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Biomedical subjects

H Friedman

Publications and source records attributed to H Friedman.

At least 19 recordsLinked to original sources
PubMed1992

A homolog of the proteasome-related RING10 gene is essential for yeast cell growth.

Proteasomes are intracellular protein complexes displaying multiproteolytic activities. These complexes have been implicated in the antigen degradation process that generates peptides associated with the major histocompatibility complex (MHC) class-I molecule. RING10 and RING12 are genes encoded by the class-II region of the human MHC that have sequence homology to proteasome-encoding genes. We have identified a yeast gene, called PRG1, that encodes a protein predicted to contain 55.6% sequence identity to 80% of the RING10 gene product. Genomic disruption of PRG1 revealed that it is essential for yeast cell growth. These data strongly indicate that the antigen-processing system present in vertebrates evolved from a basic cellular process present in all organisms.

Amino Acid Sequence↗
PubMed1992

Differing macrophage and lymphocyte roles in resistance to Legionella pneumophila infection.

Similar to guinea pig macrophages and human monocytes, macrophages from the peritoneal cavity of thioglycolate pretreated A/J mice are permissive for growth of Legionella pneumophila. In contrast, macrophages from BDF1 mice are not permissive for L. pneumophila. Lymphocytes from A/J and BDF1 mice proliferated in response to Legionella Ag but guinea pig lymphocytes did not. Also, splenocyte cultures from A/J mice treated with either Con A or Legionella vaccine produced supernatants which induced A/J macrophages to restrict Legionella growth, but guinea pig splenocyte culture supernatants obtained after stimulation with L. pneumophila vaccine did not induce Legionella growth restriction activity by guinea pig macrophages. Murine rIFN-gamma but not rIFN-alpha markedly inhibited growth of Legionella in A/J mouse macrophages and monoclonal anti-IFN-gamma antibody neutralized the anti-Legionella activity of culture supernatants from A/J mouse splenocytes responding to Legionella Ag. From these data, IFN-gamma appears to be an important factor in anti-Legionella activity of Ag-activated mouse splenocyte culture supernatants. Cyclosporin A, when given to either A/J or BDF1 mice, reduced the proliferation responses of splenocytes to T cell mitogens and also decreased the IFN production of A/J spleen cells to Legionella Ag. In addition, drug treatment decreased the resistance of A/J mice to Legionella infection as shown by an increase in the number of viable bacteria in the liver. However, injection of drug treated mice with lymphokine-rich splenocyte culture supernatant reconstituted the resistance of these animals. These results suggest an important role for lymphocyte activation and lymphokine production in the resistance of A/J mice to Legionella infection. The greater resistance of BDF1 mice, however, may result from nonpermissive macrophages and responsive lymphocytes. In the case of guinea pigs, susceptibility to Legionella infections may result from both the permissive nature of the macrophages and the relatively unresponsive nature of the lymphocytes in these animals.

Animals↗
PubMed1992

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in health volunteers.

The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design. No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST. These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.

Adolescent↗
PubMed1992

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state.

We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P less than 0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng.ml-1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h.ng.ml-1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.

Administration, Oral↗
PubMed1992

Delta 9-tetrahydrocannabinol suppresses concanavalin A induced increase in cytoplasmic free calcium in mouse thymocytes.

