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Biomedical subjects

M Lopez

Publications and source records attributed to M Lopez.

At least 109 records · Page 6Linked to original sources
PubMed1998

Quantitative and qualitative alterations of long-term culture-initiating cells in patients with acute leukaemia in complete remission.

Bone marrow (BM) samples from 24 patients with acute leukaemia (AML 17, ALL seven) in first complete remission were compared to samples from 10 normal donors with regard to their content in long-term culture-initiating cells (LTC-IC) as assessed by a limiting dilution assay and the clonogeneic capacity of these cells, in order to determine whether remission marrow cells displayed any specific defect at the primitive stem cell level. The frequency of LTC-IC in the whole patient group was 1 in 3487 +/- 3125 mononuclear cells (MNC) as compared to 1 in 794 +/- 492 MNC in normal controls (P = 0.0009), with no difference between AML and ALL. Moreover, the clonogeneic capacities were 2.66 +/- 0.7 (range 1.8-1.6) and 4.0 +/- 1.6 (range 2.2-7.9) CFC per LTC-IC in patients and controls respectively (P = 0.0015). These quantitative and qualitative defects were aggravated by treatment with mafosfamide at a dose of 50 microg/10(7) MNC/ml, where the mean recovery of LTC-IC after in vitro purging was 42%. In nine patients autografted with purged marrow following high-dose radiochemotherapy, no correlation could be detected between the dose of LTC-IC (mean 6742 +/- 7877/kg) and the kinetics of recovery of haemopoiesis. We concluded that, in acute leukaemia patients in complete remission, the presumably normal residual stem cell pool was not only quantitatively diminished but also qualitatively altered in its capacity to give rise to clonogeneic progenitor cells.

Acute Disease↗
PubMed1998

The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells.

We report on the functional cloning of a hitherto unknown member of the immunoglobulin (Ig) superfamily selected for its ability to confer susceptibility to herpes simplex virus (HSV) infection on a highly resistant cell line (J1.1-2 cells), derived by exposure of BHKtk- cells to a recombinant HSV-1 expressing tumor necrosis factor alpha (TNF-alpha). The sequence of herpesvirus Ig-like receptor (HIgR) predicts a transmembrane protein with an ectodomain consisting of three cysteine-bracketed domains, one V-like and two C-like. HIgR shares its ectodomain with and appears to be an alternative splice variant of the previously described protein PRR-1 (poliovirus receptor-related protein). Both HIgR and PRR-1 conferred on J1.1-2 cells susceptibility to HSV-1, HSV-2, and bovine herpesvirus 1. The viral ligand of HIgR and PRR-1 is glycoprotein D, a constituent of the virion envelope long known to mediate viral entry into cells through interaction with cellular receptor molecules. Recently, PRR-1, renamed HveC (herpesvirus entry mediator C), and the related PRR-2, renamed HveB, were reported to mediate the entry of HSV-1, HSV-2, and bovine herpesvirus 1, and the homologous poliovirus receptor was reported to mediate the entry of pseudorabies virus (R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear, Science 280:1618-1620, 1998; M. S. Warner, R. J. Geraghty, W. M. Martinez, R. I. Montgomery, J. C. Whitbeck, R. Xu, R. J. Eisenberg, G. H. Cohen, and P. G. Spear, Virology 246:179-189, 1998). Here we further show that HIgR or PRR-1 proteins detected by using a monoclonal antibody to PRR-1 are widely distributed among human cell lines susceptible to HSV infection and commonly used for HSV studies. The monoclonal antibody neutralized virion infectivity in cells transfected with HIgR or PRR-1 cDNA, as well as in the human cell lines, indicating a direct interaction of virions with the receptor molecule, and preliminarily mapping this function to the ectodomain of HIgR and PRR-1. Northern blot analysis showed that HIgR or PRR-1 mRNAs were expressed in human tissues, with the highest expression being detected in nervous system samples. HIgR adds a novel member to the cluster of Ig superfamily members able to mediate the entry of alphaherpesviruses into cells. The wide distribution of HIgR or PRR-1 proteins among human cell lines susceptible to HSV infection, coupled with the neutralizing activity of the antibody in the same cells, provides direct demonstration of the actual use of this cluster of molecules as HSV-1 and HSV-2 entry receptors in human cell lines. The high level of expression in samples from nervous system makes the use of these proteins in human tissues very likely. This cluster of molecules may therefore be considered to constitute bona fide receptors for HSV-1 and HSV-2.

