Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S phase.

Two-thirds partial hepatectomy (PH) induces differentiated cells in the liver remnant to proliferate and regenerate to its original size. The proliferation-specific HNF-3/fork head homolog-11B protein (HFH-11B; also known as Trident and Win) is a family member of the winged helix/fork head transcription factors and in regenerating liver its expression is reactivated prior to hepatocyte entry into DNA replication (S phase). To examine whether HFH-11B regulates hepatocyte proliferation during liver regeneration, we used the -3-kb transthyretin (TTR) promoter to create transgenic mice that displayed ectopic hepatocyte expression of HFH-11B. Liver regeneration studies with the TTR-HFH-11B mice demonstrate that its premature expression resulted in an 8-h acceleration in the onset of hepatocyte DNA replication and mitosis. This liver regeneration phenotype is associated with protracted expression of cyclin D1 and C/EBPbeta, which are involved in stimulating DNA replication and premature expression of M phase promoting cyclin B1 and cdc2. Consistent with the early hepatocyte entry into S phase, regenerating transgenic livers exhibited earlier expression of DNA repair genes (XRCC1, mHR21spA, and mHR23B). Furthermore, in nonregenerating transgenic livers, ectopic HFH-11B expression did not elicit abnormal hepatocyte proliferation, a finding consistent with the retention of the HFH-11B transgene protein in the cytoplasm. We found that nuclear translocation of the HFH-11B transgene protein requires mitogenic signalling induced by PH and that its premature availability in regenerating transgenic liver allowed nuclear translocation to occur 8 h earlier than in wild type.

An important role for major histocompatibility complex class I-restricted T cells, and a limited role for gamma interferon, in protection of mice against lethal herpes simplex virus infection.

Herpes simplex virus (HSV) inhibits major histocompatibility complex (MHC) class I expression in infected cells and does so much more efficiently in human cells than in murine cells. Given this difference, if MHC class I-restricted T cells do not play an important role in protection of mice from HSV, an important role for these cells in humans would be unlikely. However, the contribution of MHC class I-restricted T cells to the control of HSV infection in mice remains unclear. Further, the mechanisms by which these cells may act to control infection, particularly in the nervous system, are not well understood, though a role for gamma interferon (IFN-gamma) has been proposed. To address the roles of MHC class I and of IFN-gamma, C57BL/6 mice deficient in MHC class I expression (beta2 microglobulin knockout [beta2KO] mice), in IFN-gamma expression (IFN-gammaKO mice), or in both (IFN-gammaKO/beta2KO mice) were infected with HSV by footpad inoculation. beta2KO mice were markedly compromised in their ability to control infection, as indicated by increased lethality and higher concentrations of virus in the feet and spinal ganglia. In contrast, IFN-gamma appeared to play at most a limited role in viral clearance. The results suggest that MHC class I-restricted T cells play an important role in protection of mice against neuroinvasive HSV infection and do so largely by mechanisms other than the production of IFN-gamma.

Antenatal urologic intervention: current status.

The devastation caused by fetal obstructive uropathy is now well known. At the most severe end of the spectrum of obstructive uropathy not only is the developing kidney damaged but the resultant oligohydra-mnios prevents pulmonary development and causes skeletal defects. The most significant changes are noted in patients with posterior urethral values (PUV). The obvious solution to the problem is to either correct or by pass the obstruction prior to the development of permanent changes. Unfortunately, this simple concept is not easy to apply since it raises numerous ethical, legal, economic and technical problems.

The natural history of sacrococcygeal teratomas diagnosed through routine obstetric sonogram: a single institution experience.

BACKGROUND/PURPOSE: The antenatal diagnosis of sacrococcygeal teratoma (SCT) is increasingly being made with fetal sonography. However, the natural history of SCT detected on routine obstetric sonogram is not well defined. METHODS: A retrospective chart review of 21 fetal SCT diagnosed on routine sonography at Hospital Sainte-Justine between 1980 and 1997 were performed. The patients' clinical and sonographic characteristics, prenatal, and perinatal outcomes were examined. Prognostic criteria were identified by correlating patients' characteristics with outcome. RESULTS: In utero mortality rate was 19% and perinatal mortality rate was 14%. The incidence of premature labor was 50%. Of the various criteria examined as an independent variable, the presence of a solid tumor was found to be a important negative prognostic factor with a 67% incidence of death in utero and an overall mortality rate of 100%. Patients with new onset polyhydramnios were at significant risks for premature labor (100%). All of the perinatal deaths were attributable to tumor rupture. CONCLUSIONS: The course of sacrococcygeal teratoma diagnosed on routine sonograms is associated with a higher-than-expected incidence of prenatal and perinatal complications. Close antenatal follow-up for new onset polyhydramnios and the presence of a completely solid tumor will help optimize patient counseling and treatment.

Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4Ig administration.

Recombinant adenovirus vectors are efficient at transferring genes into somatic tissues but are limited for use in clinical gene therapy by immunologic factors that result in the rapid loss of gene expression and inhibit secondary gene transfer. This study demonstrates that systemic coadministration of recombinant adenovirus with soluble CTLA4Ig, which is known to block co-stimulatory signals between T cells and antigen presenting cells, leads to persistent adenoviral gene expression in mice without long-term immunosuppression. This form of immunotherapy greatly enhances the likelihood that recombinant adenovirus vectors will be useful for human gene therapy.