PubMed Health⌕ Search

Biomedical subjects

M E Martin

Publications and source records attributed to M E Martin.

At least 19 recordsLinked to original sources
PubMed2006

Lack of effect of donor-recipient ABO mismatching on outcome following allogeneic hematopoietic stem cell transplantation.

Several recently published studies have suggested that patients who undergo ABO mismatched hematopoietic stem cell transplantation may be at increased risk for relapse, graft-versus-host disease, transplant-related mortality, and/or all-cause mortality. To investigate this issue further, we analyzed potential associations between the donor-recipient ABO mismatch pattern and the above outcome measures among 240 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation at our institution. Our analyses uncovered no significant associations between donor-recipient ABO mismatch pattern and overall survival, event-free survival, transplant-related mortality, incidence of acute graft-versus-host disease (GVHD), or incidence of chronic GVHD. Our data do not support recent assertions that donor-recipient ABO mismatching is a major risk factor for patients undergoing allogeneic transplant, nor do they support recent assertions that ABO matching should be an important consideration in selecting allogeneic hematopoietic stem cell donors.

ABO Blood-Group System↗
PubMed2001

H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload.

Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)

Alleles↗
PubMed2001

CD28 signaling augments Elk-1-dependent transcription at the c-fos gene during antigen stimulation.

Untransformed CD4(+) Th1 cells stimulated with Ag and APC demonstrated a dependence on B7- and CD28-mediated costimulatory signals for the expression and function of AP-1 proteins. The induction of transactivation by the c-fos gene regulator Elk-1 mirrored this requirement for TCR and CD28 signal integration. c-Jun N-terminal kinase (JNK) (but not extracellular signal-regulated kinase or p38) protein kinase activity was similarly inhibited by neutralizing anti-B7 mAbs. Blockade of JNK protein kinase activity with SB 202190 prevented both Elk-1 transactivation and c-Fos induction. These results identify a unique role for B7 costimulatory molecules and CD28 in the activation of JNK during Ag stimulation in Th1 cells, and suggest that JNK regulates Elk-1 transactivation at the c-fos gene to promote the formation of AP-1 complexes important to IL-2 gene expression.

Adjuvants, Immunologic↗
PubMed2001

Immunopathology and ehrlichial propagation are regulated by interferon-gamma and interleukin-10 in a murine model of human granulocytic ehrlichiosis.

Previous studies of human granulocytic ehrlichiosis (HGE) suggest a role for host immune response in resolving infection and in causing histopathological lesions. We hypothesize that interferon (IFN)-gamma allows tissue injury that is suppressed by interleukin (IL)-10 after initiation by ehrlichia infection. Thus, parental C57BL/6, IL-10-/-, and IFN-gamma-/- strains of mice were infected and then assayed for hepatic histopathological lesions, ehrlichial burden, and cytokine responses to ehrlichial antigen in primary splenic cultures during the first 21 days after infection. Histopathological severity in C57/BL6 and IL-10-/- mice rose in parallel through day 7, but then diverged as pathology in IL-10-/- mice continued to increase and remained high throughout the course of the study. The histopathological rank of C57BL/6 of mice decreased at day 10 and returned to baseline levels at days 14 and 21. In contrast, the IFN-gamma-/- strain had baseline pathology scores throughout the course of the infection, yet had significantly higher ehrlichial burden both in the blood and tissues than C57BL/6 or IL-10-/- mice. This suggests that histopathological lesions in the HGE murine model do not result from direct ehrlichia-mediated injury but from immunopathological mechanisms initiated by ehrlichial infection. The similarities with lesions in humans suggest an immunopathological basis for HGE.

Animals↗
PubMed2000

Isolation of a bi-directional promoter directing expression of the mouse GABPalpha and ATP synthase coupling factor 6 genes.

