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PubMed1995

NF-M (chicken C/EBP beta) induces eosinophilic differentiation and apoptosis in a hematopoietic progenitor cell line.

CAAT/enhancer binding proteins (C/EBPs) are transcriptional activators implicated in the differentiation processes of various cell lineages. We have shown earlier that NF-M, the chicken homolog of C/EBP beta, is specifically expressed in myelomonocytic and eosinophilic cells of the hematopoietic system. To investigate the role of NF-M in hematopoietic cell lineage commitment, we constructed a conditional form of the protein by fusing it to the hormone binding domain of the human estrogen receptor. This construct was stably expressed in a multipotent progenitor cell line transformed by the Myb-Ets oncoprotein. We report here that both NF-M-dependent promoter constructs and resident genes could be activated by addition of beta-estradiol to the NF-M-estrogen receptor expressing progenitors. At the same time, we observed a down-regulation of progenitor-specific surface markers and the up-regulation of differentiation markers restricted to the eosinophil and myeloid lineages. In addition to the onset of differentiation, cell death was induced with typical apoptotic features. Our results suggest that NF-M plays an important role in commitment along the eosinophil lineage and in the induction of apoptosis.

Animals↗

PubMed1994

Multiple activation of chloroform in kidney microsomes from male and female DBA/2J mice.

Microsomes from the renal cortex of DBA/2J mice can metabolize chloroform through oxidative and reductive pathways, similar to hepatic microsomes. The oxidative or reductive nature of CHCl3 activation is strictly dependent on the oxygenation of the incubation mixture, as indicated by the formation of qualitatively different adducts to phospholipids (PLs). The protein and lipid binding levels measured in kidney microsomes from control females differed significantly from the binding levels observed with kidney microsomes from male and testosterone-treated female DBA/2J mice in aerobic conditions only. Therefore, the sex-dependent CHCl3-induced acute nephrotoxicity seems related only with the oxidative CHCl3 activation. The levels of adducts to PL polar heads and to protein showed a strict correlation with each other. Therefore, the assay of adducts to PL polar heads may be used as a substitute for the assay of adducts to protein. This might be especially convenient when studying the effects of both phosgene and the trichloromethyl radicals.

Animals↗

PubMed1976

Hypoxia: a succinate-fumerate electron shuttle between peripheral cells and lung.

The objective of this investigation was to determine if the succinate that accumulates in anoxic or hypoxic tissues of mammals is (a) increased in concentration in the blood, (b) excreted in the urine or (c) recycled in some manner. Rats were subjected to 0.4 atm and the plasma analyzed for succinate and fumarate at 2 hours, 24 hours and 28 days. Significant increases of succinate or succinate plus fumarate were obtained at 2 hours and 28 days at 0.4 atm. Analysis of 24-hour samples of urine obtained from controls and animals at 0.4 atm for 28 days demonstrated that no substantial increase in succinate excretion occurred with acclimation. Lung slices were incubated in Krebs-Ringer bicarbonate and succinate and gassed with O2:CO2 (95:5). Such oxygenated lung slices not only utilized succinate but produced a comparable quantity of fumerate plus malate. It is concluded that succinate produced from fumarate and alpha-ketoglutarate in peripheral hypotic tissue is transported by the blood to the oxygenated lungs. There it is oxidized to fumarate and recycled as fumarate and malate to the periphery. In this way metabolites can act as electron shuttles between peripheral cells and lung.

Animals↗

PubMed2002

Unusual manifestations of primary cytomegalovirus infection in patients without HIV infection and without organ transplants.

