Incidence of childhood type 1 diabetes mellitus in Yamanashi Prefecture, Japan, 1986-2018.

Introduction: Several studies have examined the incidence of childhood T1DM in Japan from the 1970s onwards, but none have been long-term studies using registration data. We estimate the incidence of childhood type 1 diabetes mellitus (T1DM) from 1986 to 2018 in Yamanashi Prefecture, Japan. Methods: We began a population-based, long-term study of childhood T1DM in 1986 involving every hospital paediatrics department in Yamanashi Prefecture. In the Prefecture, every child newly diagnosed with T1DM is referred to a hospital, and therefore, almost 100% of new patients aged <15 years are registered. We calculated the incidence of T1DM among children aged <15 years from 1986 to 2018. All cases met the Japan Diabetes Society diagnostic criteria and were tested for T1DM-related autoantibodies whenever possible. Results: Ninety-nine patients (44 boys and 55 girls) were newly diagnosed with T1DM. The annual incidence among 5- to 9-year-olds increased by 5.35% over the study period (95% confidence interval 2.34%-8.35%, p = .0005), and there was a trend towards increasing 3-year incidence (15.52% increase, p = .0516). There were also trends towards increasing annual and 3-year incidence among 0- to 14-year-olds. However, there were no changes over time in annual or 3-year incidence in the 0-4 year or 10-14 year age groups. Conclusions: The incidence of T1DM in Yamanashi Prefecture increased among children aged 0-14 years over the study period, with the most significant increase occurring among 5- to 9-year-olds. These data suggest that the number of children aged <15 years with T1DM is gradually increasing in one of the local prefectures in Japan, Yamanashi Prefecture and that the age of onset is decreasing.

Bullous Pemphigoid Triggered by Thermal Burn Under Medication With a Dipeptidyl Peptidase-IV Inhibitor: A Case Report and Review of the Literature.

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies mainly target the hemidesmosomal component BP180 (also known as type XVII collagen) in basal keratinocytes. Various triggering factors are known to induce BP onset, including radiotherapy, burns, ultraviolet exposure, surgery, and the use of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used antihyperglycemic drugs. Here, we present a case of BP triggered by a thermal burn under medication with DPP4i. A 60-year-old man with type II diabetes had been treated with the DPP4i linagliptin for 1 year. After the right forearm experienced a thermal burn, blisters developed around the burned area and gradually spread over the whole body with the production of autoantibodies targeting the non-NC16A domain of BP180. The diagnosis of BP was confirmed by immunohistopathological examination. Upon withdrawal of linagliptin and treatment with topical steroid and minocycline, complete remission was achieved after 4 months. Previously, 13 cases of BP that developed after thermal burns have been reported, and our case shared some of the clinical features of these thermal burn-induced BP cases. Interestingly, the present case also showed the typical clinical, histopathological, and immunological features of the non-inflammatory type of DPP4i-associated BP (DPP4i-BP). Although the pathogenesis of BP remains uncertain, the present case suggests that DPP4i may trigger the onset of BP similarly to a thermal burn. In addition, the clinical and histopathological features of DPP4i-BP may be distinct from other types of BP.

Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases.

Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do.

Maternal exposure of low dose of TCDD modulates the expression of estrogen receptor subunits of male gonads in offspring.

We have analyzed the effects of low-dose transplacental and lactational exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression relating to the dioxin and sexual hormone cascade, and demonstrated the effects on testicular growth and sexual maturation in male offspring rats. TCDD (10 ng/kg) was administered to dams on Days 7 and 14 of gestation, and on Days 0, 7 and 14 after delivery. Gene expression of cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) in the liver of 17-day-old rats was significantly increased compared with controls. Furthermore, expression of estrogen receptors (ER)alpha and ERbeta was significantly increased at 17 and 42 days old, respectively in the testis of TCDD-administered rats compared with controls. Although testicular weight and the seminiferous tubule diameter were increased in 17-day-old rats, there was no difference in the number of germ cells between TCDD-treated and control animals. The expressions of androgen receptor and inhibin subunit genes were not significantly changed. These findings suggest that low-dose exposure of TCDD leads to unusual development of the testis by perturbation of steroid hormone homeostasis.

Utilization study of stems and leaves of Tienchi Ginseng. I. Anti-hypertensive effect of stems and leaves of Tienchi Ginseng on stroke-prone spontaneously hypertensive rat (SHRSP).

Tienchi ginseng tea was prepared from stems and leaves of Tienchi ginseng which is a special product in China. The increase in systolic blood pressure (SBP) was significantly inhibited by the consumption of a 4% this tea solution as drinking water from the prehypertensive stage (6 weeks of age) in male stroke-prone spontaneously hypertensive rats (SHRSP). A similar intake from the hypertensive stage also showed an anti-hypertensive effect. In contrast, a similar intake had no effect on SBP of normotensive Wistar Kyoto rats. We found that the rhizome of Tienchi ginseng contained two types of saponin: 20(s)-protopanaxadiol (PPD) such as ginsenosides Rb(1) and Rd having a hypotensive effect, and 20(s)-protopanaxatriol (PPT) such as ginsenosides Rg(1) and Re having a hypertensive effect. In contrast, the tea sample contained PPD and gamma-aminobutyric acid (GABA), but no PPT. These results suggest that drinking this tea infusion would be useful for controlling hypertension.