The GA-binding protein (GABP) is a ubiquitous heteromeric transcription factor implicated in the regulation of several genes involved in mitochondrial energy metabolism including subunits of cytochrome c oxidase, ATP synthase, and mitochondrial transcription factor 1 (mtTF1). GABPalpha subunit binds the PEA3/Ets binding sites (EBS), while GABPbeta contains a transcription activation domain and mediates alphabeta dimer and alpha(2)beta(2) tetramer formation essential for activation of transcription. Here we report the cloning of 2449 bp of the mouse (m) GABPalpha promoter region including 201 bp of the 5' end of the published mGABPalpha cDNA sequence. Surprisingly, sequences homologous to the 5'UTR of mouse, rat and human mitochondrial ATP synthase coupling factor 6 (ATPsynCF6) cDNAs were found165-240 bp upstream of the mGABPalpha cDNA. A search of the non-redundant nucleotide database revealed a human genomic sequence derived from chromosome 21 (21q22) bearing significant homology to the mGABPalpha/ATPsynCF6 promoter region and encompassed the entire hGABPalpha and hATPsynCF6 genes. Primer extension analysis revealed multiple transcription start sites for both mGABPalpha and mATPsynCF6 mRNAs that mapped near the published cDNA 5' ends. Sequence analysis identified several binding sites upstream of the GABPalpha cDNA sequence including sites for GABP (-86, -104, -169, -257, and -994), YY1 (-57), Sp1 (-242 and -226), and NRF1 (-5). No 'TATA' motif was identified near either the GABPalpha or ATPsynCF6 transcription start sites. The human and mouse promoters retain significant sequence identity including binding sites for several tissue-specific transcription factors. Transient transfection assays using Luciferase reporter constructs containing the intergenic region and flanking sequences confirmed that this region of DNA promotes transcription in both directions.

Animals↗
PubMed2000

Rapid desensitization and slow recovery of the cyclic AMP response mediated by histamine H(2) receptors in the U937 cell line.

The present study focused on the desensitization process of the H(2) receptor in U937 cells and the recovery of the cyclic AMP (cAMP) response. Treatment of U937 leukemic cells with the H(2) histamine receptor agonists (+/-)-N(1)-[3-(3, 4-difluorophenyl)-3-(pyridin-2-yl)propyl]-N(2)-[3-(1H-imidazol-4-yl)p ropyl]guanidine (BU-E-75) and amthamine produced a rapid desensitization characterized by decreased cAMP production (T(1/2) = 20 min). Pretreatment with 10 microM BU-E-75 did not induce modifications in the responses to prostaglandin E(2), isoproterenol, or forskolin. H(2) receptor desensitization was not affected by protein kinase A and C inhibitors, but was reduced drastically by Zn(2+) and heparin, known to act as inhibitors of G protein-coupled receptor kinases. Recovery studies of the cAMP response showed that cAMP levels reached 50% of the initial values within 5 hr. Furthermore, desensitization produced an important decrease in the basal level of this cyclic nucleotide. The minimal value was observed 12 hr later, and corresponded to approximately 1.3% of the initial basal level (7.5 vs 0.1 pmol/10(6) cells). This result could be explained by an increase in phosphodiesterase activity following 10 microM BU-E-75 treatment. When cells were exposed for 2 hr to an H(2) agonist, binding assays showed no modification in the number of H(2) receptors; internalization began just after 8 hr. Although the initial desensitization seems to involve G protein-coupled receptor kinases, results indicate that additional mechanisms of regulation were triggered by the H(2) agonists.

Cimetidine↗
PubMed2000

Effect of protein kinase A activity on the association of ADP-ribosylation factor 1 to golgi membranes.