Amino Acid Sequence↗
PubMed1998

Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas.

PURPOSE: We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity. PATIENTS AND METHODS: Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies. RESULTS: In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004). CONCLUSION: DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.

Adult↗
PubMed1998

Autologous stem-cell transplantation for non-Hodgkin's lymphomas: the role of graft purging and radiotherapy posttransplantation--results of a retrospective analysis on 120 patients autografted in a single institution.

PURPOSE: To analyze retrospectively survival and prognostic factors of patients with non-Hodgkin's lymphoma (NHL) autografted from 1979 to 1995 in a single institution. PATIENTS AND METHODS: A total of 120 patients, 64 with aggressive and 56 with low-grade NHL, were autografted. The carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) regimen was used in 104. The autograft was marrow in 101 patients. Marrow was purged in vitro by mafosfamide for 63 patients (adjusted dose [AD] in 32; unique dose [UD] in 31); 27 patients received a CD34+-selected graft. Following intensification, 45 patients received additional radiotherapy on previous sites of involvement. RESULTS: Outcome at 5 years for patients transplanted with low-grade NHL in first complete remission (CR1), in first partial remission (PR1), and in second complete remission (CR2) or beyond showed an event-free survival (EFS) of 75% +/- 12%, 46% +/- 18%, and 57% +/- 24%, a relapse incidence (RI) of 21% +/- 12%, 49% +/- 19%, and 43% +/- 25%, and a transplant-related mortality (TRM) of 5% +/- 5%, 10% +/- 7%, and 0%, respectively. For patients with aggressive NHL transplanted in CR1, in PR1, in CR2 or beyond, and in resistant relapse or in primary refractory disease, the EFS was of 73% +/- 9%, 58% +/- 19%, 29% +/- 16%, and 10% +/- 9%, the RI 22% +/- 9%, 14% +/- 9%, 77% +/- 18%, and 66% +/- 20%, and the TRM 6% +/- 6%, 32% +/- 21%, 11% +/- 10%, and 71% +/- 22%, respectively. In patients autografted upfront in first remission, additional radiotherapy was associated with a higher EFS, in univariate (P = .03) and multivariate analysis (P = .02, relative risk [RR] = .021). The role of graft purging with mafosfamide on the outcome reflected by the dose of colony-forming unit-granulocyte-macrophage (CFU-GM) per kilogram infused postpurging was assessed by univariate analysis: patients in first remission who received lower doses of CFU-GM had a lower RI and a higher EFS. CONCLUSION: This retrospective analysis suggests that marrow purging and posttransplant radiotherapy improve the outcome of patients with NHL autografted in first remission.

Adult↗
PubMed1998

Anti-GM-CSF monoclonal antibody therapy for refractory acute leukemia.

Several phase I trials and pilot studies using Monoclonal Antibody (MoAb) have been performed in B-cell neoplasms, but this approach has not until now been extensively tested in myeloid leukemias. Recently, we evaluated the use of anti-Granulocyte-Macrophage Colony-Stimulating Factor MoAb (Anti-GM-CSF MoAb) in acute myeloid leukemia (AML). Eight patients fulfilled inclusion criteria and received a single course of Anti-GM-CSF MoAb infusion during 5 to 15 days. Anti-GM-CSF MoAb was well tolerated and was detectable in pharmacokinetics studies. Using Human Anti-Rat Antibodies (HARA), we also observed an immunological response to the MoAb. Despite sufficient levels detected in the serum and biological activity of Anti-GM-CSF MoAb in vivo, no anti-leukemic effect was noted, except for one patient who had a decrease of 50% in the marrow blast cell mass. These observations indicate that leukemic proliferation in vivo involves a complex network spanning many mechanisms, and inhibition of leukemia is not effective if only one of these key targets is attacked. The development of these new approaches may be more effective in the future.

