The age of onset of diabetes and glutamic acid decarboxylase titer measured long after diagnosis are associated with the clinical stage of slow-onset type 1 diabetes.

AIMS: Diabetes mellitus is divided into 3 clinical stages: not insulin requiring, insulin requiring for control, and insulin requiring for survival. We investigated the clinical characteristics of patients with slow-onset type 1 diabetes (T1D) to examine which clinical factors influence the clinical stage. METHODS: One hundred fifty patients with slow-onset T1D were divided into 3 groups based on disease stage, and clinical features were compared among these groups. The patients were also divided into 4 groups based on the age of onset and the glutamic acid decarboxylase antibody (GAD-Ab) titer, which was measured long after diagnosis (mean, 9.2 years). The frequencies of the 3 stages were compared among these 4 groups. RESULTS: The age of onset and the log (GAD-Ab) titer differed significantly among the 3 stages. The number of patients not requiring insulin was significantly higher and the number of those requiring insulin for survival was significantly lower in the group in which the age of onset was ≥50 and the log (GAD-Ab) titer <0.6, while the opposite pattern was observed in the group in which the age of onset was <50 and the log(GAD-Ab) titer ≥0.6. CONCLUSIONS: Our results suggest that the combination of the age of onset and GAD-Ab titer measured long after diagnosis might predict the clinical stage of slow-onset T1D.

Effect of human leukocyte antigen class II genes on insulin deficiency in slow-onset type 1 diabetes in the Japanese population.

The aim of this study is to determine the contribution of human leukocyte antigen (HLA) class II genes to insulin deficiency in slow-onset type 1 diabetes (T1D). Our results suggest that the susceptibility conferred by HLA subtypes to slow-onset T1D differs between insulin-deficient patients and non-insulin-deficient patients.

Effect of human leukocyte antigen class II genes on acute-onset and slow-onset type 1 diabetes in the Japanese population.

The contribution of the human leukocyte antigen (HLA) subtype to slow-onset type 1 diabetes (T1D), which includes latent autoimmune diabetes in adults (LADA), remains unclear in the Japanese population. We compared the frequencies of HLA DR-DQ haplotypes and genotypes of 72 acute-onset T1D patients, 100 slow-onset T1D patients, and 292 control subjects. The frequencies of DRB1*0405-DQB1*0401 (DR4) and DRB1*1302-DQB1*0604 (DR13) haplotypes were significantly higher in acute-onset patients, whereas that of the DRB1*1502-DQB1*0601 haplotype was significantly lower than those in slow-onset diabetes patients and controls. In contrast, DRB1*0802-DQB1*0302 (DR8) and DRB1*0901-DQB1*0303 (DR9) haplotypes were significantly more frequent, and the DRB1*1501-DQB1*0602 haplotype was extremely rare, in acute-onset patients and slow-onset diabetes patients. Genotype analysis revealed that DR4/9, DR4/13, and DR9/13 in acute-onset patients indicated high odds ratios (6.81, 12.0, and 15.6, respectively), whereas DR4/8 was significantly more frequent in slow-onset diabetes patients, but not in acute-onset patients. Our study demonstrated for the first time that the DR8 haplotype confers susceptibility to slow-onset T1D in the Japanese population. Moreover, there potentially are hierarchies for predisposing haplotypes, namely, DR13 > DR4 > DR9 > DR8 and for protective haplotypes, namely, DRB1*1501-DQB1*0602 > DRB1*1502-DQB1*0601.

The human leukocyte antigen class II gene has different contributions to autoimmune type 1 diabetes with or without autoimmune thyroid disease in the Japanese population.

AIM: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AITD). The human leukocyte antigen (HLA) has been extensively studied in these diseases. We aimed to clarify the contribution of AITD on the susceptibility and resistance of the HLA subtype to autoimmune T1D in the Japanese population. METHODS: The frequency of the HLA DR-DQ haplotype was compared between 56 autoimmune T1D patients with AITD and 71 autoimmune T1D patients without AITD, and control subjects. RESULTS: The frequencies of DRB1 0405-DQB1 0401, DRB1 0802-DQB1 0302, and DRB1 0901-DQB1 0303 haplotypes were significantly higher in T1D patients with AITD than in control subjects. The frequencies of DRB1 0101-DQB1 0501, DRB1 0901-DQB1 0303, and DRB1 1302-DQB1 0604 haplotypes were significantly higher in T1D patients without AITD than in control subjects. The frequencies of DRB1 1101-DQB1 0301 and DRB1 1501-DQB1 0602 haplotypes were significantly lower in T1D patients with or without AITD than in control subjects. CONCLUSIONS: Our results suggest that the susceptibility of the HLA subtype to autoimmune T1D differs between T1D with AITD and T1D without AITD, whereas there is no difference between the two groups with regard to HLA subtypes that confer protection against autoimmune T1D.

Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese population.

