An investigation of Japanese subjects maps susceptibility to type 1 (insulin-dependent) diabetes mellitus close to the DQA1 gene.

Insulin-dependent diabetic and control subjects of Japanese origin were HLA-DRB1, -DQB1, and -DQA1 typed using restriction fragment length polymorphism analysis and sequence-specific oligonucleotide gene probing. The DQA1 allele DQA1*0301 was positively associated with the disease [48/52 (92%) diabetic patients versus 44/64 (69%) control subjects, Pc less than 0.03, RR = 4.97]. Alleles of the DRB1 and DQB1 genes showed no significant association with the disease. The frequency of DQB1 genotypes encoding the amino acid aspartic acid at position 57 of the DQ beta chain did not differ significantly between subjects with insulin-dependent diabetes mellitus (IDDM) and controls. These findings suggest that a susceptibility allele for IDDM in the Japanese is more closely associated with the DQA1 gene than the DQB1 gene.     

Thermodynamic studies on poly(a) · poly(u) duplex-dye systems

The interaction between poly(A) · poly(U) duplex and dyes (proflavine (PF) and 9-aminoacridine (9-AA)) was studied by means of the heat of mixing. From the results, thermodynamic quantities of poly(A) · poly(U) duplex-dye systems for the intercalation process were estimated. The free energy change for the poly(A) · poly(U) duplex-(PF) system is smaller than that for the poly(A) · poly(U) duplex-(9-AA) system, indicating that PF intercalated into poly(A) · poly(U) duplex is more stable than the intercalated 9-AA. This conclusion is based on the absolute value of the heat of interaction between PF and poly(A) · poly(U) duplex being larger than that between 9-AA and the poly(A) · poly(U) duplex.     

Nature and significance of calcium oxalate crystals in normal human thyroid gland

To elucidate the significance and nature of calcium oxalate crystals in the thyroid, we studied these crystals clinicopathologically and immunohistochemically in 182 normal thyroids from patients autopsied within 5 h of death. Under polarized light, calcium oxalate crystals showed brilliant birefringence and were invariably found within the colloid. The crystals were found in 73.1% of all cases but were more prevalent and denser in older individuals, with the highest prevalence (85.2%) being observed in those over 70 years of age. No crystals were seen in those under 10 years of age. Although underlying diseases seemed to have little influence, post-mortem delay apparently affected the prevalence and density of occurrence since the crystals tended to disappear with hours after death. An immunohistochemical study using anti-thyroid hormone antibodies revealed that the crystals were within negatively or weakly stained colloid and were not common in strongly stained colloid. These findings support the hypothesis that the occurrence of calcium oxalate crystals in normal human thyroid is associated with a low functional state of the thyroid follicles.     

Hepatitis C virus is a more likely cause of chronic liver disease in the Japanese population than hepatitis B virus.

508 Japanese patients with chronic liver disease, including chronic hepatitis, cirrhosis and hepatocellular carcinoma, and 500 controls matched for sex and age were studied. Antibody to hepatitis C virus (anti-HCV) alone was found in 233 (45.9%) patients and hepatitis B surface antigen (HBsAg) alone was present in 128 (25.2%) patients. Both anti-HCV and HBsAg were present in 18 (3.5%) patients. Anti-HCV was found in 8 (1.6%) controls and HBsAg was present in 4 (0.8%) controls. The prevalence of anti-HCV alone was 36.9% in chronic hepatitis, 49.0% in cirrhosis and 67.0% in hepatocellular carcinoma, respectively. The prevalence of anti-HCV increased with the progress of severity of liver disease. Anti-HCV was more prevalent than HBsAg both in cirrhosis and hepatocellular carcinoma (p less than 0.001). The prevalence of anti-HCV increased with age. Among patients under age 39 years, HBsAg was detected more often than anti-HCV, however, in those over age 50 years, anti-HCV was detected more often than HBsAg (p less than 0.001). It would appear that hepatitis C virus more than hepatitis B virus is a prominent cause of chronic liver disease among Japanese patients.     

Established histological identity and cell destruction treatments for cancer

During cancerous cell turnover activity maintained by two types of mitosis, maturation and heteroduplication, cancer tissue consists of two types of cells, maturable and non-maturable. Most of the tissue is composed of maturable cells, which eventually disappear in the terminally matured cell phase. These cells do not participate in cell turnover activity or the organoid identity of cancer tissue. However, a small portion of the tissue is comprised of non-maturable cells, which replicate themselves endlessly, while producing maturable cells through each mitotic division in hetero-duplication mitosis. Thus, cell turnover activity and organoid identity are established in the cancer tissue. This organoid identity is solely responsible for carcinogenesis. Since most typical features of cancer are only detectable in maturable cells during maturation mitosis, cell destruction targeting these features should not be regarded as eradication. To eradicate cancer, the organoid identity of cancer, which is only established by heteroduplication mitosis, should clearly be recognized, and a new concept of cancer treatment based on destruction of the organoid identity should be devised in the future. This does not appear to be an insurmountable task.     

