Fetal death as a result of placental immune reconstitution inflammatory syndrome.

A 26-year-old woman was HIV-1 diagnosed at 11 weeks of pregnancy (CD4 = 7/mm(3), HIV-1 RNA = 108,000 copies/mL) with immunity against toxoplasmosis (Toxoplasma IgG = 1800 UI/mL). A fetal death was diagnosed 7 weeks after starting HAART (CD4 = 185/mm(3), HIV-1 RNA = 391 copies/mL) with a positive Toxoplasma PCR on fetal tissues and amniotic fluid. The absence of severe toxoplasmic foetopathy, the very exaggerated and atypical placental inflammation and the immune restoration context led to the diagnosis of placental IRIS associated with Toxoplasma gondii reactivation. This outcome remains undescribed and could represent an issue in resource-limited settings where HIV-pregnant patients are often severely immunodeficient and infected with opportunistic pathogens.

Thrombocytopenic c-mpl(-/-) mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response.

Administration of 5-fluorouracil (5-FU) to mice results in a marked increase in the level of circulating platelets in 10 days. Mice lacking Mpl, the receptor for thrombopoietin (TPO), are thrombocytopenic. To gain insight into the mechanism by which 5-FU produces such a substantial stimulation of platelet production, this study investigated whether 5-FU (150 mg/kg) produced thrombocytosis in c-mpl(-/-) mice, thus establishing whether TPO was required for this response. A 5- to 6-fold increase in platelet levels in c-mpl(-/-) mice (to approximately 1000 x 10(9)/L) was observed on days 20 and 25 after 5-FU injection. Thus, at the peak of the response, c-mpl(-/-) mice had platelet levels comparable to those in normal mice. Administration of 5-FU also produced thrombocytosis in previously splenectomized c-mpl(-/-) mice. Comparison of the platelet response to 5-FU in young (6-12 weeks) and old (33-46 weeks) c-mpl(-/-) mice found that older mice produced a much more marked response than younger mice, with a mean maximum platelet level of approximately 1700 x 10(9)/L. To determine whether this increase in circulating platelets was preceded by an increase in hematopoietic progenitors, serial cultures of bone marrow and spleen were evaluated. A considerable increase in all colony types studied was observed on days 15 and 20 in spleens of c-mpl(-/-) mice, but no similar elevations were detected in bone marrow. These results indicate that c-mpl(-/-) mice can achieve a normal level of platelets after 5-FU injection, by means of a TPO-independent mechanism, and that they respond to 5-FU myelosuppression by producing large numbers of megakaryocytic, myeloid, and erythroid progenitors. (Blood. 2001;98:1019-1027)

Dye-loaded zeolite L sandwiches as artificial antenna systems for light transport

The synthesis and characterization of dye loaded zeolite L sandwiches acting as artificial antenna systems for light harvesting and transport is reported. A set of experimental tools for the preparation of neutral dye-zeolite L materials ranging from low to maximum packing densities has been developed. The role of co-adsorbed water and the distribution of molecules between the inner and the outer surface were found to be the determining parameters. p-Terphenyl (pTP) turned out to be very suitable for studying these and other relevant parameters of neutral dye-zeolite L materials. We observed that pTP located in the channels of zeolite L can reversibly be displaced by water. This can be used when synthesizing such materials. We also observed that all-trans-1,6-diphenyl-1,3,5-hexatriene (DPH) which is very photolabile in solution is stable after insertion into zeolite L. By combining our extensive knowledge of these systems with ion-exchange procedures developed in an earlier study, we have realized the first bi-directional three-dye antenna. In this material the near UV absorbing compounds DPH or 1,2-bis-(5-methyl-benzoxazol-2-yl)-ethene (MBOXE) are located in the middle part of zeolite L nanocrystals followed on both sides by pyronine (Py) and then by oxonine (Ox) as acceptors. Fluorescence of the oxonine located at both ends of the cylindrical zeolite L crystals was observed upon excitation of the near UV absorber in the middle section at 353 nm, where neither oxonine nor pyronine absorb a significant amount of the excitation light.

A new feature of Mpl receptor: ligand-induced transforming activity in FRE rat fibroblasts.

Mpl is the receptor for thrombopoietin, the primary regulator of platelet production by megakaryocytes. Upon stimulation by its ligand, Mpl receptor induces proliferation and differentiation of hematopoietic cell lines of various origins. In this paper, we show that Mpl is also able to transform FRE rat fibroblasts in the presence of MGDF (pegylated Megakaryocyte Growth and Development Factor), a modified form of its ligand. We also demonstrate that upon MGDF stimulation Mpl receptor activates the classical transduction pathways described for hematopoietic cell lines in FRE cells. Introduction of Mpl deletion mutants in FRE cells allowed us to demonstrate that the C-terminal region of the Mpl intracytoplasmic domain, which is involved in hematopoietic differentiation, is necessary for the transformation process. Within that region, site-directed mutagenesis showed that the Y112 residue, which is required for Shc phosphorylation, is essential for rat fibroblast transformation by Mpl/MGDF, suggesting the involvement of Shc in Mpl-mediated transformation. Interestingly, we showed that transformation correlated with strong and sustained MAPK activation. Neither Jak2, Stat3 nor Stat5 phosphorylation was sufficient to induce the transformation process. Taken altogether, our results suggest the oncogenicity of Mpl in fibroblastic cells in the presence of its ligand.

Clinical and prognostic aspects of adrenocortical neoplasms in childhood.