The small GTP-binding protein ADP-ribosylation factor 1 (ARF1) is an essential component of the molecular machinery that catalyzes the formation of membrane-bound transport intermediates. By using an in vitro assay that reproduces recruitment of cytosolic proteins onto purified, high salt-washed Golgi membranes, we have analyzed the role of cAMP-dependent protein kinase A (PKA) on ARF1 incorporation. Addition to this assay of either pure catalytic subunits of PKA (C-PKA) or cAMP increased ARF1 binding. By contrast, ARF1 association was inhibited following C-PKA inactivation with either PKA inhibitory peptide or RIIalpha as well as after cytosol depletion of C-PKA. C-PKA also stimulated recruitment and activation of a recombinant form of human ARF1 in the absence of additional cytosolic components. The binding step could be dissociated from the activation reaction and found to be independent of guanine nucleotides and saturable. This step was stimulated by C-PKA in an ATP-dependent manner. Dephosphorylated Golgi membranes exhibited a decreased ability to recruit ARF1, and this effect was reverted by addition of C-PKA. Following an increase in the intracellular level of cAMP, ARF proteins redistributed from cytosol to the perinuclear Golgi region of intact cells. Collectively, the results show that PKA exerts a key regulatory role in the recruitment of ARF1 onto Golgi membranes. In contrast, PKA modulators did not affect recruitment of beta-COP onto Golgi membranes containing prebound ARF1.

ADP-Ribosylation Factor 1↗
PubMed2000

The alpha and beta subunits of the GA-binding protein form a stable heterodimer in solution. Revised model of heterotetrameric complex assembly.

We have studied the assembly of GA-binding protein (GABP) in solution and established the role of DNA in the assembly of the transcriptionally active GABPalpha(2)beta(2) heterotetrameric complex. GABP binds DNA containing a single PEA3/Ets-binding site (PEA3/EBS) exclusively as the alphabeta heterodimer complex, but readily binds as the GABPalpha(2)beta(2) heterotetramer complex on DNA containing two PEA3/EBSs. Positioning of the PEA3/EBSs on the same face of the DNA helix stabilizes heterotetramer complex binding. These observations suggest that GABPalphabeta heterodimers are the predominant molecular species in solution and that DNA containing two PEA3/EBSs promotes formation of the GABPalpha(2)beta(2) heterotetrameric complex. We analyzed the assembly of GABPalpha(2)beta(2) heteromeric complexes in solution by analytical ultracentrifugation. GABPalpha exists as a monomer in solution while GABPbeta exists in a monomer-dimer equilibrium (K(d) = 1.8 +/- 0.27 microM). In equimolar mixtures of the two subunits, GABPalpha and GABPbeta formed a stable heterodimer, with no heterotetramer complex detected. Thus, GABP exists in solution as the heterodimer previously shown to be a weak transcriptional activator. Assembly of the transcriptionally active GABPalpha(2)beta(2) heterotetramer complex requires the presence of specific DNA containing at least two PEA3/EBSs.

Binding Sites↗
PubMed2000

Early embryonic lethality of H ferritin gene deletion in mice.

Ferritin molecules play an important role in the control of intracellular iron distribution and in the constitution of long term iron stores. In vitro studies on recombinant ferritin subunits have shown that the ferroxidase activity associated with the H subunit is necessary for iron uptake by the ferritin molecule, whereas the L subunit facilitates iron core formation inside the protein shell. However, plant and bacterial ferritins have only a single type of subunit which probably fulfills both functions. To assess the biological significance of the ferroxidase activity associated with the H subunit, we disrupted the H ferritin gene (Fth) in mice by homologous recombination. Fth(+/-) mice are healthy, fertile, and do not differ significantly from their control littermates. However, Fth(-/-) embryos die between 3.5 and 9.5 days of development, suggesting that there is no functional redundancy between the two ferritin subunits and that, in the absence of H subunits, L ferritin homopolymers are not able to maintain iron in a bioavailable and nontoxic form. The pattern of expression of the wild type Fth gene in 9.5-day embryos is suggestive of an important function of the H ferritin gene in the heart.

Animals↗
PubMed2000

Coordinating development with the cell cycle in Caulobacter.

