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H Friedman

Publications and source records attributed to H Friedman.

At least 73 records · Page 4Linked to original sources
PubMed1998

Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.

BACKGROUND AND OBJECTIVE: The etiology of neurologic impairments among very low birth weight (VLBW, <1.5 kg) children is poorly understood. We sought to investigate the perinatal predictors of major neurologic impairment, including cerebral palsy, among VLBW children. METHODS: Antenatal, intrapartum, and neonatal events and therapies were compared between 72 singleton inborn VLBW children born between 1983 to 1991 who had neurologic impairment at 20 months corrected age (including 50 with cerebral palsy and 22 with other neurologic impairments) and 72 neurologically normal VLBW children matched by birth weight, gestational age, race, and sex via a retrospective case-control method. Multiple logistic regression was conducted, entering only those variables found to be significant at the bivariate level. RESULTS: There were no significant differences in the rates of pregnancy-induced hypertension, maternal tocolytic use including magnesium, or antenatal steroid therapy. Higher rates of clinical chorioamnionitis were found among the mothers of the neurologically impaired children as compared with controls (31% vs 11%), but not among the subgroup of mothers of children with cerebral palsy (22% vs 12%). Significant differences in neonatal factors among the total neurologically-impaired group (n = 72) versus controls included oxygen dependence at 36 weeks (31% vs 15%), septicemia (53% vs 31%), severe cranial ultrasound abnormality (50% vs 17%), and hypothyroxinemia (43% vs 25%). In the subgroup with cerebral palsy (n = 50), significant differences included days on the ventilator (23 vs 14 days), septicemia (54% vs 33%), and severe cranial ultrasound abnormality (52% vs 12%). Multivariate analysis controlling for birth weight, gestational age, race, sex, and the birth period (before 1990 versus 1990 and after) revealed direct and independent effects of clinical chorioamnionitis [odds ratio (OR), 3. 79; confidence interval (CI), 1.34-10.78], severe cranial ultrasound abnormality (OR, 9.97; CI, 3.84-25.87), and septicemia (OR, 2.46; CI, 1.10-5.52) on total neurologic impairment. Consideration of the 50 cases with cerebral palsy revealed direct and independent effects of severe cranial ultrasound abnormality only (OR, 15.01; CI, 4.34-51. 93). CONCLUSIONS: Both antenatal and neonatal risk factors contribute to the development of severe neurologic impairment, including cerebral palsy among VLBW children. Because prevention of chorioamnionitis may not be feasible in the near future, attempts to decrease neonatal risk factors such as severe cranial ultrasound abnormalities and sepsis may be most feasible at this time.

Birth Weight↗
PubMed1998

Immunologic response and pathophysiology of Legionella infection.

Legionella pneumophila, the causative agent of legionnaires' disease, is a gram-negative pleomorphic bacillus and fastidious in its growth in artificial medium. These bacteria grow readily intracellularly, including growth in macrophages and other phagocytic cells. Humoral antibodies develop readily to these bacteria not only in infected patients, but also in persons who have had subclinical exposure. High-levels of serum antibodies may also occur in individuals who recover from infection. However, cell-mediated immunity based on lymphocytes reacting with the organisms and cytokines produced by such lymphocytes are important in resistance. Vaccines prepared from killed Legionella or their components readily induce cell-mediated immunity. Immune resistance to disease depends on lymphocyte-based immunity, activating cytokine formation, some of which activate macrophages to resist infection. Resistance to Legionella infection by experimental animals such as mice correlates with activation of macrophages, which can inhibit replication of the bacteria. Much recent experimental work has involved studies using inbred animals, including inbred mice genetically resistant to Legionella versus mice genetically susceptible. Detailed studies show that regulation of macrophage resistance versus susceptibility to infection is mediated by specific genetic mechanisms. Induction of cytokines by Legionella can activate immune cells, especially helper T cells. Th 1 type helper cells that produce type 1 class cytokines, such as interferon gamma and interleukin-2 (IL-2), are known to be important in cellular immunity to Legionella as well as to other opportunistic intracellular bacteria. In contrast, Th 2 type helper cells, which secrete type 2 class cytokines such as IL-4, IL-5, and IL-6, activate B lymphocytes to produce humoral antibodies important in resistance to extracellular bacteria which secrete toxins and extracellular factors as compared to intracellular bacteria such as Legionella. Although Legionella, similar to other ubiquitous opportunistic pathogens, can cause serious infection in immunocompromised individuals, these bacteria have many distinguishing characteristics, such as very rapid replication in macrophages from susceptible individuals. However, activated macrophages restrict the growth of these bacteria. Infection by Legionella, if recognized clinically, can be readily treated with appropriate antibiotics. Currently, many studies are in progress concerning the mechanism of pathogenicity and assessment of the molecular biologic mechanisms of protective immune responses to this bacterium, which causes serious infection in immunocompromised individuals.

