Neonatal eosinophilic gastroenteritis: possible in utero sensitization to cow's milk protein.

Rectal bleeding in neonates is an alarming sign that suggests a possible serious underlying condition, such as infection or bleeding disorder that would necessitate hospitalization and prompt intervention. We report a case of eosinophilic gastroenteritis caused by cow's milk protein allergy in a one-day- old infant, who presented with frankly bloody stools associated with massive gastrointestinal and peripheral blood eosinophilia prior to initiation of enteral feedings. The patient's outcome was favorable, with complete spontaneous recovery in one week, after a period of bowel rest, parenteral nutrition, and use of amino acid formula. The eosinophilia was also transient and gradually resolving by two months of age. Rectal bleeding secondary to allergic colitis caused by cow's milk sensitization may occur in neonates, and failure to appreciate this possibility may lead to inappropriate diagnostic or therapeutic intervention.

Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a multisystem disorder resulting from mutations in the NPC1 gene that encodes a protein involved in intracellular cholesterol trafficking. Significant liver dysfunction is frequently seen in patients with this disease. The current studies used npc1 mutant mice to investigate the association between liver dysfunction and unesterified cholesterol accumulation, a hallmark of NPC disease. Data from 92 npc1(-/-) mice (age range, 9-56 days) revealed a significant positive correlation between the plasma activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and whole liver cholesterol content. In 56 day old npc1(-/-) mice that had been fed from 35 days of age a rodent diet or the same diet containing either cholesterol (1.0%, w/w) or ezetimibe (a sterol absorption inhibitor; 0.0125%, w/w), whole liver cholesterol content averaged 33.5 +/- 1.1, 87.9 +/- 1.7, and 20.8 +/- 0.9 mg, respectively. Again, plasma ALT and AST activities were positively correlated with hepatic cholesterol content. In contrast, plasma transaminase levels remained in the normal range in npc1(+/+) mice, in which hepatic esterified cholesterol content had been increased by 72-fold by feeding a high-cholesterol, high-fat diet. These studies suggest that the late endosomal/lysosomal content of unesterified cholesterol correlates with cell damage in NPC disease.

Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.

Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease.

In Niemann-Pick type C (NPC) disease, cholesterol associated with either apoE or apoB100 is taken up by cells in all tissues, including the central nervous system, through clathrin-coated pits and becomes trapped in late endosomes and lysosomes. This study defines the functional, biochemical, and molecular events that ensue as nerve cell death occurs. In mice homozygous for a mutation in NPC1, neuromuscular dysfunction begins at 5 weeks and death occurs at 13 weeks of age. Cholesterol accumulates in every tissue in the body. Purkinje cell loss in the cerebellum begins at 3 to 4 weeks of age and is nearly complete by 11 weeks. This neurodegeneration in the cerebellum is associated with increases in the levels of mRNA for caspase 1, caspase 3, NPC2, LipA, apoE, apoD, glial fibrillary acidic protein, and tumor necrosis factor-alpha, but not for most target genes of the LXR nuclear receptors. The level for apoER2 is significantly reduced. These studies show there is a compensatory increase in NPC2 and LipA in an attempt to overcome the physiological defect caused by the mutation. Nevertheless, neurodegeneration proceeds utilizing apoptosis with activation of glial cells, increased apoE and apoD synthesis, and increased cholesterol turnover across the CNS.