A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

Seroprevalence survey on measles, mumps, rubella and varicella antibodies in healthcare workers in Japan: sex, age, occupational-related differences and vaccine efficacy.

A seroprevalence survey on measles, mumps, rubella and varicella was conducted on healthcare workers (HCWs) at Shimane University Hospital, Japan utilizing an enzyme immunoassay. Of 1811 HCWs tested, 91.8% were seropositive to measles, 92.1% to mumps, 89.5% to rubella and 96.3% to varicella. Sex-related differences in seroprevalence were found in rubella (males vs. females: 84.7 vs. 92.2%, P < 0.001). Moreover, males aged 30-39 years were most susceptible to rubella (22.4%), which may be attributed to the design of childhood immunization programmes in Japan. Individuals aged ≤ 29 years were more susceptible to measles (14.3%) and mumps (10.9%), compared to other age groups. There were no significant sex- and age-related differences in varicella seroprevalence. The physician occupational group was more susceptible to rubella, but no significant occupational-related difference was observed in the other diseases. Susceptible subjects, with negative or equivocal serological results were given a vaccine which induced seroconversion in most vaccinees. Seroconversion occurred more frequently in the equivocal group than in the negative group. These findings provide a new insight for the seroprevalence survey of vaccine-preventable diseases in Japanese HCWs with special reference to vaccine efficacy.

Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis.

A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10-/-) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10-/- mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4+ T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10-/- mice ameliorated the colitis, probably as a result of decreasing the number of CD4+ T cells in the colonic mucosa and an associated reduction in IFN-gamma production.

Regulation of donor T cells in the tolerant rats to graft-versus-host disease by FTY720 following small bowel transplantation.

AIMS: The potency of immunosuppression is a critical factor in small bowel transplantation (SBTx). FTY720 altered lymphocyte trafficking and prevented the donor T cells from migrating into target organs, resulting in the prolongation of recipient survival in acute graft-versus-host disease (GVHD) of SBTx. However, the effect of FTY720 on donor T cells in the chronic phase of GVHD following SBTx remains unclear. METHODS: Heterotopic SBTx was performed in a WF-to-F1 (WF x ACI) rat combination. Recipients were given FTY720 for 14 days after SBTx. The subpopulations of donor-derived T cells and the cytokine production in the target tissues were evaluated on postoperative day 150. RESULTS: FTY720 treatment significantly prolonged recipient survival over 150 days without any clinical signs of GVHD. The numbers of donor-derived CD4+ and CD8+ T cells in the peripheral blood, mesenteric lymph nodes, and Peyer's patches of recipients were maintained at low levels on postoperative 150, which were almost similar to the levels on postoperative day 14. In the host lamina propria, however, a significant higher number of donor T cells (CD4+, 18.4 +/- 4.3 x 10(4); CD8+, 13.9 +/- 3.6 x 10(4)) were still observed on postoperative day 150. Production of interferon-gamma was significantly reduced in target tissues by FTY720 treatment both in the acute and chronic phase. However, interleukin-4 and interleukin-10 production, which was significantly higher on day 14, returned to the level of naive rats in the chronic phase. CONCLUSIONS: A 14-day treatment of FTY720 induced tolerance in our SBTx model. Down-regulation of both Th1 and Th2 immune response was observed in the chronic phase.

Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation.

In small bowel transplantation (SBTx), graft-versus-host disease (GVHD) is mediated by donor-derived T cells recognizing host major histocompatibility complex (MHC) alloantigens, and represents an important immunological event influencing life in experimental and clinical situations. We evaluated the possibility that a new sphingosine 1-phosphate receptor agonist, FTY720, could diminish GVHD in a rat SBTx model through traffic alteration of donor-derived T cells in target organs. Heterotopic SBTx was performed using a parent (WF)-into-F(1) (WF x ACI) rat combination. Recipient survival, body weight, histopathology, donor-derived T cell subpopulation and cytokine production were compared with untreated controls. FTY720 inhibited lethality and histopathological changes in target organs when administered at 0.5 mg/kg, possibly due to sequestration of donor-derived T cells in the intestinal graft. FTY720 caused a significant reduction in donor T cell numbers in target organs by promoting these cells to home into donor, but not recipient, secondary lymphoid tissues. FTY720 significantly decreased production of interferon (IFN)-gamma in target organs. These findings indicate that FTY720 effectively reduced recirculation of activated donor-derived T cells and recruitment to target organs in GVHD, and was also associated with down-regulated IFN-gamma production. These properties may offer the potential to treat ongoing GVHD in SBTx.