During the Caulobacter life cycle, the timing of DNA replication, cell division and development is precisely coordinated. Recent work has begun to unravel the complex regulatory networks that couple these processes. A key aspect of these regulatory networks is the dynamic localization of multiple histidine protein kinases that control a master response regulator, thus driving downstream pathways.

Bacterial Proteins↗
PubMed2000

Neuroblastoma and bronchogenic cyst: a rare association.

A few of the known associations between paediatric cancer and congenital anomalies are attributable to contiguous-gene syndromes. Neuroblastoma (NB) has been linked with an excess of gastrointestinal malformations, but there is a significant scarcity of associated respiratory anomalies. We report on two children having an abdominal NB and a bronchogenic cyst diagnosed simultaneously and in different order of appearance. Both masses were removed in separated procedures, taking into account the priority and the time sequence of chemotherapy. Literature is reviewed, checking that the genetic basis for this association is supported by speculations about the oncogene RON.

Adrenal Gland Neoplasms↗
PubMed2000

Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model.

Human granulocytic ehrlichiosis (HGE) results in fever, pancytopenia, and mild liver injury. We used a mouse model to examine immunity in the pathogenesis of HGE. HGE agent-infected C3H/HeJ mice were necropsied over 21 days. Histologic, immunohistologic, and serologic analyses, blood culture, tissue and blood polymerase chain reaction (PCR), cell counts, serum chemistries, and plasma cytokine ELISAs were performed. No clinical signs were detected. Ehrlichiae were identified in neutrophils in hematopoietic tissues maximally on day 7. Interleukin (IL)-10 levels were high throughout, whereas interferon (IFN)-gamma levels peaked on days 7 and 10 and dropped thereafter. Hepatic lymphohistiocytic aggregates with apoptoses were maximal at day 14. HGE-agent infection of mice induces pathologic changes similar to those in infected humans, despite differences in cytokine profile. The IFN-gamma peak prior to maximal pathologic change, when ehrlichiae are absent in tissues, suggests a role for host immunity in the pathogenesis of HGE.

Animals↗
PubMed2000

Inactivation of iron responsive element-binding capacity and aconitase function of iron regulatory protein-1 of skin cells by ultraviolet A.

The ultraviolet-A (UVA) component of sunlight produces in cutaneous cells a highly toxic oxidative stress mediated by redox cycling reactions of Fe ions. A tight regulation of cell iron uptake and storage by iron regulatory proteins (IRP) of keratinocytes and fibroblasts avoids these damaging reactions. We report here that about 40 J/cm2 of UVA are required to inactivate half of the binding capacity of apo-IRP-1 to iron responsive elements (IRE) of RNA whereas 15 J/cm2 already inhibit half of the holo-IRP-1 aconitase activity. No increase in the holo-IRP-1 activity is observed during the apo-IRP-1 photoinactivation suggesting that UVA does not trigger a shift between these two forms. As opposed to holo-IRP-1, which contains a 4Fe-4S cluster, apo-IRP-1 has no UVA chromophore. Thus it should be inactivated indirectly by reactive oxygen species generated by the UVA-induced endogenous photo-oxidative stress. The apo-IRP-1 photoinactivation is weakly prevented by the lipophilic oxyradical scavenger vitamin E but not by the hydrophilic azide anion, a singlet oxygen quencher or by diethyldithiocarbamate, a superoxide dismutase inhibitor. However, full protection against photoinactivation of the apo form is observed after incubation with N-acetylcysteine but the latter only partially protects the aconitase function of the holo-IRP-1 from photoinactivation. The marked difference in the kinetics of photoinactivation of the apo and holo forms, the light dose-independent effect of the sulfhydril group reagent, 2-mercaptoethanol and the partial protection brought by the ferric ion complexing agent desferrioxamine suggest that the photochemistry of the 4Fe-4S cluster of the holo form plays little, if any, role in the photoinactivation of the apo-IRP-1/IRE interaction. It is concluded that the apo/holo equilibrium is irreversibly destroyed by UVA irradiation.

