Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1*0401 (DR4) and DRB1*0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class II haplotypes may be associated with the onset age of type 1 diabetes.     

Allochronic Overlapping Malignancies After Renal Transplantation in a Patient with p53 Gene Mutation: Report of a Case

We report a rare case of the development of various tumors over a 16-year period after renal transplantation. A 56-year-old woman underwent renal transplantation using a US kidney. Immunosuppressive treatment consisted of a triple regimen of methylprednisolone, azathioprine, and mizoribine. Left breast cancer was diagnosed 9 years after the renal transplantation, then colon cancers and meningeal epidermal meningioma were diagnosed, 10 years and 12 years post-transplant, respectively. During the investigations for the breast and colon cancers, a p53 gene mutation was detected. A deterioration of renal function was found 16 years after the transplant and graft biopsy confirmed chronic rejection. We suggest that the effects of the immunosuppressive drugs combined with the p53 gene abnormality accelerated tumor development in this patient.     

Positive association between T-182C polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a japanese population

Norepinephrinergic neurotransmission in the central nervous system appears to have a major impact on the symptomatology in major depressive disorder and the human norepinephrine transporter (NET) gene is one of the key candidates for genetic studies in major depressive disorder. The authors established a new allele-specific PCR-based genotyping procedure and examined whether the NET T-182C polymorphism was associated with the susceptibility to major depressive disorder in a Japanese population. This study included 145 patients with major depressive disorder (according to DSM-IV) and 164 healthy volunteers. There was a significant difference in the genotype distribution between major depressive disorder patients and healthy volunteers (p = 0.02), and the C/C genotype was associated with lesser susceptibility to major depressive disorder. The NET T-182C polymorphism may be in part related to the pathophysiology of major depressive disorder in a Japanese population.     

Heat shock induces neurite outgrowth in PC12m3 cells via the p38 mitogen-activated protein kinase pathway

We investigated the role of the p38 mitogen-activated protein kinase (MAPK) pathway in heat-shock-induced neurite outgrowth of PC12 mutant cells in which nerve growth factor (NGF)-induced neurite outgrowth is impaired. When cultures of the PC12 mutant (PC12m3) cells were exposed to heat stress at 44 degrees C for 10 min, activity of p38 MAPK increased and neurite outgrowth was greatly enhanced. The neurite extension was inhibited by the p38 MAPK inhibitor BS203580. Longer heat treatment of PC12m3 cells provoked cell death, which was enhanced by SB203580. These findings suggest that heat-induced activation of p38 MAPK is responsible for the neurite outgrowth and survival of PC12m3 cells.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.     

Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma

Aim: Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs. METHODS: The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells. RESULTS: Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68% of HCCs, whereas Ang-2 was expressed in 81%, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2. CONCLUSIONS: These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.     

pH-dependent translocation of alpha-tocopherol transfer protein (alpha-TTP) between hepatic cytosol and late endosomes

BACKGROUND: alpha-Tocopherol transfer protein (alpha-TTP), a member of the Sec14 protein family, plays an important role in transporting alpha-tocopherol, a major lipid-soluble anti-oxidant, in the cytosolic compartment of hepatocytes and is known as a product of the causative gene for familial isolated vitamin E deficiency. It has been shown that the secretion of hepatocyte alpha-tocopherol taken up with plasma lipoproteins is facilitated by alpha-TTP. To explore the mechanism of alpha-TTP mediated alpha-tocopherol secretion, we investigated drugs which may affect this secretion. RESULTS: We found that, in a hepatocyte cell culture system, intracellular alpha-tocopherol transport is impaired by chloroquine, an agent known for its function of elevating the pH in acidic compartments. Under chloroquine treatment, the diffuse cytosolic distribution of alpha-TTP changes to a punctate pattern. Double-staining experiments with endocytosis markers revealed that alpha-TTP accumulates transiently on the cytoplasmic surface of late endosomal membranes. This phenomenon is specific for hepatoma cell lines or primarily cultured hepatocytes. Other members of the Sec14 family, such as cellular retinaldehyde-binding protein (CRALBP) and supernatant protein factor (SPF), do not show this accumulation. Furthermore, we elucidate that the obligatory amino acid sequence for this function is located between amino acids 21 and 50, upstream of the N-terminal end of the lipid-binding domain. CONCLUSION: We hypothesize that a liver-specific target molecule for alpha-TTP exists on the late endosomal membrane surface. This transient binding may explain the mechanism of how alpha-tocopherol is transferred from late endosomes to cytosolic alpha-TTP.