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Biomedical subjects

H Friedman

Publications and source records attributed to H Friedman.

At least 109 records · Page 6Linked to original sources
PubMed1995

Alterations in peripheral blood mononuclear cell cytokine production in response to phytohemagglutinin in multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS). The disease is characterized by inflammatory lesions in the white matter of the CNS, consisting of a specific immune response to the myelin sheath. We investigated peripheral blood mononuclear cell (PBMC) cytokine production by enzyme-linked immunosorbent assays of 21 MS patients and 19 age-matched normal controls in response to the T-cell mitogen phytohemagglutinin (PHA). Peripheral blood mononuclear cells were cultured in medium alone or in medium with 5 micrograms of PHA per ml for 48 h, and culture supernatants were collected for analysis. Cytokines selected for study were interleukin-10 (IL-10), gamma interferon (IFN-gamma), IL-2, and IL-4. All cytokine activities described were expressed as concentrations per 500,000 cells. We found that 48% (10 of 21) of the MS patients produced small but detectable levels of IL-10 in medium alone, compared with 26% (5 of 18) of the controls. We found that the MS patients produced significantly higher quantities of IL-10 protein than the controls in response to PHA (mean supernatant concentrations of IL-10 for patients and controls, 421 and 204 pg/ml, respectively [P < 0.05]). No significant differences were detected in the production of IL-2, IFN-gamma, and IL-4 between patients and controls in response to PHA, although patients appeared to display a trend toward decreased production of IFN-gamma.

Adult↗
PubMed1995

MR imaging appearance of the extensor mechanism of the knee: functional anatomy and injury patterns.

Trauma to the extensor mechanism of the knee, a common clinical problem, can be accurately evaluated with magnetic resonance (MR) imaging. The extensor mechanism consists of the quadriceps muscle and tendon, patella, patellar tendon, and patellar retinacula. Injuries of these structures can be classified into partial and complete tears. Acute injuries are associated with edema, hemorrhage, and fluid collections; chronic injuries often demonstrate redundancy, atrophy, and retraction of the affected structures. MR imaging is useful in differentiating partial and complete tears and in evaluating tissue edema and hemorrhage. It also allows detection of unsuspected nondisplaced patellar fractures and chronic conditions due to repetitive trauma. Transient dislocation of the patella is an often clinically unsuspected entity for which MR imaging can serve an important diagnostic role. A detailed understanding of the functional and anatomic relationships of the extensor mechanism can greatly assist in interpretation of MR images of the traumatized knee.

Adult↗
PubMed1995

MR imaging of the posterior cruciate ligament: normal, abnormal, and associated injury patterns.

The posterior cruciate ligament (PCL) of the knee has received little attention in the radiology literature, but its importance in knee stability has come under close scrutiny in recent years. Unrepaired injury of the PCL can lead to chronic instability and early joint degeneration. Three major mechanisms of trauma that involves the PCL are posterior displacement of the tibia in a flexed knee, hyperextension, and rotation combined with an adduction or abduction force. The spectrum of PCL injuries includes partial tear or intrasubstance injury, complete ligamentous rupture, and avulsion of the PCL insertion site on the posterior tibia. Associated injuries include injury of other ligaments, meniscal tear, bone injury, and joint effusion. PCL rupture is easily identified with magnetic resonance (MR) imaging by using simple signal intensity and structural characteristics. Because clinical and arthroscopic assessment of the PCL can be difficult, MR imaging can be valuable for evaluating the acutely injured knee when operative repair of the PCL is being considered.

Humans↗
PubMed1995

delta 9-Tetrahydrocannabinol, cytokines, and immunity to Legionella pneumophila.