BACKGROUND: A retrospective study of 54 children was undertaken to define the clinical presentation and secretory patterns of adrenal tumors and to evaluate the outcome of surgical resection and medical therapy. PROCEDURES: Different factors were studied in univariate and multivariate analysis by using the Cox proportional hazard model. RESULTS: Median age at diagnosis was 4 years. Boys and girls were affected equally. The disease was revealed by virilization (61%) or by a palpable mass (39%) with a 0.1-5.5 year delay from initial symptoms. At initial examination, we found that 76% of children were virilized. Ninety-four percent of the tested tumors secreted androgens, which were associated with glucocorticoids in 36%. Adrenal tumors in children were smaller than in adults. Half of them measured less than 10 cm. There were recurrences in 40% of children. The survival rate at 5 years was 49%, 70% if resection was microscopically complete and 7% if not (P < 0.001). CONCLUSIONS: In children, rare adrenal tumors have different diagnostic and prognostic characteristics than in adults; however, recurrences remain frequent. The efficacy of chemotherapy, mainly o,p'-DDD (Mitotane), remains to be evaluated in comparative trials.

Constitutive activation of a variant of the env-mpl oncogene product by disulfide-linked homodimerization.

The myeloproliferative leukemia retrovirus (MPLV) has the v-mpl cellular sequences transduced in frame with the deleted and rearranged Friend murine leukemia virus env gene. The resulting env-mpl fusion oncogene is responsible for an acute myeloproliferative disorder induced in mice by MPLV. v-mpl is a truncated form of the c-mpl gene which encodes the receptor for thrombopoietin. We investigated the contribution of the Env-Mpl extracellular domain in the constitutive activation of this truncated cytokine receptor and found that the rearrangement of the env sequences in the env-mpl fusion gene was not required for oncogenicity. A pathogenic variant, DEL3MPLV, was generated, which differs from MPLV by the deletions of 22 amino acids of the Env signal peptide, all of the mature Env sequences, and 18 N-terminal amino acids of the v-Mpl extracellular domain. The resulting del3-mpl oncogene product conserves in its extracellular region the first 12 amino acids of the Env signal sequence including a cysteine residue, and 25 amino acids of the v-Mpl. We show here that a mutation converting this cysteine to a glycine completely abolishes del3-mpl oncogenicity and that the del3-mpl oncogene product is constitutively activated by disulfide-linked homodimerization.

Dose-dependent systemic human immunodeficiency virus infection of SCID-hu mice after intraperitoneal virus injection.

SCID mice were engrafted with human foetal liver, thymus and lung. Human cells were subsequently detected among peripheral blood leukocytes for 81% of tested animals and in tissue implants for 100% of tested animals. SCID-hu mice received intraperitoneal injections of human immunodeficiency virus type 1 (HIV1) at from 20 up to 20,000 median tissue culture infectious doses (TCID5). HIV1 infection was detected by means of cell culture and polymerase chain reaction both in blood and implants, up to 58 days after infection. The rate of infection was dependent upon the inoculated dose: the frequency of thymus infection ranged from 14% with 20-500 TCID50 up to 100% with 20,000 TCID50. HIV1 infection was detected less frequently in blood leukocytes than in thymus. Thymus virus load ranged from 40 to 50,000 HIV1 provirus copies per million cells and was not correlated with either infectious dose or viraemia. Thymus T-cell depletion was observed mainly in the CD1+4+8+ immature thymocyte compartment. The same rate of SCID-hu mouse infection was obtained using three different primary HIV1 isolates, suggesting that infection was not restricted to a few particular virus strains. The systemic infection of SCID-hu mice following intraperitoneal virus injection mimics some traits of human HIV infection and provides a promising, novel approach for future investigations in this field.

[Multiple pregnancy risk factors in medically assisted reproduction]. / Facteurs de risque de grossesses multiples en procréation médicalement assistée.

FIVNAT registry collected 4,323 clinical pregnancies from 1987 to 1991, and allowed us to analyse the risk factors for multiple pregnancies. The multiple pregnancy rate is around 28%, 23% for twin pregnancies and 5% for triplet pregnancies. The number of transferred embryos is not the only factor to be significantly related with the risk of multiple pregnancy: male infertilities, cleavage rate over 50%, and women's age (at young ages multiple pregnancy rate are higher) are also significant. A multivariate logistic model was applied to analyse the relative part of these different factors. We also estimated the success rate and the multiple pregnancy rate which should have been obtained if the number of transferred embryos has been limited, in order to reduce the multiple pregnancy rate to 3%.

HLA-binding regions of HIV-1 proteins. II. A systematic study of viral proteins.

To detect HLA-binding peptides in 10 HIV-1 proteins (Rev, Tat, Vif, Vpr, Vpu, Gag p18, Gag p24, Gag p15, Env gp120 and Env gp41), the peptide binding assay (PBA) has been performed using three HLA class I molecules. Correlations have been searched between the PBA results and the peptide competitor activity in a functional test using HLA-A2-restricted CTL and target cells. A correlation between the data found in the PBA and well-defined CTL epitopes could be attempted only for the three Gag proteins. For these proteins, our results are in agreement with the known existence of epitopes reacting with human CD8+ CTL, with some exceptions. Together with the results reported with a panel of Nef peptides, these experiments showed that at least 18/20 of the already reported CTL epitopes from HIV-1 Gag, Nef, and Env proteins could be detected by the PBA, most (17/18) corresponding to strong reactivities. Perhaps more important, the regions of HIV-1 Gag p24 or Nef proteins that contain multiple associated CTL epitopes, with different HLA restrictions, were clearly identified by the reactivities in the PBA of several overlapping peptides and the major practical interest of the PBA might be the detection of such polyepitopic regions. Prediction are proposed in this report for 10 proteins, including several proteins for which CTL epitopes remain presently unknown.