Susceptible MHC alleles,not background genes,select an autoimmune T cell reactivity

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.     

Mastoid obliteration by BMP-2/collagen composites: an experimental study using tissue engineering

PURPOSE: Several materials have been used in the application of mastoid cavity obliteration during surgery for cholesteatoma; however, nothing has won universal acceptance. Through the advancement of tissue engineering, bone morphogenetic protein-2 (BMP-2)/collagen composites have been elucidated as inducers of heterogenic bone formation. This study was performed to investigate whether these composites are potentially obliteration materials for use in the mastoid cavity by using an animal experimental study. MATERIALS AND METHODS: The composites were implanted in the rat mastoid to investigate whether new bone would be tissue engineered in the mastoid and, if so, whether the newly formed bone was stable. The composites were examined histologically over a 24-week period. RESULTS: The composites implanted in the rat mastoid were able to tissue engineer new bone, and the newly formed bone was stable as assessed histologically, with almost normal bone structure, that was not resorbed during the 24-week period. Adverse immunological reactions were not found during our observation. CONCLUSIONS: Bone that was tissue engineered by the BMP-2/collagen composites was stable as assessed by histological examination and persisted in the rat mastoid. The present study shows that the composites have the potential to become real materials for use in mastoid obliteration.     

Sleep apnea due to Kimura's disease of the larynx. Report of a case

Kimura's disease is a benign chronic granulomatous disease which presents as a subcutaneous swelling in the head and neck area. The histopathological feature consists of granuloma-forming lymphoid follicles with eosinophil infiltration. Kimura's disease of the larynx is very rare, and only a few cases have been reported. We report a 14-year-old boy who presented with sleep apnea. Laryngological study revealed a submucosal swelling of the bilateral false vocal cord. Histopathological examination showed lymphoid hyperplasia with marked infiltration of eosinophils, which was diagnosed as Kimura's disease. After laser surgery, he had recurrent swelling of the false cord. The patient was given 30 mg of prednisolone, which was gradually tapered. The laryngeal swelling resolved, and the sleep apnea immediately improved after the treatment. However, a low dose of prednisolone was necessary to maintain the remission. Oral administration of pranlukast successfully supported the tapering of prednisolone.     

Genetic and environmental factors affecting peak bone mass in premenopausal Japanese women

The purpose of this study was to examine the relationships between peak bone mass and genetic and environmental factors. We measured whole-body bone mineral density (BMD), lumbar spine BMD, and radius BMD with dual-energy X-ray absorptiometry (DXA) and analyzed eight genetic factors: vitamin D receptor (VDR)-3′, VDR-5′, estrogen receptor (ER), calcitonin receptor (CTR), parathyroid hormone (PTH), osteocalcin (OC), apolipoprotein E (ApoE), and fatty acid binding protein 2 (FABP2) allelic polymorphisms using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLPs). We also surveyed menstrual history, food intake, and history of physical activity using questionnaires. After adjusting for age, body mass index (BMI), current smoking status, current Ca intake, alcohol intake, menoxenia, and physical activity, the mean BMD in subjects with the HH/Hh genotype was significantly higher than that of subjects with the hh genotype for whole-body BMD (mean±SD, 1.20±0.10 vs. 1.18±0.09 g/cm²; HH/Hh vs. hh, p=0.04) and at lumbar spine BMD (mean±SD, 1.18±0.14 vs. 1.14±0.12 g/cm²; HH/Hh vs. hh, p=0.02) in OC allelic polymorphism. Furthermore, the results of multiple regression analyses taking the 8 genetic factors plus the 7 environmental factors listed above into account showed that the strongest factor contributing to BMD was BMI at any site (whole-body and lumbar BMD p<0.0001, radius BMD p=0.0029). In addition, OC polymorphism (p=0.0099), physical activity (p=0.0245), menoxenia (p=0.0384), and PTH polymorphism (p=0.0425) were independent determinants for whole-body BMD, and OC polymorphism (p=0.0137) and physical activity (p=0.0421) were independent determinants for lumbar BMD and radius BMD, respectively.     

Mechanism-based therapy for leukemia: a lesson from ATRA therapy

In the past two decades, there has been a tremendous increase in our understanding of the molecular mechanism of human leukemias. Leukemias are now recognized as a deregulated state of cell proliferation, differentiation and apoptosis, which is induced by gene alterations, including chromosomal translocations. Many of the mechanisms are potentially exploited as new targets for drug development. All-trans retinoic acid therapy for acute promyelocytic leukemia, which was initially developed as a differentiation therapy in an experienced-based manner, is currently known to be the first successful oncoprotein-directed therapy. Basic and clinical research into ATRA-resistance provides new directions for acute myeloid leukemia therapy. Anti-leukemia therapy will continue to lead the field of chemotherapy in the coming decades.     

Expressions of caspase-3, Tunel, and Hsp72 immunoreactivities in cultured spinal cord neurons of rat after exposure to glutamate, nitric oxide, or peroxynitrite

Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanisms are not fully understood. We examined cell damage of primary culture of 11-day-old rat spinal cord by addition of glutamate, nitric oxide (NO) or peroxynitrite (PN) with detection of caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) or 72kDa heat shock protein (HSP72). With addition of glutamate, NOC18 (a slow NO releaser) or PN, immu-noreactivity for caspase-3 became stronger in the cytoplasm of large motor neurons in the ventral horn at 6 to 24h. TUNEL positive nuclei were found in spinal large motor neurons from 24 h, and the positive cell proportion greatly increased at 48 h in contrast to the vehicle. On the other hand, the immunoreactivity of HSP72 in the ventral horn was already positive at 0 h, and gradually decreased in the course of time with glutamate, NOC18 or PN than vehicle treatment. In the dorsal horn, the proportion of caspase-3 positive small neurons greatly increased at 6 to 48 h after addition of glutamate. The present results suggest that both excitotoxic and oxidative stress play important role in the apoptotic pathway in cultured rat spinal neurons.     

Ruptured Dissecting Aneurysm in Bilateral Iliac Arteries Caused by Ehlers-Danlos Syndrome Type IV: Report of a Case

Ehlers-Danlos syndrome (EDS) is an inherited disorder of connective tissue characterized by hyperextensible skin, hypermobile joints, and ab-normalities of the cardiovascular system. Ten types and several subtypes of EDS have so far been recognized based on genetic, clinical, and biochemical characteristics. The spectrum of the disorder varies from mild to life-threatening vascular complications. EDS type IV is a particularly dangerous form with a lethal spontaneous rupture of the major arteries and aneurysmal formation. We present herein a case of a ruptured dissecting aneurysm in the bilateral iliac arteries caused by EDS type IV. A previously healthy 33-year-old man without any physical features of this connective tissue disorder experienced a metachronous vascular rupture two times. Successful synthetic bypass grafting was performed with great difficulty. The diagnosis of EDS type IV was made afterwards based on an electrophoresis analysis of a skin biopsy specimen which revealed a lack of type III collagen. Surgical intervention in cases of arterial complications in EDS type IV patients have been reported to be both difficult and frequently unsuccessful. The early clinical recognition of this syndrome is therefore of great importance due to the hazards of such surgical therapies. Received: November 16, 1999 / Accepted: July 25, 2000