[Posterior mediastinal paraganglioma with a 60-year history; report of a case].

We report a case of a 68-year-old man with a posterior mediastinal tumor. He remembered having difficulty in food passage through his esophagus in childhood. The preoperative thoracic computed tomography (CT) revealed a 5 x 3 cm mass with strong enhancement in the posterior mediastinum. A right thoracotomy was performed to resect this indeterminate mass. Complete resection was achieved. The pathologic diagnosis was paraganglioma. Postoperatively, he experienced more comfortable food passage through his esophagus than ever before. There has been no sign of recurrence 3 years after the operation. The tumor was clinically diagnosed as benign paraganglioma because of its long silent course.

Advantages of laparoscope-assisted surgery for recurrent Crohn's disease.

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.

[Epidemiological research on dementia in developing countries]. / Investigações epidemiológicas sobre demência nos países em desenvolvimento.

As the world population is ageing, dementia becomes an important public health problem, particularly in developing countries. Epidemiological research in these settings is scarce and present additional methodological difficulties, mainly regarding the socio-cultural adequacy of instruments used to identify cases of dementia. As a result of these concerns the 10/66 Dementia Research Group was founded to fill this gap. This is an international network of investigators, mostly from developing countries, and the group's name was based on the paradox that less than 10% of the population-based studies on dementia are directed to 2/3 or more cases of people with dementia living in developing countries. The aim of the paper is to update data in the literature regarding the differences in dementia prevalence and incidence seen in developed and developing countries.

Investigaçöes epidemiológicas sobre demência nos países em desenvolvimento / Epidemiological research on dementia in developing countries

Na medida em que a populaçäo mundial está envelhecendo, a demência está se constituindo em importante problema de saúde pública, particularmente nos países em desenvolvimento. Investigaçöes epidemiológicas nestes países säo escassas e apresentam dificuldades metodológicas adicionais, principalmente no que se refere à adequaçäo sociocultural dos instrumentos utilizados para a definiçäo de casos. Tendo em vista estas preocupaçöes, foi fundado o "Grupo de Pesquisa em Demência 10/66", que é constituído por uma rede internacional de pesquisadores, predominantemente de países em desenvolvimento. O nome do grupo tem como referência o paradoxo de que menos de 10 por cento dos estudos populacionais sobre demência säo dirigidos aos 2/3 ou mais de casos de pessoas com demência que vivem em países em desenvolvimento. O objetivo do artigo é atualizar informaçöes da literatura sobre as diferenças de prevalência e incidência de demência encontradas em países desenvolvidos e em desenvolvimento

The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.

Dysferlin is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited, forms of muscular dystrophy designated Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B), respectively. The function of dysferlin is not defined. Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C). We report that dysferlin co-immunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. We also describe abnormal localization of dysferlin in muscles from patients with LGMD1C including novel missense mutation (T64P) in the human caveolin-3 gene (CAV3). The immunoprecipitation data are consistent with the parallel observation that dysferlin immunostaining is not normal in LGMD1C muscles. Amino acid sequence analysis of the dysferlin protein reveals seven sites that correspond to caveolin-3 scaffold-binding motifs, and one site that is a potential target to bind the WW domain of the caveolin-3 protein. This is the first description of a possible dysferlin interacting protein; it suggests the hypothesis that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae.

Antigen-presenting hybridoma cells expressing MHC antigens of the LEW rat.

Towards the eventual purpose of facilitating analyses of specificities and functions of LEW rat T lymphocytes involved in the induction and development of organ-specific autoimmune disorders, hybridoma cells expressing class I and class II MHC antigens of LEW rat have been developed. B cell hybridomas produced between a murine B cell tumor M12.4.5 and stimulated LEW B cells expressed high levels of LEW class II MHC antigen but the expression of LEW class I MHC antigens on these cells was rather low. The B hybridoma cells were capable of presenting soluble protein antigens to LEW CD4(+) T cells. Furthermore, The use of this hybridoma revealed antigen-specific cytolytic activity of rat CD4(+) T cells. T cell hybridomas produced between murine thymoma BW5147 and LEW T cells expressed class I MHC antigens of the LEW rat. The expression was confirmed by surface staining and specific cytolysis by rat allogeneic CTL.

Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.

We report a family with a new phenotype of autosomal recessive muscle dystrophy caused by a dysferlin mutation. The onset of the illness is distal, in the muscles of the anterior compartment group. The disease is rapidly progressive, leading to severe proximal weakness. Muscle biopsy showed moderate dystrophic changes with no vacuoles. Dysferlin immunostaining was negative. Gene analysis revealed a frameshift mutation in the exon 50 (delG5966) of the DYSF gene. This phenotype further demonstrates the clinical heterogeneity of the dysferlinopathies.

Experimental autoimmune myocarditis and its pathomechanism.

The pathomechanisms of autoimmune myocarditis are quite different from viral infection. In this type of myocarditis, cardiac myosin fragments, proper dendritic cells and autoreactive T cells are the 3 major elements in initiating and promoting the inflammation. The causative epitope is locating on the S2 rod portion of the myosin heavy chain (MHC). Through our recombinant study, the peptide was found to be located on the latter half of MHC residues 1070 to 1165. Activity of antigenicity was not different between alpha and beta chain. The cardiac dendritic cell presents a unique structure with large mononuclear and interdigitating processes. This antigen presenter is quickly activated and suppressed by the antigen. The autoreactive T cell is closely linked with cytokine production. In the initial stage of myocarditis, IL-2 and IL-12 are increased. According to the progression of inflammatory changes, a great amount of IL-1b, INF-gamma and TNF-alpha is released around the diseased tissue. At the same time, NO is massively produced from infiltrating macrophages. Cytokines secreted from inflammatory cells accelerate T cell induction from Th0 to Th1. In the convalescent stage, production of TGF-beta 1 and IL-10 become dominant. They contribute to cell induction from Th0 to Th2.

Brachioplasty technique with the use of molds.

Over previous years many surgical techniques have been developed to correct lipodystrophy and brachial skin laxity while providing a natural, discreet contour and symmetrical scars, a goal that has not always been achieved. In this study, the authors classify the alterations of the arm into three degrees and propose a different surgical treatment, to be used alone or associated with another procedure, for each classification. They developed a new technique that uses a mold to mark the incision in an italic double S-shape. From 1996 to 1998, 20 patients who underwent this surgery showed symmetrical and smaller scars with better results and minimal complications.

Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy.

Recently we reported that mutations in a muscle protein "dysferlin" are present in limb girdle muscular dystrophy-2B and a related, adult-onset, distal dystrophy known as Miyoshi myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.

Salivary gland aplasia with cleft lip and palate: a case report and review of the literature.

We report the case of a patient with lifelong symptoms of xerostomia and a repaired bilateral cleft lip and palate. The clinical evaluation demonstrated aplasia of the major salivary glands. A review of the literature pertaining to salivary gland aplasia is presented, along with a summary of the data regarding patient gender, defect sites, hereditary background, and combined manifestations. The diagnostic methods, possible pathogenesis, and management are also discussed.

Identification of the sex chromosomes of the medaka, Oryzias latipes, by fluorescence in situ hybridization.

In the medaka, Oryzias latipes, which does not have cytologically recognizable sex chromosomes, the sex is genetically determined and the mechanism of sex determination (XX/XY) can be revealed by genetic crosses using a particular pigment gene. In a previous study, we isolated a sex-linked DNA marker (SL1) using the genomic differences between inbred strains of medaka. In the present paper, we further isolated another sex-linked clone (pHO5.110). The pHO5. 110-related sequences were tightly linked to sex in O. latipes. We designated the locus of the pHO5.110-related sequence on sex chromosomes of medaka as Sex-Linked 2 (SL2). Southern blot analyses suggested that the pHO5.110-related sequence was tandemly repetitive in the medaka genome. Using the clone as a probe for FISH analysis, strong hybridization signals were obtained in a couple of chromosomes that formed one of two large submetacentric chromosome pairs. The pHO5.110-related sequences were repetitive in the genomes of other species of Oryzias (O. curvinotus, O. luzonensis and O. mekongensis) that are karyologically related to O. latipes (all are members of the so-called biarmed group). By contrast, the sequences were not detected as repetitive in other Oryzias species. Hence, it is thought that pHO5.110-related sequences were amplified in the genome of a common ancestor of the biarmed group.