Primary cytomegalovirus (CMV) infection with marked constitutional symptoms is rare in immunocompetent individuals and in those with iatrogenic immunosuppression, except transplant recipients. Four patients admitted to hospital with clinical illnesses associated with primary CMV infection were identified over a 12-month period. Their medical records were reviewed with regard to clinical and laboratory data, and outcome. Primary CMV infection was defined by the concomitant presence of CMV IgM and low avidity CMV IgG antibody. Of two patients with no known underlying illness, one presented with thrombocytopenic purpura and the other with vasculitis. Two patients receiving immunosuppressants for underlying ulcerative colitis presented with CMV-induced pancytopenia and CMV colitis. Atypical lymphocytosis was a feature on blood film examination in three of the four cases. One patient with disseminated CMV infection died of progressive multiorgan failure despite antiviral treatment. CMV disease following primary CMV infection should be considered in otherwise immunocompetent individuals with atypical lymphocytosis on blood film analysis, and particularly in patients on immunosuppressants such as those with ulcerative colitis, since early diagnosis and treatment with antiviral drugs may improve outcome.

Adult↗

PubMed2005

Genotype characterization and phylogenetic analysis of hepatitis B virus isolates from Iranian patients.

Hepatitis B virus (HBV) is one of the major causative agents of acute and chronic liver disease worldwide and is believed to be responsible for a million deaths annually. Eight genotypes of HBV, A to H, have been described on the basis of similarity of the complete genomes sequence. Although, it is reported that the predominant HBV genotype in the Mediterranean area and the middle east is genotype D, there are no reports on HBV genotypes prevalent in Iran. In this study, the C and S regions of HBV from 26 chronic hepatitis B Iranian patients were amplified and sequenced. Phylogenetic analysis revealed that all Iranian HBV isolates sequences were classified into genotype D with bootstrap values of 100%, 73%, and 100% (1,000 replicates each) for S, C, and preS2 regions, respectively. The mean percent intra-distance of S and C regions were 0.8% and 2.3%, respectively. The mean percent inter-distance of S and C regions between Iranians and genotype D isolates were 1.7% and 3.0%, respectively, and the range of mean percent nucleotide distance of S and C regions between Iranians and the other reference isolates were 7.9%-17.5% and 4.8%-14.7%, respectively. Thirteen out of 23 HBV C region sequences showed nucleotide "A" at position 1896 (precore mutant) in C region. Nucleotide 1858 showed presence of "T" in all isolates. No insertion or deletion was found in both regions. SimPlot and BootScanning analyses did not show any recombination between Iranian isolates and other genotypes in both regions.

Adult↗

PubMed2005

Complete genomic sequence and phylogenetic relatedness of hepatitis B virus isolates from Iran.

Hepatitis B virus (HBV) is one of the main etiological agents of acute and chronic liver disease that is still a major public health problem in the world. Numerous HBV isolates have grouped into eight genotypes, A to H, based on the complete genome sequence. To date, no study has been carried out on the complete HBV genome sequence in Iran. The objective of this study was to investigate the complete genome sequence organization and phylogenetic analysis of the five HBV strains, which obtained from Iranian chronic infected patients. Results showed that Iranian strains were closely related to each other, with 97-100% nucleotide similarity. Phylogenetic analysis based on the complete genome sequences and the precore/core gene sequences revealed that all strains were of genotype D, sub-genotype D1 with bootstrap value 100 and 99%, respectively. The S gene encoded Arg122, Pro127, and Lys160 corresponding to subtype ayw2. Iranian HBV isolates had closely related with Turkish HBV strains. All strains had a nucleotide length of 3,182 base pair (bp) except IR-P4 strain, with a 3,185 bp in length and with a unique Phe89 insertion in the X gene. The intragenotypic divergence of the complete genome sequence of Iranian strains was 1.8% and the intergenotypic in genotype D was 3.8% and with the other genotypes was 7.9-15.4%. In conclusion, this study revealed that the HBV genotype D, sub-genotype D1, subtype ayw2 dominates in the Iranian infected patients. A single Phe89 insertion in the X gene of the one Iranian strain with an unforeseen length of 3185 bp was identified.

Adult↗

PubMed2006

Hepatitis B virus genotyping, core promoter, and precore/core mutations among Afghan patients infected with hepatitis B: a preliminary report.

