Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.

A phase I study was performed to determine the safety and tolerability of injecting autologous CD34؉ cells into five patients with liver insufficiency. The study was based on the hypothesis that the CD34 ؉ cell population in granulocyte colony-stimulating factor (G-CSF)-mobilized blood contains a subpopulation of cells with the potential for regenerating damaged tissue. We separated a candidate CD34؉ stem cell population from the majority of the CD34 ؉ cells (99%) by adherence to tissue culture plastic. The adherent and nonadherent CD34؉ cells were distinct in morphology, immunophenotype, and gene expression profile. Reverse transcription-polymerase chain reactionbased gene expression analysis indicated that the adherent CD34؉ cells had the potential to express determinants consistent with liver, pancreas, heart, muscle, and nerve cell differentiation as well as hematopoiesis. Overall, the characteristics of the adherent CD34 ؉ cells identify them as a separate putative stem/progenitor cell population. In culture, they produced a population of cells exhibiting diverse morphologies and expressing genes corresponding to multiple tissue types. Encouraged by this evidence that the CD34 ؉ cell population contains cells with the potential to form hepatocyte-like cells, we gave G-CSF to five patients with liver insufficiency to mobilize their stem cells for collection by leukapheresis. Between 1 ؋ 10 6 and 2 ؋ 10 8 CD34 ؉ cells were injected into the portal vein (three patients) or hepatic artery (two patients). No complications or specific side effects related to the procedure were observed. Three of the five patients showed improvement in serum bilirubin and four of five in serum albumin. These observations warrant further clinical trials.

To test whether pancreatic duct cells are in vitro progenitors, they were purified from dispersed islet-depleted human pancreatic tissue using CA19-9 antibody. The purified fraction was almost entirely CK19؉ with no insulin ؉ cells, whereas the unpurified cells (crude duct) were 56% CK19 W hereas islet transplantation is an effective and beneficial treatment for type 1 diabetes, its application is limited by the shortage of islets. A possible solution is to generate insulin-producing cells from adult stem/progenitor cells of the pancreas. In vivo new ␤-cells are generated through replication of preexisting ␤-cells and neogenesis, the latter from differentiation of non-hormone-expressing progenitor cells (1-8). Putative adult stem/progenitor cells from mouse pancreas have been expanded clonally and after manipulation were found to express low levels of insulin and other pancreatic markers (9,10). While these findings are provocative, it has not yet been shown that such cells can become fully functional ␤-cells (11).Our group reported that islet-like structures, which secrete insulin in response to glucose, could be generated from islet-depleted pancreatic tissue remaining after human islet isolation (12). These findings were confirmed and extended by Otonkoski and colleagues (13). The cell of origin has been suspected to be ductal in origin but has not been conclusively shown. Additionally, three other groups (14 -16) have reported that putative progenitor cells, which arose from human islet preparations, could be expanded through many passages and then be manipulated to reexpress islet hormones at low levels. Gershengorn et al. (16), Habener and colleagues (14,17) and Efrat and colleagues (18) have suggested that the expanding cells are ␤-cells that have undergone epithelial-mesenchymal transition, no longer express insulin, and have great capacity for expansion. However, even the purest human islet preparations are not pure islet cells but contain many contaminating duct, acinar, and connective tissue cells. Olson and colleagues (15) showed that serpinginous cells expressing vimentin and nestin had no islet hormones during expansion but acquired low levels of islet markers after manipulation of culture conditions. Similar cells were initially suggested to be the preexisting nestinpositive cells found in the islets and in the ductal stroma (17). All of these studies have raised the possibility of generating new islet cells in vitro from human pancreatic tissue, but in each case the cell of origin has not been identified; thus, it is not clear whether ␤-cells actually undergo such a transition.The purpose of this study is to test whether highly purified human adult pancreatic duct cells can differentiate in vitro into insulin-producing cells. To this end, extremely pure duct preparations were obtained following immunomagnetic sorting with CA19-9 antibody. The affinity purification step is highly selective for pancreatic duct epithelial cells and is performed immediately after islet purification. Our method is qu...

Adult Scandinavian H1-antihistamine-refractory CU patients reported high rates of healthcare usage and QoL impairment. Rates of pharmacological treatment use were low before study enrolment but increased to almost 100% during the baseline visit.

Patients with severe psoriasis have increased mortality risk compared with matched controls, due to a number of causes. Evidence to support an increased risk for patients with PsA was less convincing.

