In contrast to the considerable body of data on pancreas development in rodents, information on pancreas development in humans is scant. We previously described a model in which mature beta cells developed from human embryonic pancreas: human embryonic pancreas was grafted under the kidney capsule of scid mice, beta cells were then seen to develop in the graft. Here, we showed that not only beta cells, but also other endocrine cells, acinar cells and ducts develop in this model. We then used this model to probe the mechanisms underlying acinar and beta cell development in the human embryonic pancreas. BrdU pulse/chase experiments produced evidence of clonal acinar cell development: the first acinar cells to appear proliferated, thereby expanding the acinar cell population. In contrast, beta cell development was regulated by the proliferation of pancreatic progenitor cells, followed by beta-cell differentiation. We then showed that early progenitors expressing PDX1 proliferated, whereas late endocrine progenitors expressing Ngn3 did not. This proliferative capacity of early endocrine progenitor cells in embryonic human pancreas may hold promise for obtaining human beta-cell expansion. Developmental Dynamics 234: 339 -345, 2005.
Aims/hypothesis: Gene transfer into pancreatic beta cells, which produce and secrete insulin, is a promising strategy to protect such cells against autoimmune destruction and also to generate beta cells in mass, thereby providing a novel therapeutic approach to treat diabetic patients. Until recently, exogenous DNA has been directly transferred into mature beta cells with various levels of success. We investigated whether exogenous DNA could be stably transferred into pancreatic stem/progenitor cells, which would subsequently differentiate into mature beta cells expressing the transgene. Methods: We designed transplantation and tissue culture procedures to obtain ex vivo models of pancreatic development. We next constructed recombinant lentiviruses expressing enhanced green fluorescent protein (eGFP) under the control of either the rat insulin promoter or a ubiquitous promoter, and performed viral infection of rat embryonic pancreatic tissue. Results: Embryonic pancreas infected with recombinant lentiviruses resulted in endocrine cell differentiation and restricted cell type expression of the transgene according to the specificity of the promoter used in the viral construct. We next demonstrated that the efficiency of infection could be further improved upon infection of embryonic pancreatic epithelia, followed by their in vitro culture, using conditions that favour endocrine cell differentiation. Under these conditions, endocrine stem/progenitor cells expressing neurogenin 3 are efficiently transduced by recombinant lentiviral vectors.Moreover, when eGFP was placed under the control of the insulin promoter, 70.4% of the developed beta cells were eGFP-expressing cells. All of the eGFP-positive cells were insulin-producing cells. Conclusions/interpretation: We have demonstrated that mature rat pancreatic beta cells can be stably modified by infecting pancreatic stem/progenitor cells that undergo endocrine differentiation.
It is unusual to diagnose pleuro-pulmonary herpes simplex virus (HSV) infection during the neonatal period when no skin lesions or meningo-encephalitis are present, especially with no antecedents of maternal herpes. We describe such a case here.The patient was born at 38 weeks gestation by vaginal delivery (no maternal herpes antecedents) and on day 4 of life, presented with hyperthermia and signs of shock, leading to a suspected diagnosis of septic shock. Intravascular fluid replacement and vasoactive drugs were administered and a wide ranging course of antibiotics was initiated. Biological analysis revealed a discrete inflammatory syndrome (CRP 40 mg/l), thrombocytopenia (61,000/mm 3 ) and hepatic cytolysis (ALAT 440 IU/l, ASAT 114 IU/l). The leukocyte count was 6,800/mm 3 (84% neutrophils, 11% lymphocytes). The chest X-ray film revealed an alveolo-interstitial syndrome. The alveolar syndrome became aggravated with the presence of a bilateral pleural effusion. Pleural drainage produced an exudate with 52 nucleate cells/ mm 3 containing 95% mono-macrophages and some giant cells with hyper-basophilic cytoplasm,characteristic of a viral infection (Fig. 1). Treatment with acyclovir and gancyclovir was therefore initiated. On day 8, the clinical condition deteriorated further with a profound state of haemodynamic shock, major hepatocellular failure (ALAT 5521 IU/l, ASAT 1099 IU/l, prothrombin time 16%, fibrinogen 0.24 g/l), and renal failure leading to death. Within the last 48 h, a very large amount of pleural fluid (ca. 350 ml/day) was produced.Diagnosis of HSV type II infection was confirmed by cell culture of the pleural fluid and the tracheal aspirate; and by PCR of the pleural fluid, the tracheal aspirate, the CSF (no cells) and the blood. Serology, on the other hand, was negative. A maternal vaginal sample taken 1 week after delivery showed no signs of the presence of HSV; maternal serology, however, was positive (IgM). A post-mortem examination was carried out. HSV DNA detection by PCR was positive in the samples from the liver and lungs.This case with such significant pleural effusions during a neonatal herpetic infection is the fifth such to be documented to date. In neonatal HSV infection, there are localised and disseminated forms. The localised cutaneous and mucosal forms have a good short-term prognosis but there is a 5% risk of neuro-sensorial sequelae if the problem recurs [6]. With the localised CNS forms, the mortality rate is 10% to 50% with the rate of neurosensorial sequelae being 50% [2]. The disseminated forms, affecting the lungs, liver, adrenal glands and brain have a poor prognosis with a mortality rate of between 57% and 85% [2].The clinical signs of our patient were those traditionally described in disseminated neonatal infections Fig. 1 Giant cell with hyper-basophilic cytoplasm Eur
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