp) of 1:5,630, which were comparable frequencies of naive rats. Suppressor T cells did not contribute in this model. In cardiac grafts of tolerant rats induced by IT injection, expression of both Th1 (interferon-gamma and IL-2) and Th2 (IL-4 and IL-10) cytokines was detected in the early phase; thereafter, expression was completely inhibited, except for interferon-gamma in the chronic phase., Conclusions: Perfect donor-specific tolerance was obtained by IT injection of donor BMC at the time of transplantation, while alloimmune responses were maintained at levels similar to those of naive rats.

We examined the use of an abdominal wall retraction method instead of pneumoperitoneum in laparoscopic cholecystectomy for patients with cardiac disease to prevent the hemodynamic deterioration associated with pneumoperitoneum. Eight patients with cardiac diseases, mainly valvular or coronary artery diseases, underwent laparoscopic cholecystectomy under hemodynamic monitoring. Five patients without cardiac disease served as controls. As hemodynamic parameters, heart rate, mean systemic arterial pressure (mAP), mean pulmonary arterial pressure (mPAP), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and cardiac index (CI) were measured. The patients with cardiac disease showed significantly elevated mPAP and PCWP compared with the control group under pneumoperitoneum, and one patient showed critically decreased CI due to increased tricuspid regurgitation under pneumoperitoneum. These changes, however, were resolved on the abdominal wall retraction. There was no major perioperative complication. This abdominal wall retraction method is, therefore, favorable for patients with underlying cardiac disease to minimize the hemodynamic deterioration during laparoscopic cholecystectomy.

Diabetes-prone (DP) BB rats (RT1(u), RT6.1) spontaneously develop insulin-dependent diabetes mellitus (IDDM) and the disease manifestation resembles that in human IDDM. DP rats are immunodeficient with severe T lymphocytopenia due to the absence of T cells expressing the RT6 differential alloantigen, which have immunoregulatory functions. MHC- and non-MHC-compatible Wistar Furth (WF; RT1(u), RT6.2) pancreases were transplanted into DP rats. WF pancreas grafts were destroyed by IDDM recurrence (insulitis), but not by rejection, with a mean survival time of 65.3 +/- 21.7 days. To prevent the recurrence of IDDM in the grafts, monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associated antigen-1 were administered. WF pancreas grafts were indefinitely accepted (>108.0 +/- 26.8 days) in monoclonal antibody-treated DP recipients. The number of T cells was increased and cellular immune responses restored only in the DP rats that had accepted grafts. The increased number of T cells was due to the peripheral appearance of donor-type RT6.2+ T cells, which represented 34.3 +/- 7.0% of total splenic T cells. The cytotoxicity of splenic T cells to WF islet cells was suppressed in the presence of RT6+ T cells in vitro. These findings demonstrated that stable macrochimerism of donor-derived RT6+ T cells could restore the immune responses and prevent the recurrence of IDDM in the DP recipients.