Adult↗
PubMed1998

A third human CBL gene is on chromosome 19.

CBL genes encode cytoplasmic proteins involved in signal transduction downstream of a number of receptors including tyrosine kinases, cytokine receptors, and T-cell or B-cell receptors. They seem to be transducers associated with negative regulation of signals, and, as such, may be potential tumor suppressors. Using a probe derived from an expressed sequence tag, we isolated a cosmid containing part of a new CBL gene, CBLc, related to the two characterized paralogous genes CBLa and CBLb. Using the cosmid in fluorescence in situ hybridization of human metaphase chromosomes, we localized the CBLc gene to band 13.2 of chromosome 19. We show that the 19q12.2-13.3 region where CBLc is located shows paralogy with two other regions of the human genome, 3q22-q27 and 11q22-q24 where CBLb and CBLa are located, respectively. Genes from several other families are located in these regions.

Chromosome Mapping↗
PubMed1998

Adherent-free generation of functional dendritic cells from purified blood monocytes in view of potential clinical use.

There is increasing interest in dendritic cells (DC) that are capable of initiating antitumor immune responses. An in vitro cell differentiation method has recently been developed that uses GM-CSF and IL-4 to generate human DC from adherent blood mononuclear cells cultured on tissue culture plastic. These cells are competent for antigen uptake but express relatively low levels of co-stimulatory molecules and thus correspond to immature resident tissue DC. We have adapted this method to consider some variables that are pertinent to clinical use, including a large scale differentiation of functional DC in a culture system suitable for clinical use. We report here that sizable numbers of monocytes purified by elutriation from blood leukocytes and cultured in Teflon bags develop with high efficiency into typical DC, as defined by morphology and membrane phenotype. When compared with usual adherent DC, cells generated under our adherent-free conditions exhibited lower CD1a expression and antigen capture capacity, but maintained the ability to present soluble antigens to T cells. They neoexpressed a high level of the co-stimulator molecule B7-2 (CD86) and was potent accessory cells for T cell proliferation, but they lacked the CD83 marker of DC full maturation. This study may constitute a prerequisite step for clinical investigations in tumor immunotherapy.

Antigens, CD↗
PubMed1998

Cryopreservation and culture of human corneal keratocytes.

PURPOSE: To assess the effects of two different concentrations of albumin in a cryoprotective solution and two freezing methods on human corneal keratocyte ctyopreservation. METHODS: Isolated keratocytes were used for cryopreservation. Solutions of 10% dimethylsulfoxide with either 2% or 10% human albumin were used as cryoprotective agents. Cells either were transferred directly into a -80 degrees C freezer (freezing rate, 2 degrees C/min) or were cooled in a programmed freezer (1 degrees C/min until -40 degrees C and then 10 degrees C/min), which resulted in four different cryopreservation protocols. Cells were stored at -80 degrees C, then were thawed at 37 degrees C, and subsequently were cultured. Keratocytes were studied by means of trypan blue staining, growth assay, apoptosis assays, transmission electron microscopy, and immunochemistry. RESULTS: The percentage of cells that were alive after thawing ranged from 80% to 99% by trypan blue staining and from 45% to 60% by flow cytometry. The ratio of the number of living cells at the end of primary culture after cryopreservation to that before cryopreservation was significantly (P=0.04) higher after direct transfer into the -80 degrees C freezer than after controlled-rate freezing, whereas the albumin concentration had no significant influence on this ratio (P=0.45). The percentage of apoptotic cells was significantly higher after cryopreservation than in the control group of noncryopreserved cells; more than 5% 24 hours after thawing. Cryopreservation did not modify the keratocyte ultrastructure. Fibroblast growth factor dramatically decreased the serum-induced cell expression of alpha smooth muscle actin, whereas cryopreservation had no influence on this cell expression. CONCLUSIONS: A freeze-thaw trauma, which was related to cryopreservation-induced cell apoptosis, was revealed during primary culture after thawing. Direct transfer into the -80 degrees C freezer resulted in better postcryopreservation growth in the culture than controlled-rate freezing. A change in albumin concentration from 2% to 10% did not affect the results.

