In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to β cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent β cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.

Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic β cell-specific cholesterol homeostasis in insulin secretion as well as in β cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in β cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in β cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse β cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.

Since their earliest description, keloids and hypertrophic scars have beleaguered patients and clinicians alike. These scars can be aesthetically disfiguring, functionally debilitating, emotionally distressing, and psychologically damaging, culminating in a significant burden for patients. Our current understanding of keloid pathophysiology has grown and continues to advance while molecular biology, genetics, and technology provide ever-deepening insight into the nature of wound healing and the pathologic perturbations thereof. Greater understanding will lead to the development and application of refined therapeutic modalities. This article provides an overview of our current understanding of keloids, highlighting clinical characteristics and diagnostic criteria while providing a comprehensive summary of the many therapeutic modalities available. The proposed mechanism, application, adverse events, and reported efficacy of each modality is evaluated, and current recommendations are summarized.

OBJECTIVE-The activation of ␤-cell genes, particularly of those encoding preproinsulin, requires an appropriate euchromatin (or "open") DNA template characterized by hypermethylation of Lys4 of histone H3. We hypothesized that this modification is maintained in islet ␤-cells by the action of the histone methyltransferase Set7/9. RESEARCH DESIGN AND METHODS-To identify the role of Set7/9, we characterized its expression pattern and gene regulation and studied its function using RNA interference in both cell lines and primary mouse islets.RESULTS-Within the pancreas, Set7/9 protein shows striking specificity for islet cells, including ␣-and ␤-cells, as well as occasional cells within ducts. Consistent with these findings, the Set7/9 gene promoter contained an islet-specific enhancer located between Ϫ5,768 and Ϫ6,030 base pairs (relative to the transcriptional start site) that exhibited Pdx1-responsive activation in ␤-cells. To study Set7/9 function, we depleted insulinoma cells and primary mouse islets of Set7/9 protein using siRNA. Following siRNA treatment, we observed striking repression of genes involved in glucose-stimulated insulin secretion, including Ins1/2, Glut2, and MafA. These changes in transcription were accompanied by loss of dimethylated H3 Lys4 and RNA polymerase II recruitment, particularly at the Ins1/2 and Glut2 genes. Consistent with these data, depletion of Set7/9 in islets led to defects in glucose-stimulated Ca 2ϩ mobilization and insulin secretion.CONCLUSIONS-We conclude that Set7/9 is required for normal ␤-cell function, likely through the maintenance of euchromatin structure at genes necessary for glucose-stimulated insulin secretion. Diabetes 58: [185][186][187][188][189][190][191][192][193] 2009

Three-dimensional (3D) printing refers to a number of manufacturing technologies that create physical models from digital information. Radiology is poised to advance the application of 3D printing in health care because our specialty has an established history of acquiring and managing the digital information needed to create such models. The 3D Printing Task Force of the Radiology Research Alliance presents a review of the clinical applications of this burgeoning technology, with a focus on the opportunities for radiology. Topics include uses for treatment planning, medical education, and procedural simulation, as well as patient education. Challenges for creating custom implantable devices including financial and regulatory processes for clinical application are reviewed. Precedent procedures that may translate to this new technology are discussed. The task force identifies research opportunities needed to document the value of 3D printing as it relates to patient care.

The Association of University Radiologists Radiology Research Alliance Task Force on three-dimensional (3D) printing presents a review of the logistic considerations for establishing a clinical service using this new technology, specifically focused on implications for radiology. Specific topics include printer selection for 3D printing, software selection, creating a 3D model for printing, providing a 3D printing service, research directions, and opportunities for radiologists to be involved in 3D printing. A thorough understanding of the technology and its capabilities is necessary as the field of 3D printing continues to grow. Radiologists are in the unique position to guide this emerging technology and its use in the clinical arena.

No abstract

The antioxidant and anti-inflammatory compound AGI-1067 (succinobucol) has potential as an oral anti-diabetic agent. AGI-1067 reduces H b A1c, improves fasting plasma glucose, and reduces newonset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10uM AGI-1067 increased glucose-stimulated insulin secretion (11mM) without affecting secretion in basal (3mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7mM and 11mM glucose, but had no effect in 28mM or basal glucose. AGI-1067-pretreated islets also showed enhanced calcium responses to methyl pyruvate and alphaketoisocaproate at low doses, but not high doses. The AGI-1067-mediated effects on glucosestimulated calcium were maintained during continuous diazoxide exposure, suggesting effects on the KATP-channel-independent pathway. AGI-1067 also reduced cytokine-induced islet cell death and expression of iNOS, a key component in cytokine signaling. This is the first report of direct stimulatory and protective effects of a first-in-class potential anti-diabetic agent on pancreatic islets.