In spite of hepatitis B virus (HBV) vaccination, HBV infection remains an important public health problem worldwide. Although the HBV genotype distribution has been determined in some parts of South Central Asia, no survey has been conducted to determine the HBV genotype in Afghanistan. Twelve Afghan patients infected with HBV living in Afghanistan were enrolled in this study. Partial HBsAg and basic core promoter, precore, and core (BCP/preC/C) regions were amplified and subjected for direct sequencing. In parallel, precore G1896A mutation was also determined by an amplification-created restriction site method. Results revealed HBV genotype D (95% bootstrap value), sub-genotype D1 (98% bootstrap value), and subtype ayw2 in all Afghan isolates. Afghan isolates clustered in a separate branch in the D1 sub-genotype called D1', while supported by 82% bootstrap value. The percentage of intra-genotypic distance among Afghan isolates was 1.05% and inter-genotypic distance with the other genotype D was 2.87% and with other genotypes was 7.50%-11.1%. The wild-type, mixed infection, and precore mutant were found in six, two, and four HBV isolates, respectively. The A1762T/G1764A BCP dual mutation was found in one isolate. Three isolates presented single mutation in the BCP dual mutation region, whereas two showed a novel G1764T mutation. In conclusion, this preliminary study revealed HBV genotype D, sub-genotype D1, and subtype ayw2 of HBV among hepatitis B infected patients from Afghanistan. Further investigation should be carried out.

Adolescent↗

PubMed2006

Molecular analysis and phylogenetic characterization of HIV in Iran.

The rate of human immunodeficiency virus type 1 (HIV-1) infection in Iran has increased dramatically in the last few years. While the earliest cases were found in hemophiliacs, intravenous drug users are now fueling the outbreak. In this study, both the 122 clones of HIV-1 gag p17 and the 131 clones of env V1-V5 region were obtained from 61 HIV-1 seropositives belonging to these two groups in Iran. HIV-1 subtyping and phylogenetic analysis was done by heteroduplex mobility assays (HMA) and multiple clone sequencing. The result indicated all hemophiliacs are infected with HIV-1 subtype B and all intravenous drug users are infected with HIV-1 subtype A. Since intravenous drug abuse is the major transmission route in Iran, HIV-1 subtype A is likely to be the dominant viral subtype circulating in the country. The analysis of genetic distances showed subtype B viruses in Iran to be twice as heterogeneous as the subtype A viruses. In conclusion, this first molecular study of HIV-1 genotypes in Iran suggests two parallel outbreaks in distinct high-risk populations and may offer clues to the origin and spread of infection in Iran.

Amino Acid Sequence↗

PubMed2003

A chain of evidence with mixed comparisons: models for multi-parameter synthesis and consistency of evidence.

Multi-parameter evidence synthesis is a generalization of meta-analysis in which several parameters are estimated jointly. Here this approach is applied to a common form of data structure in which mixed pairwise comparisons are made between treatments in a 'chain of evidence' structure. The data set investigated here, which first appeared in the confidence profile method literature, features three types of data relating to thrombolytic treatment following acute myocardial infarction. There is information on reperfusion (coronary patency) following treatment, information on survival in reperfused and non-reperfused patients (conditional survival), and independent information on the effect of treatment on survival without specifying reperfusion state (overall survival). The objective of this study is to explore models for combining these three types of evidence within a single model, and some of the evidence consistency issues that arise. Bayesian Markov chain Monte Carlo methods are used to fit two models. The first, proposed in the confidence profile literature, assumes there are no differences between studies in baseline effects (equal study effects). The second model assumes fixed treatment effects but allows for study differences in baseline reperfusion and conditional survival rates by assuming random study effects. The equal study effects model fits the data poorly, and cross-validation shows that the overall survival evidence is not consistent with the reperfusion and conditional survival evidence under this model. The evidence appears to be consistent within the more loosely structured random study effects model, but results are sensitive to prior assumptions about the between-study variance. The inconsistency between the three evidence types relates to overall survival, rather than to the effect of treatment on survival. Multi-parameter evidence synthesis, with suitable checks for evidence consistency, can be used to help determine whether chains of evidence 'add up' epidemiologically within an overall model, and to construct parameter distributions for an entire model simultaneously, consistent with all the available data.