The major psychoactive component of marijuana, delta 9-tetrahydrocannabinol (THC), has been shown to suppress the functions of various immune cells. However, the relationship of these findings to THC-induced suppression of host resistance to infection has not been firmly established. In this report, we review the literature concerning THC's effects on cytokine production and resistance to infection with Legionella pneumophila (Lp). Recent reports have linked THC-induced immunomodulation with drug-induced modulation of the cytokine network. Specifically, THC in vivo suppresses interferon (IFN) production while in vitro modulates the production of tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-2 receptor (IL-2R). These results suggested that THC treatment might alter host immunity by disrupting the cytokine network. Immunity and resistance to infection with Lp depends upon the activation of killer cells and the stimulation of the cytokine network. THC injection into rodents was observed to augment acute phase cytokine mobilization in response to a primary Lp infection; on the other hand, the drug suppressed the development of protective immunity and resistance to secondary Lp infection by causing a change in the profile of T helper cell cytokines produced by Th1 and Th2 cells. Thus, it appears that THC injection suppresses resistance to Lp infection by disrupting the cytokine network. Regarding the molecular mechanisms of these effects of THC, data is reviewed concerning the role of cannabinoid receptors (CR) in cells of the immune system. In summary, the literature to date supports the role of THC as an immunomodulator capable of suppressing resistance to infection through mechanisms involving alteration of the cytokine network. The role of CR receptors in these events has yet to be determined.

Cytokines↗
PubMed1995

Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta.

Infecting mice with the opportunistic intracellular pathogen Legionella pneumophila markedly inhibited place learning of infected C57BL/6 mice as determined by the Morris water maze test. Mice infected with L. pneumophila evinced much less ability to learn the position of a hidden platform than did normal noninfected mice, which quickly learned the location of the hidden platform and escaped from the cool water of the pool with increasing efficiency. However, infected mice treated with anti-interleukin-1 (anti-IL-1) neutralizing antibody learned the task with about the same efficiency as the controls. When the animals were tested 1 week after learning, control animals remembered the task well and were able to escape with near maximal efficacy. On the other hand, L. pneumophila-infected mice performed as poorly after the 1 week rest as during the training period, indicating that infection blocked learning and not merely performance. Mice infected with L. pneumophila and given the antibody treatment were found to be indistinguishable from controls in that they remembered the task and escaped with good efficiency. Thus, the results of this study suggest that the pro-inflammatory cytokine, IL-1 beta, is involved, at least partly, in the attenuation of spatial navigational learning in mice infected acutely with a sublethal concentration of L. pneumophila. These results, therefore, suggest that cognitive impairment of L. pneumophila-infected mice may be related to the cytokine IL-1 beta and, furthermore, that cytokines may be related to learning and memory changes experienced by individuals suffering acute bacterial infections.

Animals↗
PubMed1995

delta 9-Tetrahydrocannabinol (THC) causes the variable expression of IL2 receptor subunits.

Previously, we reported that the cannabinoid delta 9-tetrahydrocannabinol (THC) suppressed interleukin 2 (IL2)-induced proliferation of a cloned, natural killer-like cell line (NKB61A2) and decreased the number of high- and intermediate-affinity IL2 binding sites. However, the surface expression of interleukin 2 receptor alpha (IL2R alpha) chain, as measured by flow cytometry, was increased rather than decreased by THC treatment. This suggested that the drug-induced deficiency in IL2 binding and cell activation involved a defect in the cell-surface expression of IL2R subunits other than the alpha chain. Because the IL2 receptor complex is composed of alpha, beta and gamma chains, we examined the effect of THC treatment on the expression of these chains. In a result consistent with our previous findings, we observed that treatment of NKB61A2 cells with THC increased the cellular immunoprecipitable IL2R alpha protein (p55) and mRNA. Furthermore, the cellular production of IL2R beta chain protein (p75) and mRNA, determined by immunoprecipitation and Northern blotting, respectively, was also increased. The mRNA stability assay showed that THC increased the stability of IL2 beta mRNA, and nuclear run-on experiments suggested that the increase in subunit production was not due to a drug effect on gene transcription. The IL2R gamma chain was also affected by THC treatment in that Northern blotting studies showed a drug-induced decrease in the cellular level of gamma chain mRNA. In addition, THC treatment decreased the 125I-labeled IL2 internalization under high-affinity binding conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Detection of cerebrospinal fluid metastasis: CT myelography or MR?