AIM: This study aims at clarifying the human leukocyte antigen haplotypes and genotypes conferring susceptibility or resistance to type 1 diabetes in the Japanese population. METHODS: The frequencies of human leukocyte antigen DR-DQ haplotypes and genotypes were compared between 83 type 1 diabetic patients, except for fulminant type 1 diabetes, and control subjects in the Japanese population. The patients were divided by onset age into four groups (ages 5-14, 15-29, 30-49, and 50-71 years); the haplotype frequency was compared between each group. RESULTS: The frequencies of DRB1*0405-DQB1*0401 (DR4), DRB1*0802-DQB1*0302 (DR8), DRB1*0901-DQB1*0303 (DR9), and DRB1*1302-DQB1* 0604 (DR13) haplotypes were significantly higher in the patients than in the control subjects. The frequencies of DRB1* 1501-DQB1*0602 and DRB1*1502-DQB1*0601 haplotypes were significantly lower in the patients than in the controls. The frequencies of DR4/8, DR4/13, DR9/9, and DR9/13 genotypes were significantly higher in the patients than in the control subjects. The DR13 haplotype was the most frequent haplotype in the age group 30-49 years, whereas the other haplotypes but DR13 were the most frequent in the other age groups. CONCLUSION: DR4, DR8, DR9, and DR13 haplotypes confer susceptibility to type 1 diabetes in Japanese patients.

A case of symptomatic primary HIV infection.

A 30-year-old homosexual Japanese man had fourteen days of fever, malaise, appetite loss, sore throat, and four days of diarrhea and slightly congested eyes before he developed a skin eruption. He presented with measles-like exanthems on his face, trunk, and extremities. Deep red enanthems were seen on his left buccal mucosa opposite the premolar teeth, and whitish enanthems were seen on the buccal and gingival mucosa. HIV RNA was detected at the high concentration of 5.8 x 10(6) copies /ml in his serum. Cerebrospinal fluid examination revealed aseptic meningitis with 5,488 copies /ml of HIV RNA. Anti-HIV 1 antibodies against Gp160 and p24 tested by Western blot assay showed seroconversion on day 5 of his admission, seven days after he developed the skin eruptions. The fever lasted for three weeks from the initial onset, and the skin eruptions lasted for twelve days. Histopathologically, a mononuclear cell infiltration was seen mainly in the upper dermis surrounding small vessels and sweat ducts, with CD8+ cytotoxic T lymphocytes predominant. Additionally, CD1a+ putative interdigitating dendritic cells had also infiltrated perivascularly, and were surrounded by CD8+ and CD4+ T cells. In situ hybridization study failed to detect HIV products in skin biopsy specimens. Our findings suggested that CD8+ T cells and their interaction with CD1a+ dendritic cells in the skin may be important in inducing skin manifestations in acute HIV infections.

Intracellularly labeled pyramidal neurons in the cortical areas projecting to the spinal cord. I. Electrophysiological properties of pyramidal neurons.

To study cortical motor control, we examined electrical characteristics of pyramidal neurons in the present report, and intra- or juxta-columnar connections of the pyramidal neurons to corticospinal neurons in the accompanying report. Pyramidal neurons were intracellularly recorded and stained in slices of rat motorsensory cortices (areas FL, HL and M1) where many corticospinal neurons were labeled retrogradely. They were morphologically classified into classical, star and other modified pyramidal neurons, and electrophysiologically into regular-spiking (RS), intrinsic bursting (IB) and irregular-spiking (IS) neurons on the basis of spiking pattern in response to 500 ms depolarizing current pulses. RS responses were further divided into RS with slow adaptation (RS-SA) and RS with fast adaptation (RS-FA). The electrical properties were associated with the laminar location of the neurons; RS-SA responses were observed frequently in layer II/III and less frequently in layers IV-VI, and IB and IS responses were exclusively found in layers V and VI, respectively. Interestingly, all layer IV neurons in area FL/HL were RS-FA star-pyramidal neurons, whereas layer IV neurons in area M1 were RS-SA classical pyramidal neurons. Although weak stimulation of areas FL/HL and M1 is known to elicit movement, these results suggest different information processings between the two areas.

Intracellularly labeled pyramidal neurons in the cortical areas projecting to the spinal cord. II. Intra- and juxta-columnar projection of pyramidal neurons to corticospinal neurons.

Intra- or juxta-columnar connections of pyramidal neurons to corticospinal neurons in rat motorsensory cortices were examined with brain slices by combining intracellular staining with Golgi-like retrograde labeling of corticospinal neurons. Of 108 intracellularly labeled pyramidal neurons, 27 neurons were selected for morphological analysis by successful staining of their axonal arborizations and sufficient retrograde labeling of corticospinal neurons. Many varicosities of local axon collaterals of each pyramidal neuron were closely apposed to the dendrites of corticospinal neurons, suggesting the convergent projections of layer II-VI pyramidal neurons to corticospinal neurons. Particularly, the varicosities of a layer IV star-pyramidal neuron made two- to three-fold more appositions to the dendrites of corticospinal neurons than those of a pyramidal neuron in the other layers. Fifteen appositions were examined electron-microscopically and 60% of them made asymmetric axospinous synapses. The present results together with those of the preceding report suggest that thalamic inputs are conveyed to corticospinal neurons preferentially via layer IV star-pyramidal neurons with phasic response properties, and thereby might contribute to the initiation or switching of movement. In contrast, inputs with tonic response properties from the other layers seem to be integrated in corticospinal neurons, and might be useful in maintaining the activity of corticospinal neurons.