Trefoil factors (TFFs) 1, 2, and 3 are expressed in mucosal epithelia. TFFs are particular abundant in the intestine in which they play a crucial role in maintenance and restitution of the epithelium. Because pancreas developmentally arises from the primitive foregut, we explored the expression of TFFs in the pancreas in man and rat. Immunocytochemical staining of adult human pancreas showed abundant TFF3 immunoreactivity in pancreatic islets and some duct cells, whereas weak TFF1 and no TFF2 staining were detected. In the islets TFF3 localized to most insulin and some glucagon and pancreatic polypeptide-producing cells. TFF3 immunoreactivity was colocalized with insulin and glucagon in distinct cell clusters in human fetal pancreas at wk 14 and in the newborn rat pancreas. In isolated human and rat islets, TFF3 and TFF1 mRNA was identified by RT-PCR, and TFF3 protein was detected in human pancreas and islets by ELISA. Exposure of neonatal rat islets or insulinoma cells to GH, a known beta-cell growth factor, resulted in markedly increased TFF3 but decreased TFF1 mRNA levels. The effect of GH on TFF3 expression was confirmed by Western blot. Culture of neonatal rat islets in the presence of TFF3 resulted in attachment and migration of the islet cells, but no effects on proliferation, insulin secretion or cytokine-induced apoptosis were seen. These data demonstrate expression of TFFs in the endocrine pancreas, but their possible functions remain unknown.

Background: To date, there are no nationwide studies of the social and economic burden of psoriasis to patients in Denmark. Incentives for health care management based on patient-related outcomes and value (IMPROVE) in psoriasis and psoriatic arthritis is a project aimed at assisting movement from activity-based to outcome-based health care management. One of the key objectives in IMPROVE is to describe the disease-associated socioeconomic burden of psoriasis. Methods: A case-matched study of the impact of psoriasis on patients’ income, employment and health care costs in Denmark was performed. The IMPROVE study was a retrospective analysis of patients with a hospital diagnosis of psoriasis identified from the Danish National Patient Registry (NPR). In total, 13,025 psoriasis patients and 25,629 matched controls were identified from the NPR. Data from psoriasis patients and matched controls were compared for social and economic factors including income, employment, health care costs and risk of comorbidities. Results: Psoriasis was associated with increased health care costs (mean annual costs +116% compared to control, p < 0.001), peaking in the year of referral to hospital for psoriasis and sustained thereafter. Both direct and indirect costs were significantly higher for patients with psoriasis than controls (p < 0.001). In the years before and immediately following hospital diagnosis, the rates of employment were lower in psoriasis patients than controls. Comorbidities, including cardiovascular (odds ratio 1.93 [95% CI 1.77–2.09]) and psychiatric conditions (odds ratio 2.61 [95% CI 2.30–2.97]), were more prevalent in patients with psoriasis than controls. Conclusion: In Denmark, psoriasis has a significant impact on health care costs, income and employment, and is associated with a range of comorbidities.

Islet neogenesis, or the differentiation of islet cells from precursor cells, is seen in vitro and in vivo both embryonically and after birth. However, little is known about the differentiation pathways during embryonic development for human pancreas. Our previously reported in vitro generation of islets from human pancreatic tissue provides a unique system to identify potential markers of neogenesis and to determine the molecular mechanisms underlying this process. To this end, we analyzed the gene expression profiles of three different stages during in vitro islet generation: the Initial Adherent-, Expanded-, and Differentiated- stages. Samples from four human pancreases were hybridized to Affymetrix U95A GeneChips, and data analyzed using GeneSpring 7.0/9.0 software. Using Scatter plots we selected genes with a 2-fold or greater differential expression.. Of the 12,000 genes/ESTs present on these arrays, 295 genes including 38 acinar–enriched genes were selectively lost during the progression from the Initially Adherent stage to the Expanded stage; 468 genes were increased in this progression to Expanded tissue; and 529 genes had a two-fold greater expression in the Differentiated-stage than in the Expanded tissue. Besides the expected increases in insulin, glucagon and duct markers (mucin 6, aquaporin 1 and 5), the beta cell auto-antigen IA-2/phogrin was increased 5-fold in Differentiated. In addition developmentally important pathways, including Notch/jagged, Wnt/Frizzled, TGFβ superfamily (follistatin, BMPs and SMADs), retinoic acid (COUP-TFI, CRABP1, 2 and RAIG1) were differentially regulated during the expansion/differentiation. Two putative markers for islet precursor cells, UCHL1/PGP9.5 and DMBT1, were enhanced during the progression to differentiated cells, but only the latter could be a marker of islet precursor cells. We suggest that appropriate manipulation of these differentiation-associated pathways will enhance the efficiency of differentiation of insulin-producing beta cells in this in vitro model.