Cytokines↗
PubMed1998

Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1.

Apoptosis is programed cell death characterized by certain cellular changes and regulated by various gene products including Bcl-2 and caspase-1. The marijuana cannabinoid, Delta9tetrahydrocannabinol (THC), has been reported to suppress in culture the proliferation of splenocytes and increase the release of IL-1 from macrophages; however, the mechanisms of these effects remain unclear. Because cannabinoids have also been reported to induce apoptosis and because the release of IL-1 and suppression of lymphoproliferation are related to apoptosis, we tested for the induction of apoptosis by THC in murine immune cell cultures. Splenocytes cultured with Con A for up to 24 hr showed evidence of DNA fragmentation determined by gel electrophoresis, terminal deoxynucleotide transferase-mediated dUTP-fluorescein nick end labeling and 3H-thymidine labeling and THC (15-30 microM) treatment increased fragmentation under these conditions. Resident peritoneal macrophages cultured with lipopolysaccharides showed no obvious fragmentation unless they were also treated with THC. Time course studies examining DNA fragmentation and cell membrane integrity (assessed by dye exclusion) showed that fragmentation preceded membrane damage indicating that THC induced apoptosis rather than cell necrosis. In addition, THC treatment of splenocytes resulted in a decrease of Bcl-2 mRNA and protein as measured by Northern and Western blotting, respectively, and the drug induced apoptosis was blocked by the caspase inhibitor, Ac-Tyr-Val-Ala-L-aspartic acid aldehyde. These data suggest that THC treatment of cultured immune cells induces apoptosis through the regulation of Bcl-2 and caspase activity.

Animals↗
PubMed1997

Differential effects of granulocyte/macrophage colony-stimulating factor (GM-CSF) in enhancing macrophage resistance to Legionella pneumophila vs Candida albicans.

It has been reported that granulocyte/macrophage colony-stimulating factor (GM-CSF), one of the hemopoietic growth factors which regulates the function of phagocytic cells, is a potent activator of cultured macrophages and induces antimicrobial activities as well as differentiation of precursor cells. In this study, we examined the ability of recombinant murine GM-CSF to activate mouse peritoneal macrophages to restrict the growth of two different microorganisms, Candida albicans and Legionella pneumophila, both of which are important opportunistic pathogens in an immunocompromised host. Treatment of thioglycollate-elicited BDF1 mouse macrophages with GM-CSF for 24 hr enhanced the anti-C. albicans activity of the macrophages in terms of inhibiting growth of the fungi. Reactive oxygen (H2O2) and IL-1 production by the macrophages were also enhanced by treatment with GM-CSF. However, no enhancement of anti-L. pneumophila activity of macrophages obtained from either susceptible A/J or resistant BDF1 mice to L. pneumophila infection after treatment with up to 1000 units/ml GM-CSF was observed under the same conditions. When the treatment time was extended to 72 hr. GM-CSF was still unable to induce anti-L. pneumophila activity. As a control study, treatment with recombinant IFN-gamma enhanced both anti-Candida and anti-Legionella activity in cultured macrophages under the same conditions used in the GM-CSF study. Measurement of cellular iron content revealed the low iron content in IFN-gamma-treated macrophages, but no decrease of iron in GM-CSF-treated macrophages compared with the control group, indicating a possible involvement of iron as a key factor in anti-L. pneumophila activity. Thus, the results of the study show that GM-CSF activation of elicited peritoneal macrophages is selective with regard to the type of antimicrobial activity induced.