It has been shown that delta-9-tetrahydrocannabinol (THC) suppresses thymocyte, lymph node, and splenic lymphocyte proliferation in response to a mitogenic stimulus. It has also been reported that increases occur in the cytosolic free calcium concentration (Ca2+) in mitogen treated lymphocytes. In an attempt to understand a portion of the molecular basis of the THC induced suppression of lymphocyte proliferation, we have examined the effects of THC on the Concanavalin A (Con A) induced cytosolic free Ca2+ mobilization in mouse thymocytes measured by fluorescent Ca2+ probes and spectrofluorometry. The results show that a 10 minute pretreatment with THC suppresses the normal rise in intracellular free Ca2+ in response to Con A. A THC concentration of 4 micrograms/ml (13 microM) was suppressive and the drug vehicle, DMSO, had no effect. In addition, we found that THC pretreatment did not inhibit the binding of FITC labeled Con A to the thymocytes suggesting that the drug did not interfere with lectin binding to the cell surface. To further define the nature of the Ca2+ response affected by THC, mouse thymocytes containing fura-2 were exposed to Con A either in the presence or absence of Ca(2+)-containing medium. It was observed that THC abrogated both intracellular release (measured in Ca(2+)-free medium) as well as extracellular Ca2+ influx. These results suggest that a portion of the proliferation defect in THC treated lymphocytes may be related to a drug induced inhibition of Ca2+ mobilization that normally occurs following mitogen treatment.

Aminoquinolines↗
PubMed1992

Splenocyte blastogenesis suppressed in rats implanted with an osmotic pump.

Rats implanted subcutaneously with an empty osmotic pump connected by a polyethylene catheter to a jugular vein for 5 to 10 days evinced a decreased splenocyte responsiveness to blastogenic stimulation in vitro to bacterial lipopolysaccharide, a known B cell stimulator, as well as to the plant mitogens pokeweed mitogen (PWM), a known stimulator of T and B cells, and Concanavilan A, a known T cell stimulator. The surface of the implanted pumps became infiltrated with lymphoid cells, especially macrophages. Suppression of blastogenic responsiveness after implantation for 10 days with an empty pump or even a pump dispensing pyrogen free saline only in a continuous manner was nearly as marked as that which occurred at 2-5 days after continuous infusion with endotoxin. These depressed blastogenic responses, although less, were also evident when rats were implanted with a catheter into a jugular vein connected by means of a swivel to either an empty pump or one dispensing pyrogen free saline. Suppression of blastogenic responsiveness was not related to alteration in serum complement or corticosteroid levels. Since administration of immunomodulatory substances systemically to individuals often involves implantation of an osmotic pump, investigation into the mechanisms of lymphoid cell suppression associated with an implanted pump itself has potential significance.

Animals↗
PubMed1992

Inhibition by delta-9-tetrahydrocannabinol of tumor necrosis factor alpha production by mouse and human macrophages.

Suppression by delta-9-tetrahydrocannabinol (THC) of tumor necrosis factor (TNF) production by macrophages has not been reported previously. The present study evaluated the effect in vitro of THC on soluble TNF-alpha production by cultured murine peritoneal macrophages. THC at 5 or 10 micrograms/ml added to medium [RPMI 1640 containing 10 ng LPS/ml, mouse IFN-gamma (100 u/ml), and 0.5% bovine serum albumin (BSA)] used to induce TNF significantly decreased TNF-alpha production by BALB/c mouse macrophages. Macrophages pretreated with THC at 0.1, 0.5, or 1.0 micrograms/ml in protein-free medium for 3 h at 37 degrees C, prior to TNF induction, also showed a decreased ability to produce TNF-alpha in a dose-dependent manner. Increasing the protein concentration from 0.5 to 5% BSA in the medium which was used to induce TNF prevented the inhibitory activity of THC. Human peripheral blood adherent cells treated with THC-containing medium produced less TNF-alpha than controls that were not exposed to THC. Thus, our data provide evidence that THC can inhibit TNF production by mouse and human macrophages. The drug's activity is concentration dependent and is related to the amount of serum protein in the medium used to induce this cytokine.

Animals↗
PubMed1992

Cocaine augments proliferation of human peripheral blood T-lymphocytes activated with anti-CD3 antibody.