Bayes Theorem↗

PubMed2004

Combination of direct and indirect evidence in mixed treatment comparisons.

Mixed treatment comparison (MTC) meta-analysis is a generalization of standard pairwise meta-analysis for A vs B trials, to data structures that include, for example, A vs B, B vs C, and A vs C trials. There are two roles for MTC: one is to strengthen inference concerning the relative efficacy of two treatments, by including both 'direct' and 'indirect' comparisons. The other is to facilitate simultaneous inference regarding all treatments, in order for example to select the best treatment. In this paper, we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS. These are multivariate random effects models that allow for variation in true treatment effects across trials. We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models. We also compare models with fixed (unconstrained) baseline study effects with models with random baselines drawn from a common distribution. These models are applied to an illustrative data set and posterior parameter distributions are compared. We discuss model critique and model selection, illustrating the role of Bayesian deviance analysis, and node-based model criticism. The assumptions underlying the MTC models and their parameterization are also discussed.

Humans↗

PubMed1994

Estimates of disease incidence in women based on antenatal or neonatal seroprevalence data: HIV in New York City.

Piecewise constant incidence models were developed to estimate the force of infection in women from age- and time-specific antenatal or neonatal seroprevalence data. Differential inclusion of infected women in sero-surveys compared to uninfected women was taken into account, with respect to both changes in inclusion rate following infection, and changes in relative inclusion rate over calendar time. These models were applied to anonymous HIV seroprevalence data collected from neonates born to black and Hispanic women in New York City 1988-1992, with incidence and fertility parameters estimated by maximum likelihood. Estimates of inclusion rate parameters accorded well with what is known about the natural history of HIV. The data could not distinguish between additive and multiplicative combination of the effects of age and time on incidence. Incidence was strongly dependent on age with the highest incidence in women aged 20-34 years. There was strong evidence that incidence had been falling in Hispanic women since 1982-1984. The results illustrate the extent to which trends in incidence over time may be confounded by changes in the relative inclusion rate of infected and uninfected women.

Adolescent↗

PubMed1994

Age-related reference ranges: significance tests for models and confidence intervals for centiles.

A method of fitting age-related reference ranges using maximized likelihood is presented. The method is illustrated using CD4 counts of uninfected children born to HIV-1 infected women. The likelihood incorporates exponential functions to describe the Box-Cox transformation parameter that induces Normality and the mean and standard deviation of the transformed data, at all ages in the range. This guarantees that the centiles are asymptotic to notional adult values and avoids edge effects. Likelihood ratio tests were used to assess the significance of the model parameters, and profile likelihood confidence intervals were constructed around the fitted centiles. The asymptotes of the resulting CD4 reference range for the childhood dataset were compared with CD4 counts available from a group of uninfected adults. The proposed approach limits the need for arbitrary decisions about grouping of the data, degree of smoothing or choice of model.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Age-related standards for ordinal data: modelling the changes in visual acuity from 2 to 9 years of age.

The visual acuities of 1140 children between the ages of 2 and 9 years were measured using the Sonksen-Silver Acuity System (SSAS) from a distance of 3 metres. Ordered logistic regression was used to construct smoothly changing age-related reference ranges for the proportions of children at different ages expected to have acuities in each of three ordinal categories. Exponential functions of age fitted the data better than polynomials. The resulting reference ranges can be used to derive the ages at which a given percentage of children achieve each of the acuity cut-offs. However, since it is unlikely that all children will be available for testing at the exact appropriate age, two possible alternatives are introduced and discussed. First, a new ordinal category that would result in a chosen outcome at a pre-selected age is calculated. Secondly, because it may be more feasible to use the current SSAS system whilst varying the distance of measurement, age-related standards showing the distances required to give constant pass-rates with the usual letter-sizes are also presented.

