Mother-to-child HCV transmission.
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Female↗
Biomedical subjects
S Fiore
Publications and source records attributed to S Fiore.
Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?
Navajo neurohepatopathy (NNH) is an autosomal recessive disease of full-blooded Navajo children living in the Navajo Reservation of southwestern United States. Clinical features of NNH include peripheral and central nervous system involvement, acral mutilation, corneal scarring or ulceration, liver failure, and metabolic and immunologic derangement. The cause of NNH is unknown, but the clinical features of NNH are similar to those of patients with mitochondrial DNA (mtDNA) depletion. Therefore, we studied mtDNA concentration in the liver from 2 patients with NNH. Using histochemical, biochemical, and molecular techniques, we found evidence of mtDNA depletion, and we propose that the primary defect in NNH is in the nuclear regulation of mtDNA copy number.
Citrate (si)-Synthase↗
Mutations of serine 236-237 and tyrosine 302 residues in the human lipoxin A4 receptor intracellular domains result in sustained signaling.
Lipoxin A(4) (LXA(4)) is a potent negative modulator of the inflammatory response. The antiinflammatory activities of LXA(4), such as inhibition of agonist-induced polymorphonuclear cell (PMN) chemotaxis and upregulation of beta-2 integrins, require the expression of a G-protein-coupled, high-affinity LXA(4) receptor (LXA(4)R). We now report that stimulation of PMN with proinflammatory agonist N-formyl peptides (FMLP), calcium ionophore A(23187), or phorbol mirystate acetate (PMA) is followed by marked downregulation of LXA(4) binding (B(max) decrease of approximately 45%) and decreased activation of phospholipases A(2) (PLA(2)) and D (PLD). Elucidation of the mechanisms underlying these effects was addressed by structure-function analyses of the intracellular domains of LXA(4)R. Mutant molecule, S236/S237 --> A/G (LXA(4)R(pk)) and Y302 --> F (LXA(4)R(tk)) were obtained by site-directed mutagenesis to yield receptors lacking the putative targets for serine/threonine kinase- or tyrosine kinase-dependent phosphorylation. Expression of wild-type and mutated LXA(4)R sequences in CHO and HL-60 cells was used to examine LXA(4) ligand-receptor interactions and signal transduction events. Results indicated that cells expressing LXA(4)R(pk) or LXA(4)R(tk) displayed sustained activation of PLA(2) and PLD in contrast to the transient ones obtained with LXA(4)R(wt) (peak activation at 2-3 min). Moreover, inhibition of LXA(4)-dependent PLA(2) activity by PMA in LXA(4)R(wt) transfected CHO cells was not observed in cells expressing LXA(4)R(pk). Phosphopeptide immunoblotting revealed that the functional differences between wild-type and mutant LXA(4) receptors are accompanied by distinct changes in the receptor protein phosphorylation pattern. Further characterization of these and related LXA(4)R intracellular domains will help to better understand specific events that regulate the antiinflammatory activities of LXA(4).
Animals↗
Structure elucidation of the O-chain from the major lipopolysaccharide of the Xanthomonas campestris strain 642.
A novel O-polysaccharide consisting of D-Xylp and L-Rhap in the molar ratio of 1:2.5 was identified as the major component in the lipopolysaccharide fraction of Xanthomonas campestris strain 642, which is responsible for a new bacterial disease of the strawberry plant. Its structure was mainly determined using chemical analysis, Smith degradation and 1D and 2D NMR spectroscopy experiments as: carbohydrate sequence [see text].
Carbohydrate Sequence↗
Detection of maternal DNA in cord blood at birth after elective caesarean section or vaginal delivery.
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Blood Cells↗
Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases.
Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A4 (LXA4) down-regulates inflammation in vivo. Here we demonstrate, for the first time, the expression of LXA4 receptors, and their up-regulation by IL-1 beta, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 abrogated IL-1 beta stimulation of SF in vitro. IL-1 beta induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited these IL-1 beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respectively, and prevented IL-1 beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA4 induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a approximately 3-fold increase of TIMP-2 protein levels. LXA4 inhibitory responses were dose dependent and were abrogated by pretreatment with LXA4 receptor antiserum. LXA4-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA4 in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro. These findings suggest that LXA4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.
Cells, Cultured↗
The changing HIV epidemic in Italian pregnant women.
OBJECTIVE: To describe changes in the characteristics of HIV-pregnant women in Italy and the impact of strategies for prevention of HIV vertical transmission. STUDY DESIGN: Since 1985, HIV-infected women and their children are followed in 23 European centres in the European Collaborative Study (ECS), according to a standard protocol. Eight Italian Obstetric units participating in the ECS enrolled 815 patients. RESULTS: Overall use of zidovudine to reduce HIV vertical transmission has increased significantly since 1994 and between 1995 and 1997, 57% of Italian women were treated. However, 27% of babies received the infant component of the 076 regimen. Over the years, age at delivery has increased and their CD4 count at delivery decreased, most likely reflecting heterosexually infected women with a longer duration of infection. The increasing rate of elective caesarean section (42%) is not related to maternal, foetal or obstetrical indications, but its use as an intervention to reduce HIV vertical transmission. CONCLUSIONS: The identification of HIV-infected women during pregnancy or before delivery ensures the appropriate management of the woman and her child, and clinicians should be aware of the increasing number of women with heterosexual acquisition of HIV-infection who may be less easily identified.