Previously we observed that cocaine can suppress the phytohemagglutinin-induced proliferation of cultured, purified human T-lymphocytes. However, because the receptor activation pathways stimulated by this mitogen are not fully understood, we decided in the present study to examine the effects of cocaine on T-lymphocyte cultures stimulated with the anti-CD3 antibody which is known to stimulate these cells through the T-cell receptor complex. The results show that cocaine augments T-lymphocyte proliferation to anti-CD3 stimulation at drug concentrations observed in the blood of cocaine abusers. This augmentation was dose dependent reaching a plateau at a concentration above 0.75 microM. The amount of interleukin-2 (IL-2), as measured by ELISA, in the supernatants of T-cell cultures and the level of cytosolic free-calcium (Ca2+) mobilization in the T-cells were also increased at approximately the same concentrations that increased proliferation. Cocaine treatment alone had no effects on proliferation, IL-2 production, or Ca2+ mobilization. These results suggest that cocaine augments proliferation of human T-lymphocytes when the cells are activated through the T-cell receptor complex by increasing cytosolic Ca2+ mobilization and subsequent IL-2 production.

Adjuvants, Immunologic↗
PubMed1992

Differing effects of delta-9-tetrahydrocannabinol (THC) on murine spleen cell populations dependent upon stimulators.

Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, can suppress the immune response, both in vitro and in vivo. In the present study, THC was found to either up-regulate or down-regulate lymphocytes depending on the method of stimulation. When the mitogens concanavalin A (Con A) or phytohemagglutinin (PHA) were used to stimulate THC-treated splenocytes, a down-regulation of lymphocyte proliferation occurred, which reflected lower T-cell numbers in general and Ly2 positive cells specifically. When splenocytes were stimulated directly by using anti-CD3 antibody it was found that low concentrations of THC enhanced lymphocyte proliferation, T-cell numbers in general, and Ly2 cells specifically. These results emphasize that THC can either enhance or suppress aspects of the immune response, depending on the specific immune stimulants used and the specific parameter of immunity measured.

Adjuvants, Immunologic↗
PubMed1992

Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time.

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12-hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased 1/4 to 2 1/2 hours after 5 mg diazepam, (maximum, +7.3%) and 3/4 to 12 hours after 10 mg diazepam (maximum, +15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Administration, Oral↗
PubMed1992

Granulocyte-colony stimulating factor facilitates the restoration of resistance to opportunistic fungi in leukopenic mice.

Administration of recombinant human granulocyte-colony stimulating factor (G-CSF), which induces hemopoietic precursor cells to proliferate and differentiate into neutrophils, protected leukopenic mice infected with opportunistic fungi. Mice were injected with cyclophosphamide and were then subcutaneously (s.c.) or intravenously (i.v.) administered 15-120 micrograms G-CSF kg-1 day-1 for 3 days. The number of peripheral blood neutrophils in the G-CSF treated mice was significantly increased 48 h after G-CSF administration. All leukopenic mice infected with either Candida albicans, Cryptococcus neoformans or Aspergillus fumigatus were significantly protected by treatment with the G-CSF. Moreover, G-CSF treatment caused a decrease in the number of viable yeasts in kidneys of Candida infected mice. These data suggest that prophylactic therapy with G-CSF may be useful against fungal infections in an immunocompromised host.

Animals↗
PubMed1992

Further characterization of the biological and pathogenic properties of erythromelalgia-related poxviruses.

Six isolates of erythromelalgia-related poxvirus (ERPV) were characterized with respect to host range, c.p.e. and inclusions, pock formation on chorioallantoic membrane (CAM), morphogenesis, serological reactivity, pathogenesis in animals and DNA restriction fragment profile. The results suggest that ERPV is either a new member of the Orthopoxvirus genus or a subspecies of ectromelia virus. Evidence is provided that (i) ERPV has a wide host range in vitro in which characteristic viral c.p.e. and inclusion bodies are induced; (ii) ERPV, unlike ectromelia virus, causes the formation of tiny greyish-white pocks on CAM both at 34 degrees C and 39 degrees C; (iii) eosinophilic A-type inclusions of ERPV do not contain viral particles; (iv) ERPV isolates are neutralized by both rabbit anti-vaccinia virus and mouse anti-ectromelia virus sera, but not vice versa; (v) young rabbits are not susceptible to ERPV by skin and/or corneal scratch infection even though ERPV is lethal for mice by intraperitoneal inoculation; (vi) the HindIII and SalI fragment profiles of ERPV P-4 DNA are similar to, but obviously different from, those of Chinese ectromelia virus. These biological and pathogenic characteristics of ERPV are distinguishable from those of other members of the genus Orthopoxvirus currently described in the literature.