Aconitate Hydratase↗
PubMed2000

Comparative pathology, and immunohistology associated with clinical illness after Ehrlichia phagocytophila-group infections.

The Ehrlichia phagocytophila-group also includes E. equi and the human granulocytic ehrlichiosis (HGE) agent that are probably a single species. Disease is mild to severe illness in ruminants, horses, and humans, but the comparative pathology and ehrlichial distribution in tissues is poorly described. We compared pathology and ehrlichial distribution in humans with HGE, horses with E. equi infection, and a sheep with E. phagocytophila infection. Frequent findings included splenic lymphoid depletion, small macrophage aggregates and apoptoses in liver, and paracortical hyperplasia in lymph nodes. Bone marrow was normocellular or hypercellular. Only the spleen was frequently infected; other organs with infected cells included lung, liver, heart, and kidney, but lesions were present in lung and liver only. Most infected cells were neutrophils. Ehrlichia phagocytophila-group infections are associated with moderate tissue damage. While the pathogenesis of granulocytic ehrlichiosis is not clear, pathologic studies suggest that the process is initiated by ehrlichia-infected cells but may result from host-mediated injury and immunosuppression.

Adult↗
PubMed2000

The haptoglobin 2-2 phenotype affects serum markers of iron status in healthy males.

BACKGROUND: Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. METHODS: Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled ((125)I) hemoglobin-haptoglobin complexes. RESULTS: In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of (125)I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. CONCLUSIONS: The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.

Adolescent↗
PubMed1999

Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein.

Adenovirus E1A proteins prepare the host cell for viral replication, stimulating cell cycling and viral transcription through interactions with critical cellular regulatory proteins such as RB and CBP. Here we show that the E1A zinc-finger domain that is required to activate transcription of viral early genes binds to a host-cell multiprotein complex containing homologues of yeast Srb/Mediator proteins. This occurs through a stable interaction with the human homologue of Caenorhabditis elegans SUR-2, a protein required for many developmental processes in the nematode. This human Srb/Mediator complex stimulates transcription in vitro in response to both the E1A zinc-finger and the herpes simplex virus VP16 activation domains. Interaction with human Sur-2 is also required for transcription to be activated by the activation domain of a transcription factor of the ETS-family in response to activated mitogen-activated protein (MAP) kinase.

Adenovirus E1A Proteins↗
PubMed1999

Weekly administration of prostaglandin E2 gel compared with expectant management in women with previous cesareans. Prepidil Gel Study Group.

OBJECTIVE: To compare the clinical effectiveness and safety of outpatient administration of intracervical prostaglandin (PG) E2 gel with expectant treatment for women desiring vaginal births after cesareans. METHODS: This was a randomized, multicenter investigation involving term pregnant women who each had one previous low-transverse cesarean and an unfavorable cervix (Bishop score no more than 6), and who was a candidate for vaginal delivery. They were assigned to receive 0.5 mg of PGE2, (Prepidil; Pharmacia-Upjohn, Kalamazoo, MI) intracervically at 39 weeks' gestation, repeated at weekly office visits for up to three doses, or expectant treatment. The main outcome variable was vaginal birth. RESULTS: Of 294 cases, 143 received gel and 151 were treated expectantly. No differences between groups were found for maternal age, race, or Bishop score. Compared with the expectant treatment group, the PGE2 gel group was not more likely to deliver sooner or vaginally (57% versus 55%, P = .68). The onset of labor, duration of labor among those delivering vaginally, and 1- and 5-minute Apgar scores were not different between groups. No uterine ruptures occurred, and adverse effects were equally likely in both groups. CONCLUSION: Although its safety was confirmed for outpatient use, weekly doses of intracervical PGE2 did not improve the likelihood of vaginal births after cesareans.

Adolescent↗