Adult↗
Preventing perinatal transmission of HIV-1 infection.
It is now known that with the use of antiretroviral prophylaxis with zidovudine, elective caesarean section delivery and refraining from breastfeeding the rate of mother-child transmission of HIV infection can be reduced to less than 2%.
Adolescent↗
Improved stable isotope dilution-gas chromatography-mass spectrometry method for serum or plasma free 3-hydroxy-fatty acids and its utility for the study of disorders of mitochondrial fatty acid beta-oxidation.
BACKGROUND: Disorders of fatty acid oxidation (FAO) are difficult to diagnose, primarily because in many of the FAO disorders measurable biochemical intermediates accumulate in body fluids only during acute illness. Increased concentrations of 3-hydroxy-fatty acids (3-OH-FAs) in the blood are indicative of FAO disorders of the long- and short-chain 3-hydroxy-acyl-CoA dehydrogenases, LCHAD and SCHAD. We describe a serum/plasma assay for the measurement of 3-OH-FAs with carbon chain lengths from C(6) to C(16). METHODS: We used stable isotope dilution gas chromatography-mass spectrometry (GC-MS) with electron impact ionization and selected ion monitoring. Natural and isotope-labeled compounds were synthesized for the assay. RESULTS: The assay was linear from 0.2 to 50 micromol/L for all six 3-OH-FAs. CVs were 5-15% at concentrations near the upper limits seen in healthy subjects. In 43 subjects, the medians (and ranges) in micromol/L were as follows: 3-OH-C(6), 0.8 (0.3-2.2); 3-OH-C(8), 0.4 (0.2-1.0); 3-OH-C(10), 0.3 (0.2-0.6); 3-OH-C(12), 0.3 (0.2-0.6); 3-OH-C(14), 0.2 (0.0-0.4); and 3-OH-C(16), 0.2 (0.0-0.5). 3-OH-FAs were increased in infants receiving formula containing medium chain triglycerides. Two patients diagnosed with LCHAD deficiency showed marked increases in 3-OH-C(14) and 3-OH-C(16) concentrations. Two patients diagnosed with SCHAD deficiency showed increased shorter chain 3-OH-FAs but no increases in 3-OH-C(14) to 3-OH-C(16). CONCLUSION: Measuring blood concentrations of the 3-OH-FAs with this assay may be a valuable tool for helping to rapidly identify deficiencies in LCHAD and SCHAD and may also provide useful information about the status of the FAO pathway.
3-Hydroxyacyl CoA Dehydrogenases↗
Prevalence of chromosomal abnormalities in low-risk pregnancies with fetal anomalies.
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Adult↗
Reproductive counselling for HIV-discordant couples.
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Condoms↗
Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors.
Lipoxins are bioactive eicosanoids that are immunomodulators. In human myeloid cells, lipoxin (LX) A4 actions are mediated by interaction with a G protein-coupled receptor. To explore functions of LXA4 and aspirin-triggered 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA4) in vivo, we cloned and characterized a mouse LXA4 receptor (LXA4R). When expressed in Chinese hamster ovary cells, the mouse LXA4R showed specific binding to [3H]LXA4 (K(d) approximately 1.5 nM), and with LXA4 activated GTP hydrolysis. Mouse LXA4R mRNA was most abundant in neutrophils. In addition to LXA4 and 15-epi-LXA4, bioactive LX stable analogues competed with both [3H]LXA4 and [3H]leukotriene D4 (LTD4)-specific binding in vitro to neutrophils and endothelial cells, respectively. Topical application of LXA4 analogues and novel aspirin-triggered 15-epi-LXA4 stable analogues to mouse ears markedly inhibited neutrophil infiltration in vivo as assessed by both light microscopy and reduced myeloperoxidase activity in skin biopsies. The 15(R)-16-phenoxy-17,18, 19,20-tetranor-LXA4 methyl ester (15-epi-16-phenoxy-LXA4), an analogue of aspirin triggered 15-epi-LXA4, and 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) were each as potent as equimolar applications of the anti-inflammatory, dexamethasone. Thus, we identified murine LXA4R, which is highly expressed on murine neutrophils, and showed that both LXA4 and 15-epi-LXA4 stable analogues inhibit neutrophil infiltration in the mouse ear model of inflammation. These findings provide direct in vivo evidence for an anti-inflammatory action for both aspirin-triggered LXA4 and LXA4 stable analogues and their site of action in vivo.
Amino Acid Sequence↗
Characterisation of the binding of leukotriene B4 to macrophages of the rainbow trout Oncorhynchus mykiss.