Age Factors↗

PubMed1996

In vitro translation and translocation of apolipoprotein B in a cell-free system from HepG2 cells.

An mRNA-dependent cell-free system has been developed from HepG2 cells by hydrolysis of endogenous mRNA with micrococcal nuclease. When supplied with RNA extracted from HepG2 cells, the system synthesized liver specific proteins such as albumin and apolipoprotein B100. Significant amounts of microsomes were also detected in the lysate by measuring NADH-cytochrome c reductase activity and ultracentrifugation. Protease protection assays showed the capability of the HepG2 lysate to translocate newly-synthesized proteins such as apolipoprotein Al, albumin, and apoB into the microsomes as they were protected from digestion with exogenously added protease K, but not protected in the presence of protease K and Triton X-100. The system also proved to be very active toward translation of exogenous mRNAs as evidenced by efficient translation of brome mosaic virus RNA. The HepG2 translation-translocation system appears to provide a unique homologous system for studies on the biogenesis of liver specific proteins, particulary apoB100.

Apolipoproteins B↗

PubMed1998

Effects of tocotrienol on the intracellular translocation and degradation of apolipoprotein B: possible involvement of a proteasome independent pathway.

gamma-Tocotrienol (gamma-T3), a HMG CoA reductase inhibitor, was previously shown to stimulate the intracellular degradation of apolipoprotein B (apoB) in HepG2 cells. The aim of this study was to explore the effects of gamma-T3 on the proteasome dependent co-translational degradation and the proteasome independent post-translational degradation of apoB. Previous studies have shown that apoB translocation across the endoplasmic reticulum (ER) membrane governs the co-translational degradative pathway of apoB. Therefore, we first examined the effects of gamma-T3 on this pathway using a specific translocation assay derived from HepG2 cells. Our results indicated that gamma-T3 reduced the efficiency of apoB translocation across the ER membrane, suggesting that co-translational degradation may be partially involved. Evidence of an ER associated post-translational degradation was also provided upon pre-treating digitonin-permeabilized HepG2 cells with a proteasome inhibitor, lactacystin. When chased for 2h, ER degradation of apoB was observed and was further enhanced in the presence of gamma-T3 versus untreated control, in spite of proteasome inhibition. Combined with the ability of ALLN, a proteasome and cysteine protease inhibitor, to block the post-translational degradation of apoB, the data suggest that gamma-T3 diverted more apoB to a cytosolic proteasomal dependent and possibly an ER-associated proteasomal independent degradation pathways.

Acetylcysteine↗

PubMed2000

Translocational status of ApoB in the presence of an inhibitor of microsomal triglyceride transfer protein.

Despite numerous studies demonstrating that microsomal triglyceride transfer protein (MTP) activity is critical to apoB secretion, there is still controversy as to whether MTP directly facilitates the translocation of apoB across the membrane of the endoplasmic reticulum (ER) through either the recruitment of lipids and/or chaperone activity. In the present study, a specific inhibitor of MTP (BMS 197636) was utilized in HepG2 cells to investigate whether a direct relationship exists between the translocation of apoB across the ER membrane and the lipid-transferring activity of MTP. Inhibition of MTP (with 10 and 50 nmol/L of the inhibitor) did not significantly affect the translocation of newly synthesized apoB (P = 0.77) or the translocational efficiency of the steady-state apoB mass (P = 0.45), despite a 49% decrease in apoB secretion and increased proteosomal degradation. These results compared well with subcellular fractionation experiments which showed no significant change in the fraction of apoB accumulated in the lumen of isolated microsomes in MTP-treated cells (P = 0.35). In summary, MTP lipid transfer activity does not appear to influence translocational status of apoB, but its inhibition is associated with an increased susceptibility to proteasome-mediated degradation and reduced assembly and secretion of apoB lipoprotein particles.

Apolipoproteins B↗

PubMed1996

The use of a microporous polyvinylidene fluoride (PVDF) membrane filter to separate contaminating viral particles from biologically important proteins.

