Acute fatty liver of pregnancy (AFLP) is a rare disorder which is fatal if not recognized and treated early. Delivery of the feto-placental unit results in dramatic improvement in maternal liver function, suggesting a role for the placenta. However, the mechanisms by which defects in the fetus or placenta lead to maternal liver damage are not well understood and form the focus of this study. Placenta and serum were obtained at delivery from patients with AFLP, and placental mitochondria and peroxisomes were isolated. Placental mitochondrial function, oxidative stress, and fatty acid composition as well as serum antioxidants, oxidative and nitrosative stress markers, and fatty acid analysis were carried out. Hepatocytes in culture were used to evaluate cell death, mitochondrial function, and lipid accumulation on exposure to fatty acids. Oxidative stress was evident in placental mitochondria and peroxisomes of patients with AFLP, accompanied by compromised mitochondrial function. Increased levels of arachidonic acid were also seen in AFLP placenta when compared to control. Patients with AFLP also had a significant increase in oxidative and nitrosative stress markers in serum, along with decreased antioxidant levels and elevated levels of arachidonic acid. These levels of arachidonic acid were capable of inducing oxidative stress in hepatocyte mitochondria accompanied by induction of apoptosis. Exposure to arachidonic acid also resulted in increased lipid deposition in hepatocytes. A cute fatty liver of pregnancy (AFLP) is an example of a primary mitochondrial hepatopathy 1 characterized by hepatic microvesicular steatosis, hepatic failure, and encephalopathy developing in the last trimester of pregnancy. 2,3 Although the majority of primary mitochondrial hepatopathies present in childhood, AFLP presents in a previously asymptomatic woman in late pregnancy. The disease is associated with defects in ␤-oxidation of fatty acids in mitochondria 4 especially the mitochondrial long-chain acyl coenzyme A dehydrogenase (LCHAD) 5,6 in the fetus, but it is now recognized that AFLP can occur without a mutation in LCHAD. 7,8 This suggests that the metabolic basis of AFLP is more heterogeneous than believed earlier, but the mechanism by which a fetal defect in lipid metabolism causes maternal liver damage is not well understood. Interestingly, it has been observed that patients with AFLP generally recover from liver dysfunction subsequent to delivery of the fetus, 9 suggesting a causative role for the placenta, which is expelled during delivery.During gestation, the placenta is essential for fetal development and utilizes fatty acids as a significant metabolic fuel. 10 The genetic composition of the placenta is identical to that of the fetus, and all enzymes of the mitochondrial fatty acid ␤-oxidation pathway are expressed and active in human placenta, 11 with activities being maximum in the second trimester and decreasing with gesta-AFLP, acute fatty liver of pregnancy; EDTA, ethylene diamine tetraacetic acid; LCHAD, long-cha...

Using a PCR strategy which detects disruptions in the E2 reading frame we have analysed the progression of

Equine herpesviruses 1 and 4 (EHV-1 and EHV-4) cause equine respiratory disease worldwide. However, only EHV-1 is a cause of abortion and neurological disease, despite the two viruses having all 76 genes in common. In addition EHV-1 has a broader host range in cell culture than EHV-4, as exemplified by the rabbit kidney (RK) cell line that is permissive for EHV-1, but not for EHV-4. Here we describe that when EHV-4 produced in equine cells was inoculated onto RK cells expressing glycoprotein D of EHV-1 (RKgD1), infection developed as clusters of rounded cells, and this infectivity could be passaged in RKgD1 cells. The progeny virus could also infect single RK cells, consistent with EHV-4 acquiring EHV1 gD from the complementing cell line. No such infection was observed for EHV-4 in RK cells expressing EHV-1 glycoprotein C. The results are consistent with gD homologues being major determinants of host cell tropism and raise the possibility that gD may be a factor in the differential pathogenicity of EHV-1 and EHV-4.

Oral misoprostol is as effective as conventional oxytocic agents in preventing postpartum hemorrhage and can be recommended for use in low-resource settings.

The Foley catheter was found to be an effective agent for cervical ripening in both primiparas and multiparas and its use was not associated with any complications.

A predictive model consisting of maternal age, parity and height can be used to identify low risk pregnant women who are likely to require cesarean section.

Recent efforts have focused on identifying small nonpeptide molecules that can mimic the activity of endogenous peptide hormones. Understanding the molecular basis of ligand-induced receptor activation by these divergent classes of ligands should expedite the process of drug development. Using the cholecystokinin-B/gastrin receptor (CCK-BR) as a model system, we have recently shown that both affinity and efficacy of nonpeptide ligands are markedly affected by amino acid alterations within a putative transmembrane domain (TMD) ligand pocket. In this report, we examine whether residues projecting into the TMD pocket determine the pharmacologic properties of structurally diverse CCK-BR ligands, including peptides and synthetic peptide-derived partial agonists (peptoids). Nineteen mutant human CCK-BRs, each including a single TMD amino acid substitution, were transiently expressed in COS-7 cells and characterized. Binding affinities as well as ligand-induced inositol phosphate production at the mutant CCK-BRs were assessed for peptides (CCK-8 and CCK-4) and for peptoids (PD-135,158 and PD-136, 450). Distinct as well as overlapping determinants of peptide and peptoid binding affinity were identified, supporting that both classes of ligands, at least in part, interact with the CCK-BR TMD ligand pocket. Eight point mutations resulted in marked increases or decreases in the functional activity of the synthetic peptoid ligands. In contrast, the functional activity of both peptides, CCK-8 and CCK-4, was not affected by any of the CCK-BR mutations. These findings suggest that the mechanisms underlying activation of G-protein-coupled receptors by endogenous peptide hormones versus synthetic ligands may markedly differ.

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