Actins↗
PubMed1998

European trials with dexrazoxane in amelioration of doxorubicin and epirubicin-induced cardiotoxicity.

The ability of dexrazoxane (DEX) to protect against anthracycline-induced cardiotoxicity has been evaluated in several European studies using either standard or high-dose regimens. In addition, one randomized trial investigated the value of cardiac radioimmunoscintigraphy with indium-111 antimyosin monoclonal antibodies in the early detection of cardiac damage. The results of these trials demonstrate that DEX is able to ameliorate doxorubicin- and epirubicin-induced cardiotoxicity, even when high single drug doses are used. The cardioprotective effect of DEX has been clearly documented by both clinical and laboratory cardiac evaluation. The use of DEX did not add to the toxicity of the anthracyclines, nor was there clear evidence of an adverse impact of the agent on antitumor activity of the chemotherapeutic regimen. Radioimmunoscintigraphy was very sensitive in detecting anthracycline cardiac damage, but its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.

Anthracyclines↗
PubMed1997

IL-13 induces CD34+ cells isolated from G-CSF mobilized blood to differentiate in vitro into potent antigen presenting cells.

Dendritic cells (DCs), which are antigen presenting cells of potential use in human antitumor vaccination trials, are presently the subject of intense investigation. Many recent studies have reported the possibility of generating ex vivo large numbers of DCs with high antigen presenting capacity by the culture of bone marrow or blood progenitors. In this study, we examined the differentiation into DCs of CD34+ progenitors isolated from the G-CSF mobilized blood of 3 healthy donors and 5 patients with breast cancer and cultured in the presence of GM-CSF + IL-13. The characteristics of the cells were compared to those of cells obtained in the presence of GM-CSF + TNF alpha. By day 15, one third of the bulk cells cultured with IL-13 were CD1a+/CD14- and strongly expressed CD1c, CD40, CD80 and HLA-DR. In contrast, cells obtained with TNF alpha expressed CD1a on one in three cells but with a considerably lower fluorescence intensity than on IL-13-cultured cells and strongly expressed CD14 on more than 50% of cells. CD1a+/CD14- cells emerged in IL-13 cultures at day 5, while in TNF alpha cultures CD14+ cells appeared before CD1a+ cells. Cells grown in the presence of IL-13 had an increased capacity to present antigens to autologous lymphocytes and to stimulate allogeneic T-lymphocytes. This effect was greater than that of cells grown in the presence of TNF alpha. These cells should therefore have greater effector potential in any therapeutic applications in humans.

Animals↗
PubMed1997

Bone marrow versus peripheral blood progenitor cells CD34 selection in patients with non-Hodgkin's lymphomas: different levels of tumor cell reduction. Implications for autografting.