Animals↗
PubMed1997

Differential immunologic modulatory effects of tetrahydrocannabinol as a function of age.

Tetrahydrocannabinol (THC) the major psychoactive component of marijuana, differentially modulates the immune response of lymphoid cells from young and old mice. This effect was previously shown when cells from mice of different ages were treated with THC in vitro. In the present study THC was given in vivo to mice of different ages. Lymphoid cells from the young and old mice had different immunologic potential in terms of ability to produce cytokines following stimulation with either Con A or anti-CD3 antibody. IL-4 and IL-10 production was consistently up-regulated in spleen cell cultures from the older animals. In addition, in vivo administration of THC up-regulated the proliferative response of lymphoid cells from young adult mice. Such enhancement was not evident for cells from older animals. Although the proliferative response of spleen cells in the old mice tended to be suppressed, statistical significance was not evident possibly because of marked variation of the responses of cells from the older mice. Since marijuana is used by persons of a wide range of ages, aging should be an important variable that must be considered when assessing the immunomodilatory effect of this drug.

Adjuvants, Immunologic↗
PubMed1997

Induction of interleukin-2 receptor alpha gene by delta9-tetrahydrocannabinol is mediated by nuclear factor kappaB and CB1 cannabinoid receptor.

Previously, we reported that the cannabinoid delta9-tetrahydrocannabinol (THC) increased the expression of interleukin-2 (IL-2) receptor (R) alpha and beta proteins and mRNAs in NKB61A2 cells, but decreased the level of the gamma-chain message. The drug increased beta-chain message stability rather than increased transcription. In the present study, we examined the mechanism responsible for the drug-induced increase in alpha-chain message in NKB61A2 cells. Nuclear run-on and mRNA stability studies showed THC increased the level of alpha gene transcription but had no effect on mRNA stability. Because expression of this gene is regulated by nuclear factor (NF)-kappaB, we next tested the drug effect on the nuclear level of this protein using the electromobility shift assay. These studies showed a drug-induced increase in NF-kappaB activity. To link the increased nuclear factor activity with the THC-induced increase in IL-2R alpha message, antisense oligodeoxynucleotides were used to inhibit expression of the RelA component of NF-kappaB. These results showed anti-RelA antisense eliminated the cannabinoid-induced upregulation of both alpha mRNA and RelA protein. Furthermore, inhibition of the cannabinoid receptor type 1 with antisense oligomers also eliminated the drug effect on the alpha message. These results suggest that THC treatment of NKB61A2 cells increases IL-2R alpha gene transcription by increasing the nuclear level of NF-kappaB through a mechanism involving cannabinoid receptor type 1 expression.

Animals↗
PubMed1997

Development of genetic vaccines for pathogenic genes: construction of attenuated vif DNA immunization cassettes.

OBJECTIVE: To develop a putative immunization cassette using HIV-1 vif accessory gene derived from HIV-1 clinical specimens as a component of a DNA vaccine for HIV-1. METHODS: vif genes were cloned from HIV-1-infected patients and the sequence variation present within the patients was analyzed. Prototypic genetic variants were selected and the ability of these clones to induce humoral and cellular immune responses was studied in animals. The selected protective genetic variants were biologically characterized through transcomplementation assays using primary cells infected with a vif-defective HIV-1 proviral clone. RESULTS: Analysis of vif variants from different patients revealed that vif is highly conserved with the open reading frame remaining intact in vivo. It was shown that attenuated vif clones from HIV-1-infected subjects can effectively induce both humoral and cellular responses against Vif protein in mice. Evaluation of the cellular responses in vitro using human cellular targets infected with a clinical HIV-1 isolate showed that vif clones could induce cellular responses capable of destroying the virus. CONCLUSIONS: The vif variants developed in this study exhibited non-productive phenotypes, yet were capable of inducing specific immune responses against HIV-1. These constructs could be used as part of a DNA vaccine strategy for HIV-1. This vaccine adaptation strategy could be used for the development of immunogens for any pathogen resulting in cross-reactive immunity and attenuated gene pathogenesis.