Viral agents (influenza A virus, 80-120 nm; phage T1, 50 nm head, 150 nm head, 150 nm tail; phage PR772, 53 nm; poliovirus, 28-30 nm; and phage PP7, 25 nm) were used to determine the ability of a newly developed, modified polyvinylidene fluoride (PVDF) membrane filter to remove viruses from several fluids. These included ultrapure water, Dulbecco's modified Eagle minimum essential medium (DMEM) and DMEM with 10% fetal bovine serum (DMEM-10). Small volume (10 ml) filtration experiments were done with 47-mm disks while larger volumes (1 litre) were done with virus suspended in DMEM-10, using cartridge filters with a surface area of 1.63 m2. With 47-mm disks, influenza A virus and phage T1 were removed to below detectable limits in all fluids tested (titre reduction [Tr] > 2.0 x 10(6) and > 5.8 x 10(8), respectively). The retention of phage PP7 and poliovirus was consistent but fluid dependent. The greatest concentration of phage PP7 and poliovirus was removed from ultrapure water (phage PP7, Tr = 2.1 x 10(7); poliovirus, TR > 3.2 x 10(4), while the removal efficiency from DMEM-10 was substantially lower (phage PP7, Tr = 2.3; poliovirus, Tr = 2.1 x 10(2)). Results of cartridge challenges in DMEM-10 were comparable to the corresponding small disk challenges. These results demonstrate that this PVDF membrane filter was very effective (Tr > 10(6)) in removing viral particles (> 50 nm); smaller viruses (< 50 nm) were also consistently removed, but the level of removal depended on the virus and type of fluid tested. In separate experiments, the recovery of purified albumin (69,000 Da) and IgG (150,000 Da) in the filtrate was also determined at approx. 0.015 mg/ml and approx. 10 mg/ml. Recovery of albumin and IgG was > 90%. Efficient virus retention coupled with high recovery of protein < 150,000 Da suggest potential applications of this membrane filter, when protection against adventitious viral contaminants is desired.

Animals↗

PubMed1996

Plasmodium falciparum: involvement of additional receptors in the cytoadherence of infected erythrocytes to microvascular endothelial cells.

The involvement of additional ligands in the cytoadhesion of PRBC to endothelial cells was studied by the use of human microvascular endothelial cells (HMEC-1), brain microvascular endothelial cells (HBEC-51), umbilical vein endothelial (HUVEC), and C32 melanoma cells as well as soluble CD36, ICAM-1, and thrombospondin in the adhesion assays. Immunostaining showed that ICAM-1 and thrombospondin were expressed by all cell lines, whereas CD36 and VCAM-1 were expressed constitutively only by C32 melanoma cells and HBEC-51, respectively; none of these cells had basal expression of E-selectin. Bindings of the parental HB3 parasite strain to HMEC-1 and HUVEC were higher than that to HBEC-51 and C32 melanoma cells. Selections by panning the parental HB3 through HMEC-1 (HB3EC-6 line) or C32 melanoma cells (HB3C32-6 to HMEC-1 was higher than that to C32 melanoma cells. Antibody or peptide blockade against CD36, ICAM-1, and thrombospondin or preincubation of target cells with TNF-alpha and IFN-gamma did not significantly alter the binding intensity of HB3EC-6 to HMEC-1 and HB3C32-6 to C32 melanoma cells. Preincubation of HMEC-1 with IL-4, however, reduced its binding with HB3EC-6. In vitro selection did not enhance the binding of PRBC to plate-bound CD36 or thrombospondin; binding to ICAM-1 was negligible. The binding of both selected lines was inhibited by dextran sulfate and sulfatides, but not by chondroitin sulfate A. These results suggested that in addition to CD36 and thrombospondin, sulfated glycoconjugates were probably concurrently utilized by these PRBC as receptors. Experiments with freshly isolated Kenyan parasites indicated that they also exhibited a similar mechanism of binding to endothelial cells.

Animals↗