Human CD34+ selected cells are able to reconstitute hematopoiesis in patients receiving a myeloablative treatment. Although the role of reinfused tumor cells contaminating the grafts on the determination of postautograft relapses remains unclear, the major interest of CD34+ cell selection is to reduce the tumor contamination of the graft. This can be achieved if tumor cells do not express the CD34 antigen. We previously showed that this approach was effective with bone marrow (BM) collections in patients with non-Hodgkin's lymphoma (NHL). Because peripheral blood progenitor cells (PBPC) allow faster hematologic recovery than BM and are expected to contain less tumor contamination, we have compared the results of CD34+ cell selection in 35 BM and 16 PBPC from 48 patients with NHL. The PBPC were collected after a course of chemotherapy followed by granulocyte colony-stimulating factor (G-CSF) administration. The data showed that the final CD34+ cell purity achieved with PBPC was higher than with BM (medians, 70% v 50%; P = .02). The CD34+ cell recovery was also better for PBPC (medians, 42% v 24%; P = .001). Tumor contamination was assessed by detection of BCL2/JH rearrangement using polymerase chain reaction (PCR) in 38 of 48 patients (22 BM, 16 PBPC). In addition, immunoglobulin heavy chain gene (IgH) rearrangements were investigated using PCR with consensus IgH primers. At harvesting, 10 of 22 BM and two of 16 PBPC contained BCL2/JH+ cells, one of 22 BM and 14 of 16 PBPC contained abnormal IgH+ cells (one PBPC contained both BCL2/JH+ and abnormal IgH+ cells) at harvesting. However, because lymphoma tissue specimens from patients at diagnosis were not available, the malignant character of IgH rearrangements could not be confirmed by sequencing and probing with allele-specific nucleotides. After CD34+ cell selection, a reduction to below the level of detection of BCL2/JH+ cells of BM and PBPC was effective in seven of 12 informative selections. In contrast, a reduction to below the level of detection of abnormal IgH+ cells was effective in only three of 15 informative selections. However, the detection of cells with an abnormal IgH pattern in the context of chemotherapy plus G-CSF progenitor mobilization in patients with NHL and its correlation with actual tumor contamination needs further investigation.

Adult↗
PubMed1997

First report of recombination between the HLA-DR and HLA-DQ loci within a family.

Although unusual associations of HLA-DR and HLA-DQ alleles seen in ancestral haplotypes have indicated that recombination between these genes occurred in the past, an actual crossover event between DR and DQ has never been shown within a family. In a study of families with Graves' disease we have identified an individual from a three generation family who inherited a maternal haplotype that is the result of a recombinational event between the HLA-DR and the HLA-DQ loci on her chromosomes. Family members were typed for HLA class I by the lymphocyte microcytotoxicity test and for HLA class II by polymerase chain reaction (PCR) with sequence-specific primers or with sequence-specific oligonucleotide probes after PCR. Based on linkage disequilibrium it is likely that the recombinant haplotype is present in the proband rather than his brother. This haplotype was subsequently inherited by one of the proband's sons. The data presented support the conclusion that the recombinant haplotype resulted from a crossover event between the mother's DRB1 and DQA1 genes. Thus, recombination between the HLA-DR and HLA-DQ genes has been demonstrated within this family; a recombination event not previously described.

Adult↗
PubMed1997

Lymphocyte proliferative response and tissue distribution of methylmercury sulfide and chloride in exposed rats.

The immunotoxic effects and tissue distribution of different forms of methylmercury compounds were studied in rats. Methylmercury sulfide or methylmercury chloride was fed to rats at concentrations of 5 or 500 microg/L in drinking water for 8 wk. T-cell lymphocyte proliferative response to phytohemagglutinin (PHA) and determination of tissue distribution of mercury by gas chromatography using electron capture were assayed. Four different forms of mercury compounds were employed: MeHgS-, (MeHg)2S, (MeHg)3S+, and MeHgCl. Results indicated that exposure to methylmercury significantly enhanced lymphocyte responsiveness in most of the exposed groups at the low concentration of 5 microg/L, with the highest proliferative response (fourfold increase) in the MeHgCl group. At 500 microg/L, a significant decrease in the lymphocyte proliferative response was observed in the (MeHg)3S+ and MeHgCl groups; conversely, the MeHgS(-)- and (MeHg)2S-exposed animals had a modest increase of the lymphocyte proliferative response. The largest concentrations of all four mercury forms were detected in the kidney and spleen. The levels of mercury found in kidney, spleen, liver, brain, and testis were lower in the MeHgCl group than in those exposed to (MeHg)2S and (MeHg)3S+. These data indicate that the organ distribution of mercury and immune alteration may vary according to the chemical structure of the compound. This observation may have important implications in humans potentially exposed to low levels of methylmercury present in the environment, since the immune system plays an important regulatory role in the host-defense mechanisms.