Proteomic analysis of serum, outflow dialysate and adsorbed protein onto dialysis membranes (polysulfone and pmma) during hemodialysis treatment using SELDI-TOF-MS.

AIMS: Alterations in the profiling of peptides and proteins in the serum, outflow dialysate and adsorbed protein on the dialysis membrane were investigated. METHODS: Alterations in the protein profiling of routine hemodialysis using polysulfone (TS-UL) and PMMA (moderate flux membrane of polymethylmethacrylate: BK-U) in 8 patients and that of adsorption onto polysulfone and PMMA membranes in 4 patients were evaluated by SELDI-TOF-MS and ProteinChip array. Mass-to-charge ratios (m/z) between 2,000 and 120,000 were analyzed. RESULTS: The protein with a relative intensity of m/z 11,730 measured by SELDI-TOF-MS was present in a small amount in the outflow dialysate and in a large amount in adsorption (identified as beta2-microglobulin) onto PMMA membrane. Unexpectedly, 68 molecular masses of peptides that were adsorbed more onto polysulfone than onto PMMA membrane were observed. There were more peptides less than m/z 11,730 adsorbed onto polysulfone membrane than onto PMMA membrane. Dominant peaks, m/z 6,629 and 6,431 adsorbed onto polysulfone membrane were identified as apolipoprotein CI and truncated apolipoprotein CI, respectively. 37 proteins with molecular weights larger than m/z 11,730 showed greater filtration through PMMA membrane than through polysulfone membrane. 149 molecular masses that were adsorbed onto PMMA or more onto PMMA membrane than onto polysulfone membrane were observed. CONCLUSION: This experiment suggests that membrane adsorption is an important mechanism for the removal of middle-molecular-weight proteins by hemodialysis using not only PMMA membrane but also polysulfone membrane. Adsorption of peptide or protein onto a dialysis membrane may depend not only on the membrane material, but also on the peptide or protein.

IQGAP1: a key regulator of adhesion and migration.

The dynamic rearrangement of cell-cell adhesion is one of the major physiological events in tissue development and tumor metastasis. Polarized cell migration, another key event, is a tightly regulated process that occurs during tissue development, chemotaxis and wound healing. Rho-family small GTPases, especially Rac1 and Cdc42, play pivotal roles in these processes through one of their effectors, IQGAP1. Recent studies reveal that IQGAP1 regulates cadherin-mediated cell-cell adhesion both positively and negatively. It captures and stabilizes microtubules through the microtubule-binding protein CLIP-170 near the cell cortex, leading to establishment of polarized cell morphology and directional cell migration. Furthermore, Rac1 and Cdc42 link the adenomatous polyposis coli (APC) protein to actin filaments through IQGAP1 at the leading edge and thereby regulate polarization and directional migration.

Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration.

Rho family GTPases, particularly Rac1 and Cdc42, are key regulators of cell polarization and directional migration. Adenomatous polyposis coli (APC) is also thought to play a pivotal role in polarized cell migration. We have found that IQGAP1, an effector of Rac1 and Cdc42, interacts directly with APC. IQGAP1 and APC localize interdependently to the leading edge in migrating Vero cells, and activated Rac1/Cdc42 form a ternary complex with IQGAP1 and APC. Depletion of either IQGAP1 or APC inhibits actin meshwork formation and polarized migration. Depletion of IQGAP1 or APC also disrupts localization of CLIP-170, a microtubule-stabilizing protein that interacts with IQGAP1. Taken together, these results suggest a model in which activation of Rac1 and Cdc42 in response to migration signals leads to recruitment of IQGAP1 and APC which, together with CLIP-170, form a complex that links the actin cytoskeleton and microtubule dynamics during cell polarization and directional migration.

Positive role of IQGAP1, an effector of Rac1, in actin-meshwork formation at sites of cell-cell contact.

The small guanosine triphosphatase Rac1 is activated by E-cadherin-mediated cell-cell adhesion and is required for the accumulation of actin filaments, E-cadherin, and beta-catenin at sites of cell-cell contact. However, the modes of activation and action of Rac1 remain to be clarified. We here found that suppression of IQGAP1, an actin-binding protein and an effector of Rac1, by small interfering RNA apparently reduced the accumulation of actin filaments, E-cadherin, and beta-catenin at sites of cell-cell contact in Madin-Darby canine kidney II epithelial cells under the conditions in which knockdown of Rac1 reduced them. Knockdown of Rac1 did not affect the localization of these junctional components in cells expressing a constitutively active IQGAP1 mutant defective in Rac1/Cdc42 binding. Knockdown of either Rac1 or IQGAP1 accelerated the 12-O-tetradecanoylphorbol-13-acetate-induced cell-cell dissociation. The basal Rac1 activity, which was maintained by E-cadherin-mediated cell-cell adhesion, was inhibited in the IQGAP1-knocked down cells, whereas the Rac1 activity was increased in the cells overexpressing IQGAP1. Together, these results indicate that Rac1 enhances the accumulation of actin filaments, E-cadherin, and beta-catenin by acting on IQGAP1 and suggest that there exists a positive feedback loop comprised of "E-cadherin-mediated cell-cell adhesion --> Rac1 activation --> actin-meshwork formation by IQGAP1 --> increasing E-cadherin-mediated cell-cell adhesion."