AIDS Vaccines↗
PubMed1997

An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations.

Endemic pemphigus foliaceus or fogo selvagem (FS) in an organ-specific autoimmune skin disease characterized by epidermal vesicles and mediated by autoantibodies. Family cases are frequent and not everyone living in endemic region develops FS suggesting that host factors play a role in determining whether exposed individuals will be affected. Because our previous works with Brazilian Mestizos and with Xavante Indians have shown that particular HLA alleles confer increased risk for the disease, we decided to extend these studies to another homogeneous population, the Terena Indians. 19 out of 20 Terena patients were either positive for DRB1*0404, 1402 or 1406 (p < 0.005, RR = 14). These findings were in agreement with the data obtained from the Xavante study. In Mestizos the association was with DRB1*01. All these alleles involved in predisposition to the disease in different populations shared the same amino acid sequence at position 67-74 on the third hypervariable region of the DRB1 gene: LLEQRRAA, suggesting that inheritance of this sequence is involved in the susceptibility to FS. When patients and controls data from different studies were pooled and analyzed disregarding the ethnic background and the HLA alleles involved, the results obtained clearly supported the hypothesis that matching for this epitope is highly significant and predictive of FS predisposition (p < 0.00001, RR = 6.4).

Alleles↗
PubMed1997

Involvement of mannose receptor in cytokine interleukin-1beta (IL-1beta), IL-6, and granulocyte-macrophage colony-stimulating factor responses, but not in chemokine macrophage inflammatory protein 1beta (MIP-1beta), MIP-2, and KC responses, caused by attachment of Candida albicans to macrophages.

The production of chemotactic cytokines (chemokines) and other cytokines by macrophages in response to fungal infection is thought to be critical during the course of candidiasis. However, the mechanism of cytokine synthesis by macrophages in response to fungi is not well understood. Therefore, the response of macrophages to Candida albicans was examined in terms of receptor-mediated chemokine and other cytokine mRNA induction. Attachment of C. albicans to murine thioglycollate-elicited peritoneal macrophages induced increased mRNA levels of the cytokines interleukin-1beta (IL-1beta), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein 1beta (MIP-1beta), MIP-2, and KC (a member of the platelet factor 4 neutrophil chemoattractant family), as determined by quantitative reverse transcription-PCR. However, treatment of macrophages with alpha-methyl-D-mannoside significantly reduced the cytokine GM-CSF response to C. albicans but did not affect the chemokine MIP-2 response. Antisense oligodeoxynucleotide (ODN) to mannose receptor (MR) mRNA inhibited the expression and function of MR in macrophages as determined by Western blot analysis and 125I-labeled mannose-bovine serum albumin (BSA) binding, and also inhibited the elevation of cytokine IL-1beta, IL-6, and GM-CSF mRNA levels induced by C. albicans attachment. Elevation of chemokine MIP-1beta, MIP-2, and KC mRNA levels induced by C. albicans was not affected in macrophages whose MR expression was suppressed by antisense ODN treatment. Furthermore, IL-4 treatment of macrophages, which up-regulated MR expression as determined by Western blot analysis and fluorescein isothiocyanate-labeled mannose-BSA uptake, enhanced the level of cytokine GM-CSF mRNA induced by C. albicans but not the level of the chemokine MIP-2 mRNA. These results indicate that selected cytokine responses of macrophages to C. albicans are mediated by MR, while some chemokine responses may be mediated by other receptors.

Animals↗
PubMed1997

Psychoactive cannabinoids increase mortality and alter acute phase cytokine responses in mice sublethally infected with Legionella pneumophila.