The binding of leukotriene B4 (LTB4) to macrophages from the head kidney of the rainbow trout Oncorhynchus mykiss was measured. Binding of [3H]LTB4 achieved a steady state after approximately 30 min of incubation and was 30% reversible in the presence of a minimum of 1000-fold excess of LTB4. Scatchard analysis of the kinetics of LTB4 binding over a range of [3H]LTB4 concentrations indicated the existence of only a single class of receptor with a dissociation constant, KD, of 0.14 nmol l-1 and a maximum receptor density, Bmax, of approximately 17,800 sites per macrophage. The LTB4 receptor antagonist LY223982 was ineffective in inhibiting the binding of [3H]LTB4 to trout macrophages, although another receptor antagonist, LTB4-dimethylamide, displaced a maximum of 25% of the total binding. LTB5 was equally effective as LTB4 at displacing [3H]LTB4, while other eicosanoids tested were without significant effect. It is suggested that the putative receptors for LTB4 on trout macrophages are similar to the high-affinity receptors for this compound reported to occur on mammalian granulocytes, although any structural similarities of the binding sites await further investigation.
Animals↗
Lipoxin A4 receptor activation is distinct from that of the formyl peptide receptor in myeloid cells: inhibition of CD11/18 expression by lipoxin A4-lipoxin A4 receptor interaction.
Lipoxin A4 (LXA4) interacts with high-affinity receptors in human neutrophils and differentiated HL-60 cells. Recently, we characterized a myeloid-derived cDNA that encodes a LXA4 high-affinity receptor (LXA4R) [Fiore, S., Maddox, J. F., Perez, H. D., and Serhan, C. N. (1994) J. Exp. Med. 180, 253-260] denoted earlier as a related N-formyl peptide receptor (RFP). To examine the selectivity of this receptor we tested its preference for specific binding of 3H-LXA4 versus 3H-N-formylmethionyl-leucyl-phenylalanine (3H-FMLP). When receptor-transfected Chinese hamster ovary cells were exposed to either 3H-LXA4 or 3H-FMLP, the receptor affinity for LXA4 exceeded by 1000-fold that of FMLP (6.1 nM vs 5 microM). Upon differentiation, HL-60 cells acquire high-affinity binding sites and respond to both LXA4 and FMLP. Northern blot analysis of differentiated HL-60 cells using an RFP probe showed a characteristic band at 2.1 kb. Differentiated HL-60 cells exposed to an RFP antisense oligonucleotide selectively lost 3H-LXA4 binding as well as LXA4-stimulated lipid remodeling that paralleled the loss of mRNA for LXA4R. In contrast, the specific mRNA for the FMLP receptor, 3H-FMLP specific binding, and FMLP-induced phospholipase D activity were still observed. Treatment of human neutrophils with antisera raised against a peptide in the LXA4R third extracellular domain also resulted in selective abrogation of 3H-LXA4 specific binding with polymorphonuclear leukocytes (PMN) without blocking 3H-FMLP binding. FMLP-stimulated CD11b upregulation as well as homotypic aggregation of PMN was inhibited by LXA4 (which at 10(-9) M gave approximately 1 log unit shift to the right in the FMLP dose-response curve). The addition of LXA4R antisera did not alter FMLP-induced responses in PMN but completely blocked LXA4 actions. These results indicate that altering the expression of the LXA4R protein by blockage of transcriptional mechanisms or hindrance of the LXA4R extracellular domains leads to loss of LXA4 specific binding and blockage of LXA4 signaling. Moreover, they indicate that in myeloid cells LXA4-LXA4R interactions are dissociable from those of FMLP and that LXA4 regulates CD11/18 on the PMN surface.
Animals↗
The incidence of complications after caesarean section in 156 HIV-positive women.
OBJECTIVE: To investigate the risks of post-operative complications in HIV-positive mothers who undergo a caesarean section (CS) because the delivery cannot be safely accomplished by the vaginal route or to protect the infant from viral infection. DESIGN: In a multicentre study, we reviewed the incidence and type of post-operative complications in 156 HIV-positive women who underwent a CS. These results were compared with those observed in an equal number of HIV-uninfected women who matched for the indication requiring a caesarean delivery, the stage of labour, the integrity or rupture of membranes, and the use of antibiotic prophylaxis. SETTING: Seven teaching hospitals providing obstetrical care for mothers infected with HIV. RESULTS: We found that six HIV-infected mothers suffered a major complication (two cases of pneumonia, one pleural effusion, two severe anaemia and one sepsis) compared with only one HIV-negative woman who required blood transfusion after surgery. Minor complications like post-operative fever, endometritis, wound and urinary tract infections were significantly more frequent in HIV-positive women than controls. Multivariate analysis revealed that in HIV-infected women the only factor associated with a significant increase in the rate of complications was a CD4 lymphocyte count < 200 x 10(6)/l. CONCLUSIONS: The results of our study indicate that HIV-positive mothers are at an increased risk of post-operative complications when delivered by CS. The risk of post-operative complications is higher in HIV-infected women who are severely immunodepressed.
CD4 Lymphocyte Count↗
Cell-cell interactions in lipoxin generation and characterization of lipoxin A4 receptors.
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Animals↗