Animals↗
PubMed1992

Environmental risk factors in endemic pemphigus foliaceus (Fogo selvagem). "The Cooperative Group on Fogo Selvagem Research".

Endemic pemphigus foliaceus or Fogo selvagem (FS) is an epidermal organ-specific autoimmune disease mediated by autoantibodies. Individuals at risk are peasants who live and work on farms located in the interior of certain endemic states of Brazil. This case-control study compares a group of 52 FS patients with 52 patients suffering from other dermatoses admitted and followed at the hospital for pemphigus (Hospital do Penfigo) in the city of Goiania, state of Goias. Patients and controls matched 1:1 by age, sex, and occupation were examined by two dermatologists at the time of admission and asked to respond to a prepared questionnaire. This questionnaire concerned current and past (1 and 5 years) exposure to environmental risk factors. The following risk factors were assessed: black fly bites, presence of rodents at home, exposure to cereal dust, exposure to fumes or dust released by tree and shrub removal, and exposure to insecticides. Relative risks were estimated from tabulated data by the odds ratio and tested for significance by the chi-square test. The 95% confidence interval for the odds ratio was also calculated for each of the risk factors. The only risk factor showing an odds ratio significantly different from one was exposure to simuliidae bites (odds ratio 4.7, p less than 0.001). This study reinforces the hypothesis that chronic exposure to black fly antigens may precipitate IgG4 antibody formation in predisposed individuals. These antibodies in turn may cross-react with epidermal antigens and cause acantholysis and the clinical expression of the disease known as FS.

Adolescent↗
PubMed1992

Pregnant women with endemic pemphigus foliaceus (Fogo Selvagem) give birth to disease-free babies.

Endemic pemphigus foliaceus (PF), also known as Fogo Selvagem (FS), is an organ-specific autoimmune disease mediated by autoantibodies. These autoantibodies are disease specific, predominantly restricted to the IgG4 subclass, and pathogenic, as demonstrated by passive transfer studies. In contrast to pemphigus vulgaris, neonatal skin disease does not appear to occur in babies born to mothers with non-endemic PF or FS. In the present study we have examined 19 mother/neonate pairs where the mother had documented FS. Mothers and neonates were examined soon after delivery and tested by immunofluorescent (IF) techniques for FS autoantibodies either in circulation (mothers' sera or babies' cord blood) or bound to the neonatal epidermis. All neonates included in this study were born with normal skin. Twelve biopsies from 17 neonates showed negative direct IF using both FITC-antihuman IgG or monoclonal anti-IgG subclass antibodies. In five biopsies the epidermal ICS of the babies showed weak staining. In 10 of the 19 cord sera tested, FS IgG autoantibodies were undetectable; in nine, these autoantibodies were present in low titers (less than 1:40). The sera of the mothers showed higher titers of FS autoantibodies, and IgG4 was the predominant IgG subclass autoantibodies. It appears that human placenta may modulate the expression of disease in the newborn by operating as a "biologic immunoadsorbent" of pathogenic autoantibodies.

Adult↗
PubMed1992

MRI in migraineurs.

Forty-six migraineurs and 69 age- and sex-matched controls referred for MRI scans of the brain were evaluated for the incidence of intracranial pathology. Axial long TR/short TE and long TR/long TE and sagittal short TR/short TE scans were performed in all patients. Enhancement with Gd-DTPA was performed in all controls and in nine migraineurs. Six of 46 (13%) of the migraineurs had white matter lesions versus three of 69 (4.3%) of the controls. The white matter lesions in migraineurs were seen in a younger age group than in the controls. These findings agree with recent MRI studies. Ischemia or an immune-based white matter demyelination are possible mechanisms for the white matter lesions.

Adolescent↗