Marijuana contains both psychoactive and nonpsychoactive cannabinoids which have varying effects on the immune response system. Previous studies with delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, showed that this substance augmented the susceptibility of mice to infection with the opportunistic pathogen Legionella pneumophila. The present study compared the enhancement of Legionella-induced mortality in mice due to two other major of marijuana components, cannabinol and cannabidiol, as well as the synthetic psychoactive cannabinoid CP 55,940. Inbred BALB/c mice, relatively resistant to infection with Legionella, were given the marijuana component 1 day before and 1 day after a sublethal intravenous infection with Legionella. Unlike the effect of THC, an 8 mg/kg dose of either cannabinol or cannabidiol did not affect mortality of the mice sublethally infected with Legionella. Mice given a 16 mg/kg dose of these components of marijuana, however, showed a slight to moderately increased mortality following the sublethal infection with Legionella. In contrast, a dose of 6 mg/kg of the synthetic psychoactive cannabinoid CP 55,940 given 1 day before and 1 day after infection with Legionella resulted in about 50% of the animals dying, the same level of augmentation of lethality induced by THC. Liver, spleen, and lung tissues were removed from the surviving mice 24 hr after the second THC injection and tested for the presence of viable Legionella using a standard CFU assay. The mice injected with THC before and after infection showed significantly higher levels of bacteria in their lung than mice that were not given any cannabinoid but were infected sublethally with the Legionella. Mice injected with the other cannabinoids, including the synthetic cannabinoid, showed a much smaller increase in the number of Legionella in their lung when infected with Legionella and treated with the drug. The number of bacteria recovered from the kidney and liver of the mice regardless of treatment with a cannabinoid, including with THC, did not show significant changes. RNA isolated from the spleen of the THC- and Legionella-treated animals was examined to determine at the molecular level whether acute phase pro-inflammatory cytokines (i.e., IL-1, IL-6 and TNF-alpha) were altered following drug treatment and infection, since previous studies had shown there were increased serum levels of these cytokines in the mice. It was found that the mRNA levels for IL-1 remained generally constant regardless of whether the infected animals were treated with a cannabinoid. However, the mRNA level for IL-6 was markedly increased following treatment of the infected animals with THC, suggesting the possible involvement of this pro-inflammatory cytokine in increased mortality. The mRNA level for TNF-alpha was generally low and not significantly altered in the drug treated animals. Mice given other cannabinoids, including cannabinol and cannabidiol, as well as the synthetic CP 55,940, showed no significant change in the level of mRNA for any of the cytokines tested.

Acute-Phase Proteins↗
PubMed1996

Immunoregulatory role of nitric oxide in Legionella pneumophila-infected macrophages.

Nitric oxide (NO) is an intercellular messenger molecule produced by a variety of cells, including macrophages. However, the role of NO in infection, especially its immunological role, is poorly understood. In the present study, the role of NO in Legionella pneumophila-infected macrophages was examined. Whereas infection of mouse macrophages in vitro with L. pneumophila did not induce detectable NO, when the macrophages were primed with interferon-gamma (IFN-gamma), the treated macrophages markedly inhibited bacterial replication and produced a large amount of NO. Treatment with NO inhibitors, such as NG-monomethyl-L-arginine (L-MMA) or aminoguanidine, as well as culture in arginine-free medium, significantly inhibited NO production; however, the anti-L. pneumophila activity induced by IFN-gamma was not diminished. Examination of cytokine levels in L. pneumophila-infected macrophages primed with IFN-gamma revealed a moderate increase of interleukin-6 (IL-6) production; however, inhibition of NO by L-MMA markedly increased IL-6 production. Reconstitution of NO in the L. pneumophila-infected macrophages primed with IFN-gamma and treated with L-MMA to inhibit endogenous NO production following addition of sodium nitroprusside reduced IL-6 production to normal levels. The levels of IL-6 mRNA in L-MMA-treated macrophages were the same as in nontreated macrophages, as demonstrated by quantitative RT-PCR. Thus, these results indicate that NO may regulate IL-6 production independently of its role in antimicrobial function in L. pneumophila-infected macrophages and their immunoregulation on IL-6 production may be due to a post-transcriptional mechanism.