Administration, Oral↗
PubMed1997

Immune system alteration in the rat after indirect exposure to methyl mercury chloride or methyl mercury sulfide.

Methyl mercury is a well-recognized health hazard. It is an environmental contaminant that accumulates in the food chain. The primary source of mercury exposure for humans is through the consumption of contaminated fish. We studied the effects of indirect methyl mercury exposure on the immune system of Sprague-Dawley rats. The effects of different forms of methyl mercury on immune system development were studied in Sprague-Dawley rats at 6 and 12 weeks of age. Rats were indirectly exposed to mercury during gestation and during nursing by exposing pregnant rats to either 5 or 500 micrograms/liter of methyl mercury chloride (CH3HgCl) or 5 micrograms/liter of methyl mercury sulfide [(CH3Hg)2S] in their drinking water. Total body, splenic, and thymic weights were measured, and NK cell cytolytic activity and lymphoproliferative response to T and B cell mitogens were evaluated in the offspring. At 6 weeks of age, total body and splenic weights were significantly increased in both high- and low-dose methyl mercury chloride-exposed groups. Rats exposed to methyl mercury sulfide had a significant increase in thymic weight at 6 weeks of age. At 12 weeks, the total body and organ weights were not different from controls. The lymphocyte proliferative response of splenocytes to PWM was enhanced at 6 weeks in both CH3HgCl exposed groups and not affected in the (CH3Hg)2S exposed group. NK cell activity was not affected in either group at 6 weeks of age. At age 12 weeks, NK cell activity was statistically significantly decreased by 56.6% in both CH3HgCl-exposed groups and not affected in the (CH3Hg)2S-exposed rats. The lymphocyte proliferative response of splenocytes to the B cell mitogen pokeweed remained increased in the CH3HgCl groups. Indirect exposure of rats (during gestation and nursing) to different forms of methyl mercury reveals that chloride forms have prolonged predominantly enhancing effects on lymphoproliferative response of splenocytes, followed by significant depression of NK cell activity.

Animals↗
PubMed1997

Antifungal sterol biosynthesis inhibitors.

During the course of the last decade, the development of SBIs, and particularly sterol biomethylation inhibitors, has been based on the rational design approach. Successful though this approach has been in elucidating sterol biomethylation enzymology, its limitations are becoming apparent from the findings that: (i) 24,25-double bond metabolism gives rise to cholesterol and ergosterol in a mechanistically similar manner, (ii) 25-azasterols are harmful to human physiology, and (iii) side-chain modified sterols designed to inhibit the SMT enzyme in S. cerevisiae may be ineffective or operate by another kinetic mechanism in a related organism, rendering it therapeutically nonuseful. Nevertheless, it may be possible to ultimately capitalize on the unique aspects of sterol biomethylation chemistry and enzymology to design taxa-specific inhibitors. With increased understanding of the structure and function of SMT enzymes in different fungi, it should be possible to prepare novel mechanism-based inactivators to control SMT activity uniquely and with high specific activity.

Amino Acid Sequence↗
PubMed1997

Sterol utilization and metabolism by Heliothis zea.

