OBJECTIVEIt is generally admitted that the endocrine cell organization in human islets is different from that of rodent islets. However, a clear description of human islet architecture has not yet been reported. The aim of this work was to describe our observations on the arrangement of human islet cells.RESEARCH DESIGN AND METHODSHuman pancreas specimens and isolated islets were processed for histology. Sections were analyzed by fluorescence microscopy after immunostaining for islet hormones and endothelial cells.RESULTSIn small human islets (40–60 μm in diameter), β-cells had a core position, α-cells had a mantle position, and vessels laid at their periphery. In bigger islets, α-cells had a similar mantle position but were found also along vessels that penetrate and branch inside the islets. As a consequence of this organization, the ratio of β-cells to α-cells was constantly higher in the core than in the mantle part of the islets, and decreased with increasing islet diameter. This core-mantle segregation of islet cells was also observed in type 2 diabetic donors but not in cultured isolated islets. Three-dimensional analysis revealed that islet cells were in fact organized into trilaminar epithelial plates, folded with different degrees of complexity and bordered by vessels on both sides. In epithelial plates, most β-cells were located in a central position but frequently showed cytoplasmic extensions between outlying non–β-cells.CONCLUSIONSHuman islets have a unique architecture allowing all endocrine cells to be adjacent to blood vessels and favoring heterologous contacts between β- and α-cells, while permitting homologous contacts between β-cells.

A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human beta-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of beta-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1beta and glucose-induced apoptosis. IL-1beta-induced beta-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties of HDL, apolipoprotein A1 (the main protein component of HDL), or sphingosine-1-phosphate (a bioactive sphingolipid mostly carried by HDL). In murine beta-cells, the protective effect of HDL against IL-1beta-induced apoptosis was also observed in the absence of the HDL receptor scavenger receptor class B type 1. Our data show that both LDL and HDL affect function or survival of beta-cells and raise the question whether dyslipidemia contributes to beta-cell failure and hence the manifestation and progression of type 2 diabetes mellitus.

These data suggest that, despite similar outcomes of the isolation procedure, islet graft function is significantly influenced by donor age. These results may have important consequences in the definition of pancreas allocation criteria.

Early carcinomas of the esophagus are histologically classified as adenocarcinoma or squamous cell carcinoma and microscopically subdivided into mucosal and submucosal carcinomas depending on infiltration depth. The prevalence of lymph node metastasis in mucosal carcinoma remains low. However, lymph node metastases arise frequently from tumors with submucosal infiltration, with increasing prevalence in the deeper submucosal sublayers. According to current German guidelines, endoscopic resection is the recommended treatment in mucosal adenocarcinoma without histologic risk factors (lymphatic invasion 1, vascular invasion 1, >grade 2, R1-margin). In superficial submucosal infiltration without histologic risk factors, endoscopic resection can be considered. In squamous cell carcinoma, endoscopic resection is indicated up to middle layer mucosal carcinoma. Beyond these criteria, surgical resection should be considered. The gold standard is a subtotal transthoracic esophagectomy with two-field lymphadenectomy. Total esophagectomy is performed in cervical esophageal carcinoma and transhiatal extended gastrectomy in carcinoma of the cardia. Minimally invasive procedures show good oncologic results and reduce the morbidity of radical esophagectomy. Reduced morbidity might be an argument for surgical resection in borderline cases between endoscopic and surgical resection. In early squamous cell cancer, the combination of endoscopic resection and adjuvant chemoradiotherapy is a therapeutic option with promising results.

Ex vivo labeling of islets with superparamagnetic iron oxide (SPIO) nanoparticles allows posttransplant MRI imaging of the graft. In the present study, we compare two clinical grade SPIOs (ferucarbotran and ferumoxide) in terms of toxicity, islet cellular uptake, and MRI imaging. Human islets (80-90% purity) were incubated for 24 h with various concentrations of SPIOs (14-280 µg/ml of iron). Static incubations were performed, comparing insulin response to basal (2.8 mM) or high glucose stimulation (16.7 mM), with or without cAMP stimulation. Insulin and Perl's (assessment of iron content) staining were performed. Electronic microscopy analysis was performed. Labeled islets were used for in vitro or in vivo imaging in MRI 1.5T. Liver section after organ removal was performed in the same plane as MRI imaging to get a correlation between histology and radiology. Postlabeling islet viability (80 ± 10%) and function (in vitro static incubation and in vivo engraftment of human islets in nude mice) were similar in both groups. Iron uptake assessed by electron microscopy showed iron inclusions within the islets with ferucarbotran, but not with ferumoxide. MRI imaging (1.5T) of phantoms and of human islets transplanted in rats, demonstrated a strong signal with ferucarbotran, but only a weak signal with ferumoxide. Signal persisted for >8 weeks in the absence of rejection. An excellent correlation was observed between radiologic images and histology. The hepatic clearance of intraportally injected ferucarbotran was faster than that of ferumoxide, generating less background. A rapid signal decrease was observed in rejecting xenogeneic islets. According to the present data, ferucarbotran is the most appropriate of available clinical grade SPIOs for human islet imaging.Key words: Islet imaging; Islet transplantation; Iron nanoparticles; Magnetic resonance; Imaging INTRODUCTIONone of the most promising strategies (11,12,23,(29)(30)(31).The aim of the present study is to compare the use of the two commercially available, clinical grade iron oxUnlike for other types of organ transplantation, tests allowing the detection of early rejection after islet transide nanoparticles, ferucarbotran (Resovist) and ferumoxide (Feridex), in terms of iron uptake, toxicity, inplantation are lacking (9,19). Alteration of glycemic control occurs too late in the graft destruction process to sulin response, and MRI imaging ability, both in vitro and in vivo. enable graft salvage and islet graft biopsy (i.e., liver biopsy) is not sensitive enough, due to sampling issues MATERIALS AND METHODS (3,28). New strategies are currently under development, Animal Selection including immune monitoring, molecular monitoring (2), and islet graft imaging. Magnetic resonance imaging Male Lewis rats (Janvier, Le Genest, France; 300-500 g) and athymic nu/nu (nude) mice (Janvier, Le Gen-(MRI) after ex vivo islet labeling currently appears to be est, France) were used. All experiments were performed CMRL 1066-based medium, as described above, with SPIOs at iron co...