Animals↗
PubMed1996

Legionella pneumophila heat-shock protein-induced increase of interleukin-1 beta mRNA involves protein kinase C signalling in macrophages.

Heat-shock proteins (hsp) are chaperon molecules important in protein folding and assembly. Furthermore, they may have functions in immunoregulatory processes, like T-cell stimulation and antigen presentation, which are not yet fully understood. It has been shown that several hsp of various species and family derivations modulate functions in macrophage immunity by directly increasing cytokine production. In the present study we showed that the 60,000 MW hsp of Legionella pneumophila (Lp-hsp 60) increased cellular steady-state levels of interleukin-1 beta (IL-1 beta) mRNA measured by quantitative reverse transcription-polymerase chain reaction and Northern blotting as well as IL-1 secretion, when added to cultures of thioglycollate-elicited mouse peritoneal macrophages in vitro. The level of mRNA increased in a dose-dependent manner with a minimum effective concentration of 0.5 microgram/ml and peaked 3 hr after stimulation. Lp-hsp 60-coated latex beads also increased IL-1 beta mRNA levels in the presence of cytochalasin D, which inhibits bead uptake but permits binding, indicating that binding to the macrophage surface was sufficient for induction. Accumulation of IL-1 beta mRNA was completely blocked by pretreatment with the protein kinase C (PKC) inhibitor, H7, but not decreased by prior treatment with cycloheximide. The cell lysates of macrophages stimulated with Lp-hsp 60 showed an increased PKC activity measured by phosphorylation of PKC pseudosubstrate. The IL-1 bioactivity in culture supernatants after 24 hr of stimulation with Lp-hsp 60 was increased in a dose-dependent manner but at hsp concentrations in excess of those needed to increase mRNA. Thus, the present study demonstrates that Lp-hsp 60 rapidly increases the steady-state level of IL-1 beta mRNA, possibly through a cell surface receptor system involving a PKC-dependent signalling pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension.

Present product labelling indicates that azithromycin capsules should not be taken with food. However, three recent studies demonstrated that food does not significantly decrease the bioavilabilities of three new formulations of azithromycin (250 mg tablets, 1000 mg sachet, 500 mg paediatric suspension). With a 500 mg dosage, the mean relative bioavailability of azithromycin following ingestion of a standard high-fat breakfast was 96% when administered as two 250 mg tablets and 113% when administered as a suspension. The mean relative bioavailability of a 1000 mg sachet was 112%. The absolute bioavailability of the sachet formulation, relative to a 1 h iv infusion of 1000 mg, was 44%. Thus, azithromycin tablets, suspension and sachet may be given without regard to meals, further enhancing the convenience of once-daily, short-duration dosing regimens.

Adolescent↗
PubMed1996

An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil. Cooperative Group on Fogo Selvagem Research.

Fogo Selvagem (FS) is an autoimmune disease characterized by subcorneal vesicles and antidesmoglein-1 autoantibodies. Previous epidemiologic data have linked the onset of FS to exposure to an environmental antigen(s). This investigation describes a unique human settlement with an extraordinarily high prevalence of FS. This community is made up of Amerindians belonging to the Terena tribe, which has settled on the Limao Verde reservation in the state of Mato Grosso do Sul in Brazil. Twenty-six well-characterized FS cases have been identified within a total population of 998, yielding a prevalence of 2.6%. Seventeen of the patients (65 %) were males, and over 50% were older than 30 y of age. The incidence of the disease shows temporal periodicity, i.e., years with several cases of FS alternating with years with no cases. Over one-half of the cases occurred in genetically related family members. Another Terena reservation, the Ipegue/Taunay, located 90 km west of the Limao Verde reservation, was also evaluated as a control group. This reservation, with a population of 2203, had no recorded cases of FS. Thus, the Limao Verde reservation represents a new focus of FS in which the disease exhibits temporal, geographic, and familial clustering. These results suggest that the environmental antigen or antigens precipitating FS are endemic to the Limao Verde reservation. This reservation appears to be an ideal population for carrying out sero-epidemiologic, genetic, and environmental studies aimed at disclosing the etiology of FS.

Adolescent↗