Heliothis zea (corn earworm), an insect that fails to synthesize sterols de novo, was reared on an artificial diet treated with 18 different sterol supplements. Larvae did not develop on a sterol-less medium. delta 5-Sterols with a hydrogen atom, a methylene group, an E- or Z-ethylidene group, or an alpha- or beta-ethyl group (cholesterol, ostreasterol, isofucosterol, fucosterol, sitosterol, and clionasterol, respectively) at position C-24, and delta 5-sterols doubly substituted in the side chain at C-24 with an alpha-ethyl group and at C-22 with a double bond (stigmasterol) supported normal larval growth to late-sixth instar (prepupal: maturity). The major sterol isolated from each of these sterol treatments was cholesterol, suggesting that H. zea operates a typical 24-dealkylation pathway. The sterol requirement of H. zea could not be met satisfactorily by derivatives of 3 beta-cholestanol with a 9 beta, 19-cyclopropyl group, gem dimethyl group at C-4, a delta 5,7-bond or delta 8-bond, or by side chain modified sterols that possessed a delta 25(27)-24 beta-ethyl group, delta 23(24)-24-methyl group or 24-ethyl group, or delta 24(25)-24-methyl or 24-ethyl group. The major sterol recovered from the larvae (albeit developmentally arrested larvae) treated with a nonutilizable sterol was the test compound. Sterol absorption was related to the degree of sterol utilization. The most effective sterols absorbed by the insect ranged from 27 to 66 micrograms per insect, whereas the least effective sterols absorbed by the insect ranged from 0.6 to 6 micrograms per insect. Competition experiments using different proportions of cholesterol and 24-dihydrolanosterol (from 9:1 to 1:9 mixtures) indicated that abnormal development of H. zea may be induced on less than a 1 to 1 mixture of utilizable (cholesterol) to nonutilizable (24-dihydrolanosterol) sterols. The results demonstrate new structural requirements for sterol utilization and metabolism by insects, particularly with respect to the position of double bonds in the side chain and functionalization in the nucleus. The novel sterol specificities observed in this study appear to be associated with the dual role of sterols as membrane inserts (nonmetabolic) and as precursors to the ecdysteroids (metabolic).

Animals↗
PubMed1997

Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis.

Postmenopausal osteoporosis is a progressive disorder characterized by a decreased bone mass and increased susceptibility to fractures. Several investigations have suggested that one of the mechanisms through which estrogen prevents bone loss was a modulation on secretion or release of various cytokines that are known to influence bone remodeling, even if some recent data have challenged this hypothesis. However, in established osteoporosis, the possibility that enhanced cytokines activity may account for the progression of this disease remains unclear and controversial. We sought here to determine whether production of IL-1 beta, IL-6, TNF-alpha, IFN-gamma, GM-CSF and LIF, after direct stimulation in whole blood, was different in healthy (n = 30) or osteoporotic postmenopausal women (n = 24) and whether lumbar bone density (1-BMD) correlated with the values of cytokine production observed in these conditions. A significant difference was observed between the osteoporotic and control subjects for IL-1 beta (p < 0.0001), IL-6 (p < 0.001) and TNF-alpha (p = 0.027) productions, the values being higher in the osteoporotic women. No significant differences between the groups were observed for IFN-gamma (p = 0.51), GM-CSF (p = 0.70) or LIF (p = 0.97). In the whole population, statistically significant negative correlations were observed between lumbar BMD and IL-1 beta (r = -0.46) (p < 0.0005), IL-6 (r = -0.50) (p < 0.0001) and TNF-alpha (r = -0.39) (p < 0.005) production while no such correlations were observed for IFN-gamma, GM-CSF or LIF. In conclusion, the study of cytokine production by immune cells cultured in autologous whole blood suggests that in women more than 10 years past the menopause and presenting a decrease in lumbar bone density corresponding to the new WHO definition of "osteoporosis', production of IL-1 beta, IL-6 and TNF-alpha is still increased compared to controls matched for age and ovarian function, while no differences are reported for IFN-gamma, GM-CSF or LIF production.

Bone Density↗