Use of Sponge-Foam Inserts in Compression Bandaging of Non-Healing Venous Leg Ulcers.

Objective: Venous leg ulcers (VLUs) caused by chronic venous insufficiency are difficult to treat. Outcomes after compression therapy and the current standard of care often used in conjunction with other options vary widely. We examined the effects of foam inserts on sub-bandage pressures in patients with VLUs and compared use of foam inserts in elastic and inelastic compression bandaging. Methods: Six patients (≥20 years old) with VLUs and skin perfusion pressure >40 mmHg were included. Each patient underwent weekly treatment regimens of debridement, dressing changes, and dual sponge-insert application followed by elastic (n=3) or inelastic (n=3) compression bandaging. The median resting sub-bandage pressures of the ulcer beds, wound sizes, and healing percentages were recorded. Wound beds were biopsied before and after treatment for histological assessment. Nine healthy volunteers served as controls during preliminary testing. Results: With proper sub-bandage pressures (>35 mmHg), the average healing time was 88.0±66 days, which was shorter than anticipated (i.e., ≥6 months). Combining large and local sponge-foam inserts increased sub-bandage pressures regardless of the compression bandage selected, with marked improvements seen in deeper wounds. Conclusion: Layering one or two sponge-foam inserts beneath compression bandages facilitates uniform and optimal wound-bed pressure, which accelerates the healing of VLUs.

Signaling between pancreatic ß cells and macrophages via S100 calcium-binding protein A8 exacerbates ß-cell apoptosis and islet inflammation.

Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic ß cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in ß-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked ß-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives ß-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent ß-cell loss in patients with diabetes.

Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model.

Non-alcoholic fatty liver disease (NAFLD) is associated with various metabolic disorders, and the therapeutic strategies for treating NAFLD and non-alcoholic steatohepatitis (NASH) have not been fully established. In the present study, we examined whether lipid-lowering agents inhibited the progression of NAFLD and tumorigenesis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma model mouse (STAM mice) generated by streptozotocin injection and a high-fat diet. Seven-week-old STAM mice were divided into groups fed a high-fat diet (Ctl) or a high-fat diet supplemented with ezetimibe (Ez), fenofibrate (Ff), rosuvastatin (Rs), ezetimibe plus fenofibrate (EF), or ezetimibe plus rosuvastatin (ER) for 4 weeks. At the end of the experiments, an oral glucose tolerance test, an insulin tolerance test, biochemical analyses using serum and liver, and a histological analysis of liver were performed in 11-week-old STAM mice. The lipid-lowering agents did not affect the body weight or the casual blood glucose levels in any of the groups. The serum triglyceride level was significantly decreased by Ff, Rs, and EF. Glucose tolerance was improved by Ez and Ff, but none of these agents improved insulin sensitivity. A histochemical analysis revealed that the lipid-lowering agents, with the exception of Rs, significantly inhibited the progression of hepatic steatosis. Nonetheless, no significant changes in the incidence of hepatic tumors were observed in any of the groups. Lipid-lowering agents inhibited the progression of hepatic steatosis without suppressing tumorigenesis in STAM mice. Our data has implications for the mechanism underlying steatosis-independent hepatic tumorigenesis in mice.

ß-Cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice.

The glucokinase-induced up-regulation of insulin receptor substrate 2 (IRS-2) plays an important role in ß-cell adaptive proliferation in response to high-fat diet-induced insulin resistance. This study aimed to investigate the role of IRS-2 in the proliferation of ß-cells after a 60% partial pancreatectomy. IRS-2-deficient (IRS-2(-/-)) mice or wild-type mice were subjected to a pancreatectomy (60% partial pancreatectomy) or a sham operation (Sham). The ß-cell proliferation and gene expression profiles of the islets were then assessed. Gene expression in islets from pancreatectomized and Sham C57BL/6J male mice was analyzed using a cDNA microarray analysis. To compare with ß-cell proliferation induced by a high-fat diet, Gck(+/-) mice subjected to a pancreatectomy were also analyzed. The IRS-2(-/-) mice exhibited ß-cell expansion and a significant increase in ß-cell proliferation after the pancreatectomy, compared with the Sham group. Although glucose-stimulated insulin secretion from islets was not impaired, IRS-2(-/-) mice manifested severe hyperglycemia after the pancreatectomy. The expression levels of Aurora kinase B, Cyclin A, and Cyclin B1 in the pancreatectomized islets were also enhanced in the IRS-2(-/-) mice. A gene set enrichment analysis suggested an association between the genes that were up-regulated in the pancreatectomized islets and those involved in M phase progression in the cell cycle. ß-Cell proliferation after a pancreatectomy was observed even in the Gck(+/-) mice. In conclusion, IRS-2 was not required for ß-cell proliferation but might be needed for functional ß-cell mass, after a pancreatectomy. A partial pancreatectomy in mice may be an attractive model for the development of new strategy for exploring the unique nature of ß-cell proliferation.

Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic ß-cells.

The derangement of endoplasmic reticulum (ER) homeostasis triggers ß-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in ß-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in ß-cells. GKA administration improved ß-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in ß-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in ß-cell apoptosis, compared with Akita mice. ß-cell-specific IRS-2-overexpressing (ßIRS-2-Tg) Akita mice showed less ß-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but ßIRS-2-Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against ß-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in ß-cells.

AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.

The precise role of AMP-activated protein kinase (AMPK), a target of metformin, in pancreatic ß cells remains controversial, even though metformin was recently shown to enhance the expression of incretin receptors (GLP-1 and GIP receptors) in pancreatic ß cells. In this study, we investigated the effect of AMPK in the regulation of incretin receptors expression in pancreatic islets. The phosphorylation of AMPK in the mouse islets was decreased by increasing glucose concentrations. We showed the expression of incretin receptors in bell-shaped response to glucose. Expression of the incretin receptors in the isolated islets showed higher levels under a medium glucose concentration (11.1 mM) than that under a low glucose concentration (2.8 mM), but was suppressed under a high glucose concentration (22.2 mM). Both treatment with an AMPK inhibitor and DN-AMPK expression produced a significant increase of the incretin receptors expression under a low glucose concentration. By contrast, in hyperglycemic db/db islets, the enhancing effect of the AMPK inhibitor on the expression of incretin receptors was diminished under a low glucose concentration. Taken together, AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.

Trefoil factor 2 promotes cell proliferation in pancreatic ß-cells through CXCR-4-mediated ERK1/2 phosphorylation.

Decreased ß-cell mass is a hallmark of type 2 diabetes, and therapeutic approaches to increase the pancreatic ß-cell mass have been expected. In recent years, gastrointestinal incretin peptides have been shown to exert a cell-proliferative effect in pancreatic ß-cells. Trefoil factor 2 (TFF2), which is predominantly expressed in the surface epithelium of the stomach, plays a role in antiapoptosis, migration, and proliferation. The TFF family is expressed in pancreatic ß-cells, whereas the role of TFF2 in pancreatic ß-cells has been obscure. In this study, we investigated the mechanism by which TFF2 enhances pancreatic ß-cell proliferation. The effects of TFF2 on cell proliferation were evaluated in INS-1 cells, MIN6 cells, and mouse islets using an adenovirus vector containing TFF2 or a recombinant TFF2 peptide. The forced expression of TFF2 led to an increase in bromodeoxyuridine (BrdU) incorporation in both INS-1 cells and islets, without any alteration in insulin secretion. TFF2 significantly increased the mRNA expression of cyclin A2, D1, D2, D3, and E1 in islets. TFF2 peptide increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. A MAPK kinase inhibitor (U0126) abrogated the TFF2 peptide-mediated proliferation of MIN6 cells. A CX-chemokine receptor-4 antagonist also prevented the TFF2 peptide-mediated increase in ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells. These results indicated that TFF2 is involved in ß-cell proliferation at least partially via CX-chemokine receptor-4-mediated ERK1/2 phosphorylation, suggesting TFF2 may be a novel target for inducing ß-cell proliferation.

Simple new technique for sonographic measurement of the thyroid in neonates and small children.

PURPOSE: The aim of this study was to determine whether the ratio of the thyroid width (Th) to the trachea width (Tr) is a useful technique for sonographic estimation of thyroid size in neonates and small children. METHODS: We prospectively performed sonographic examination of the thyroid gland in 30 pediatric subjects ranging in age from 1 week to 12 years. The sum of the maximum width of the left thyroid lobe and the maximum width of the right lobe was considered the Th. Each subject's thyroid was classified as small, normal sized, or large on the basis of the Th value in reference to the subject's body height. The ratios of the Th to the Tr were then calculated and compared among the 3 groups by 1-way analysis of variance. Correlation and regression analyses were performed to determine the correlation between body height and Tr. A p value of less than 0.05 was considered significant. RESULTS: The mean Th/Tr ratios (+/- standard deviations) for the 3 groups were as follows: small, 1.25 +/- 0.19; normal sized, 2.09 +/- 0.19; and large, 4.10 +/- 2.42. The difference in the Th/Tr ratios between the 3 groups was statistically significant (p < 0.0001). A significant positive correlation was found between Tr and body height (p < 0.001; r = 0.85). CONCLUSIONS: The Th/Tr ratio is a simple, practical parameter for estimating the size of the thyroid gland in neonates and small children.