Mutations in the integrin alpha7 gene cause congenital myopathy.

The basal lamina of muscle fibers plays a crucial role in the development and function of skeletal muscle. An important laminin receptor in muscle is integrin alpha7beta1D. Integrin beta1 is expressed throughout the body, while integrin alpha7 is more muscle-specific. To address the role of integrin alpha7 in human muscle disease, we determined alpha7 protein expression in muscle biopsies from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry. We found three unrelated patients with integrin alpha7 deficiency and normal laminin alpha2 chain expression. To determine if any of these three patients had mutations of the integrin alpha7 gene, ITGA7, we cloned and sequenced the full-length human ITGA7 cDNA, and screened the patients for mutations. One patient had splice mutations on both alleles; one causing a 21-bp insertion in the conserved cysteine-rich region, and the other causing a 98-bp deletion. A second patient was a compound heterozygote for the same 98-bp deletion, and had a 1-bp frame-shift deletion on the other allele. A third showed marked deficiency of ITGA7 mRNA. Clinically, these patients showed congenital myopathy with delayed motor milestones. Our results demonstrate that mutations in ITGA7 are involved in a form of congenital myopathy.

MyoD is indispensable for muscle-specific alternative splicing in mouse mitochondrial ATP synthase gamma-subunit pre-mRNA.

Muscle-specific alternative RNA splicing is an essential step during myogenesis. In this paper, we report that a muscle-specific transcription factor, MyoD, plays a central role in the induction of muscle-specific alternative splicing during myogenesis. Recently, we reported that muscle and nonmuscle isoforms of the mitochondrial ATP synthase gamma-subunit (F1gamma) were generated by alternative splicing and that acidic stimulation promoted this muscle-specific alternative splicing (Endo, H., Matsuda, C., and Kagawa, Y. (1994) J. Biol. Chem. 269, 12488-12493). In this report, mouse myoblasts are shown to express the muscle-specific isoform of F1gamma after induction with low-serum medium (differentiation medium) or acidic medium, although myotube formation was not detected after acidic induction. RNA blot analysis revealed that the expression levels of both MEF2 and myogenin were increased by low-serum induction, but not by acidic induction. High expression of MyoD mRNA was observed after both types of induction. Overexpression of exogenous MyoD in fibroblasts showed that MyoD was necessary for muscle-specific alternative splicing in both types of induction. Exogenous Id, a negative regulator of MyoD, blocked muscle-specific alternative splicing of F1gamma pre-mRNA by both types of induction. In addition, MyoD induced several muscle-specific alternative splicings, including structural protein pre-mRNAs such as beta-tropomyosin and neural-cell adhesion molecule and transcriptional protein pre-mRNAs such as MEF2A and MEF2D. Our analysis of the two induction systems shows a common MyoD-dependent mechanism of muscle-specific alternative splicing in several genes, independent of MEF2 and myogenin.

A field trial of oil adjuvanten trivalent Actinobacillus pleuropneumoniae vaccine.

The trivalent vaccine of A. pleuropneumoniae serotype 1, 2 and 5 (AP3V) was prepared in the oil-in-water type adjuvanten form. At an SPF farm, the vaccinated pigs were observed for their antibody response, finishing rate, and lung lesions at the time of slaughter and for injection scars. The CF titers against serotype 1, 2 and 5 started to rise after the second injection, showed the highest titer at 30 days after injection and then gradually decreased in vaccinated pigs. The finishing rate in the vaccinated group was 91.6% and that in the control group immunized with commercial vaccine was 60%. The lungs in the control pigs showed severe pneumonia with hyperemia, pleural adhesion and abscess. In contrast, vaccinated pigs showed slight pneumonia. Injection scars were not observed in vaccinated pigs 100 days after the second injection. In conclusion, the pigs immunized with AP3V were sufficiently protected against A. pleuropneumoniae infection and the trial proved to be satisfactory in the safety of the vaccine under field conditions.