Studies on the mechanisms of altered exocrine acinar cell differentiation and ductal metaplasia following nitrosamine exposure using hamster pancreatic explant organ culture

Syrian golden hamster pancreatic organ explants were treatedwith either methylnitrosourea (MNU) or N-methyl-N-nitroso-N'-nitroguanidine(MNNG). In control explants treated with only dimethylsulfoxide,there was evidence of autophagy and crinophagy in acinar cells.Carcinogen-exposed explants showed increased numbers of autophagicand crinophagic vacuoles. In long-term cultured explants therewas an increase in the number of ducts over zero time controltissues. Eosinophilic cells similar to hepatocyte-like cellswere seen in 90% of the carcinogen-treated explant experimentsand in 45% of the controls. Nitrosamine exposure did not inducean increase in the overall amount of necrosis measured morphometrieally.Nitrosamine exposure in vitro appears to lead to a sequenceof events that follow carcinogen metabolism by the acinar cells.The changes that follow include altered cell morphology andtoxic cell injury evidenced by autophagic and crinophagic processes,regenertion of ductal appearing cells, the appearance of hepatocyte-likecells and an overall increase in the amount of ductal metaplasia.Within some of these ductal foci, several ductules show atypicalfeatures.     

Learning and behavioural difficulties but not microcephaly in three brothers resulting from undiagnosed maternal phenylketonuria

Universal screening introduced in the 1960s has reduced the incidence of learning disability resulting from phenylketonuria (PKU), which is a treatable condition. Nonetheless, PKU may still be having an impact on the paediatric-age population. We report a woman with previously undiagnosed PKU who was born before the onset of universal screening. She is of normal intelligence, and so the diagnosis was not suspected until after the birth of her three children. Her serum phenylalanine concentration was found to be in excess of 1 mmol/L, well into the toxic range. She has had three sons, all of whom have a significant degree of learning disability resulting from intrauterine exposure to toxic levels of phenylalanine. None of the sons had microcephaly, a physical sign that, if present, might have helped to point towards the correct diagnosis. We suggest that maternal PKU should be suspected where there is sibling recurrence of cognitive impairment, particularly where the mother was born before the initiation of the neonatal screening programme for PKU.