Fetal therapy with rhIGF-1 in a rabbit model of intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) may, in part, be due to a deficiency of insulin-like growth factor-1 (IGF-1). The objectives of this study were to determine the relationship between fetal serum IGF-1 levels and fetal and placental size in a rabbit model of IUGR and to compare two techniques of selective, exogenous IGF-1 administration (transamniotic and branch uterine arterial catheter infusion) to growth-retarded fetuses in utero. MATERIALS AND METHODS: Pregnant rabbits (n = 6) had their fetuses harvested near term (31 days) for fetal and placental weighing and serum collection. Growth-retarded fetuses were selectively infused for 7 days with recombinant human IGF-1 (rhIGF-1; 1,440 ng/day) either through a transamniotic catheter (n = 8) or via an adjacent uterine arterial branch catheter (n = 6). Opposite horn runts were sham catheterized, but not infused. At term, the fetal runt pairs and their placentas were harvested and weighed, and their serum was collected. The correlation between fetal and placental weight and endogenous serum IGF-1 was calculated (Pearson coefficient, r), while paired t-tests were used to compare the means between the IGF-1-infused and control groups. RESULTS: There was a significant correlation between fetal (r = 0.4230; P = 0.022) and placental weight (r = 0.4166; P = 0.025) and endogenous serum levels of IGF-1. Transamniotic infusion of rhIGF-1 was associated with an increase in serum IGF-1 level (254 +/- 79 vs 351 +/- 101 ng/ml, P = 0.04) and placental weight (5.4 +/- 2.3 vs 7.1 +/- 3.2 g, P = 0.005), and with a trend toward increased fetal weight between matched fetal runt pairs. Fetal mortality in the uterine arterial catheterized group was 76%, and there was no significant difference in fetal or placental weight or IGF-1 levels between infused and noninfused survivors. CONCLUSIONS: Endogenous fetal serum levels correlate with fetal and placental size in the rabbit IUGR model. Transamniotic administration of rhIGF-1 significantly increases serum IGF-1 levels and placental weight of fetal runts, while uterine vessel catheterization results in prohibitive fetal mortality and does not increase fetal or placental growth or IGF-1 levels.

Genes involved in the determination of the rate of inversions at short inverted repeats.

BACKGROUND: Not all of the enzymatic pathways involved in genetic rearrangements have been elucidated. While some rearrangements occur by recombination at areas of high homology, others are mediated by short, often interrupted homologies. We have previously constructed an Escherichia coli strain that allows us to examine inversions at microhomologies, and have shown that inversions can occur at short inverted repeats in a recB,C-dependent fashion. RESULTS: Here, we report on the use of this strain to define genetic loci involved in limiting rearrangements on an F' plasmid carrying the lac genes. Employing mini-Tn10 derivatives to generate insertions near or into genes of interest, we detected three loci (rmuA,B,C) that, when mutated, increase inversions. We have mapped, cloned and sequenced these mutator loci. In one case, inactivation of the sbcC gene leads to an increase in rearrangements, and in another, insertions near the recE gene lead to an even larger increase. The third gene involved in limiting inversions, rmuC, has been mapped at 86 min on the E. coli chromosome and encodes a protein of unknown function with a limited homology to myosins, and some of the SMC (structural maintenance of chromosomes) proteins. CONCLUSIONS: This work presents the first example of an anti-mutator role of the sbcC,D genes, and defines a new gene (rmuC) involved in DNA recombination.

New approaches to understanding the etiology and treatment of total parenteral nutrition-associated cholestasis.

Total parenteral nutrition-associated cholestasis (TPN-AC) may be a fatal disease. The only known effective treatment is to discontinue TPN and institute full enteral feedings. However, this is not possible for many patients with severe gastrointestinal failure. Current research supports two theories regarding the etiology of TPN-AC. One proposes that the enteral fast disrupts the enterohepatic circulation. Cholestasis, in this hypothesis, results from a combination of altered gut hormone production and endotoxins produced by bacterial translocation. The second theory implicates the direct toxicity of TPN solution. Amino acid solutions and plant sterols in intralipid have generated much interest. Ursodeoxycholic acid and S-adenosyl-L-methionine are promising treatments for TPN-AC. They have been proven to be effective in animals and adult liver diseases. Cholecystokinin also has been investigated as a possible prophylactic agent. However, results from these experiments do not conclusively show a beneficial effect.

Nutritional support of the pediatric surgical patient.

This review discusses the important developments in pediatric surgical nutrition over the past year. Sepsis and total parenteral nutrition-associated cholestasis remain complex problems for patients on total parenteral nutrition. Investigations suggest that total parenteral nutrition may compromise bactericidal activity, increasing the risk of sepsis. Sepsis possibly sensitizes the liver to cholestatic injury. Small volume enteral feeds may restore immune system function. Current research does not support an association between phytosterols in parenteral lipid solutions and total parenteral nutrition-associated cholestasis. Methionine has been identified as a potential hepatotoxin. Ursodeoxycholic acid and S-adenosyl-L-methionine are the most promising treatments of total parenteral nutrition-associated cholestasis. Small bowel transplant is now a reasonable option for patients with irreversible intestinal failure. Patient and graft survival rates have improved with FK-506 (Tacrolimus) immunosuppression. Isolated intestinal grafts have the best survival rate (92% at 1 year). Most surviving graft recipients are weaned off of total parenteral nutrition. The Cox Proportional Hazard model may help to identify candidates for small bowel transplant. This equation predicts the duration of dependence on total parenteral nutrition. Patients with irreversible intestinal failure can then be referred for early small bowel transplantation.