Morphological features of nerve terminal degeneration as part of the remodeling process in the motor endplate in adult muscles

With the exception of signs of retraction and withdrawal, there have been few morphological data concerning degenerated neural profiles in adult motor endplates. Here, investigation into the ultrastructure of the soleus motor endplates of adult rats (4 months old) turned up particular axonal degeneration in approximately 3% of the subjects. These axons occur as synaptic debris in the synaptic matrix of the motor endplate, adjacent to thin processes of the perisynaptic cells occupying the outer most layer of the motor endplate and were devoid of basal lamina. They often possessed dense-cored vesicles (50-80 nm). Axonal debris released from Schwann cell processes occurred during the period of acute sciatic neurectomy, when nerve terminals progressively disrupted within the motor endplate associated Schwann cells. Finally, immunohistochemical staining for antibodies to label macrophages (ED1 or ED2) has shown that nerve fiber-associated macrophages are located near the motor endplate. The results suggest that during the course of endplate remodeling, a few parts of the terminal branches are disposed of through spontaneous collapse, subsequent release from the Schwann cell investment, and eventual ingestion by macrophages in the perisynaptic space.     

Prostaglandin E2 inhibits lesion formation in dextran sodium sulphate-induced colitis in rats and reduces the levels of mucosal inflammatory cytokines

Effects of rectally injected prostaglandin E2 (PGE2) in rats with dextran sodium sulphate (DSS)-induced colitis were investigated in terms of histopathology, local myeloperoxidase (MPO) activity, local mRNA expression of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and growth-regulated gene produced/cytokine-induced neutrophil chemoattractant (GRO/CINC)-1, and secretion of TNF-alpha and GRO/CINC-1. In animals with no PGE2 treatment, DSS-induced erosion and ulceration were particularly severe in the rectum and extended to the proximal colon. Neutrophil infiltration was characteristically present in the lesions and surrounding mucosa. MPO activity at lesion sites was increased. IL-1beta and GRO/CINC-1 mRNA expression was increased, while TNF-alpha mRNA expression was significantly decreased. GRO/CINC-1 secretion was increased but a similar elevation of TNF-alpha was not detected. In the PGE2-treated group, lesion formation was inhibited grossly and microscopically. Neutrophil infiltration and MPO activity in and around lesions were lessened. The reduction in TNF-alpha mRNA expression and secretion was not affected by PGE2. The expression of mRNA for IL-1beta and GRO/CINC-1 was reduced, as was the secretion of GRO/CINC-1. As mRNA expression and secretion of cytokines in lesions of non-PGE2-treated animals was similar to that reported in human ulcerative colitis, rectal injection of PGE2 may prove to be an effective therapy.     

The relationship of VEGF and PGE2 expression to extracellular matrix remodelling of the tenosynovium in the carpal tunnel syndrome

Tenosynovial thickening within the confined space of the carpal tunnel is thought to be the cause of the carpal tunnel syndrome (CTS). However, little is known about the pathological mechanism of tenosynovial thickening. In this study, the role of prostaglandin E(2) (PGE(2)) and vascular endothelial growth factor (VEGF) (two representative molecules that can induce oedema by increasing vascular permeability) was analysed in CTS by using immunohistochemistry and enzyme-linked immunosorptive assay (ELISA). Expression of these molecules was compared with the patients' clinical histories and a temporary increase in production of these molecules was found in cells within the vessels and synovial lining during the intermediate phase of the syndrome when the histology of the tenosynovium changes from oedematous to fibrotic. Statistical analysis clearly demonstrated that there is a close correlation between the expression of PGE(2) and VEGF. Furthermore, immunohistochemical analysis with anti-proliferating cell nuclear antigen (PCNA) revealed that the area with distinct VEGF expression closely matched the area where endothelial cells, vascular smooth muscle cells, and synovial lining cells proliferate. In contrast, despite marked alteration in the extracellular matrix (ECM) component of the tenosynovium, the fibroblasts responsible for most ECM framework production do not proliferate during any phase of CTS. Histological analysis demonstrated that angiogenesis takes place only during the intermediate phase. Since clusters of capillaries and arterioles are often surrounded by type III collagen-rich, disorganized, degenerate connective tissue, which contains fewer fibroblasts than normal, angiogenesis appears to take place as a part of a regenerative reaction that results in fibrosis. These findings strongly indicate that both PGE(2) and VEGF are expressed in the tenosynovium in CTS during the intermediate phase and induce the histological changes seen in the tenosynovium.     

Suppression of eosinophilic airway inflammation by treatment with alpha-galactosylceramide

To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using alpha-galactosylceramide (alpha-GalCer), a selective ligand for NKT cells. Although continuous administration of alpha-GalCer during ovalbumin (OVA) sensitization increased OVA-specific IgE levels and worsened eosinophil inflammation, a single administration of alpha-GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild-type mice. This inhibitory effect of alpha-GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN-gamma, and decreases in IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN-gamma increased in NK cells, but not in T or NKT cells, following alpha-GalCer administration. Induction of vascular cell adhesion molecule-1 in the lungs of wild-type mice was also significantly attenuated by treatment with alpha-GalCer. These effects of alpha-GalCer were abrogated in J alpha281-/- mice, which lack NKT cells, and in wild-type mice treated with anti-IFN-gamma Ab. Hence, our data indicate that alpha-GalCer suppresses allergen-induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.