PURPOSE: To determine the sensitivity of contrast MR versus myelography followed by CT in the detection of cerebrospinal fluid metastases in children with primary central nervous system tumors. METHODS: Thirty-three patients who had primary central nervous system malignancies had spinal MR with gadolinium within 2 weeks of a myelogram followed by CT. MR technique included T1-weighted image sequences of the entire spine with and without gadolinium. CT scans were routinely performed at T-12 to L-2, L-4 to S-1, and foramen magnum to C-2. All studies were reviewed blindly; the number, character, and location of all metastases was recorded and the results of the two studies compared. Cerebrospinal fluid cytologic findings were recorded for each patient, and compared with the results of the imaging studies. RESULTS: Seven of the 33 patients had metastases detected; metastases were seen on both MR and myelography followed by CT. However, MR showed 24 lesions and myelography followed by CT showed only 15. When a lesion was seen on both MR and myelography followed by CT, the MR was usually more convincing. Superficial lesions seen on MR sometimes would be missed on myelography followed by CT. Both MR and myelography followed by CT were quite sensitive in the detection of small lesions (2 to 3 mm) when present on spinal nerve roots. Whereas MR showed multiple lesions not seen on myelography followed by CT, CT failed to show any metastases not seen on MR. Imaging studies showed metastases in 3 patients who had normal cytologic findings. CONCLUSIONS: MR shows significantly more cerebrospinal fluid metastases than myelography followed by CT.

Adolescent↗
PubMed1994

Mutations in PRG1, a yeast proteasome-related gene, cause defects in nuclear division and are suppressed by deletion of a mitotic cyclin gene.

Proteasomes are ubiquitous complexes exhibiting proteolytic activity in vitro. The function(s) of these enzymes in vivo is not known. To investigate the in vivo role of proteasomes, four temperature-sensitive alleles of the Saccharomyces cerevisiae proteasome-related gene, PRG1, were constructed and analyzed. At both the permissive and restrictive temperatures, many prg1 cells have a large bud, contain replicated DNA, and have their nucleus positioned at the neck with a short spindle. These different phenotypes indicate a defect in nuclear division. Consistent with a nuclear division defect, prg1 mutant strains lose a dispensable chromosome at a higher frequency than wild-type cells. Importantly, deletion of CLB2, a gene encoding a mitotic cyclin, suppresses the temperature-sensitive growth phenotype of prg1 mutant strains. Our results indicate that proteasomes are important for nuclear division and suggest that they participate in degradation of the Clb2 protein (Clb2p).

Alleles↗
PubMed1994

delta 9-Tetrahydrocannabinol (THC) modulates IL-1 bioactivity in human monocyte/macrophage cell lines.

We have previously observed that delta 9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, increased supernatant interleukin-1 (IL-1) bioactivity in cultures of mouse resident peritoneal macrophages stimulated with lipopolysaccharide (LPS). In this study, experiments were performed to determine whether THC treatment similarly affected phagocytes of human origin. The results showed that THC increased the levels of supernatant IL-1 bioactivity of two human monocytic cell lines, but only if the cells were differentiated with phorbol myristate acetate. Undifferentiated cells displayed decreased IL-1 bioactivity in response to THC. However, under conditions in which THC augmented supernatant IL-1 bioactivity from THP-1 cells, ELISA studies showed that the levels of IL-1 alpha and IL-1 beta were unchanged and decreased, respectively. Furthermore, supernatant interleukin-6 (IL-6) levels were decreased, but tumor necrosis factor (TNF-alpha) levels were increased by THC treatment. These results show that THC treatment modulates cytokine production and/or release by mouse and human macrophages and the drug effects on IL-1-like bioactivity in the supernatants of the human THP-1 cells are due to increased levels of other cytokines, such as TNF-alpha, rather than IL-1 itself.

Animals↗
PubMed1994

The importance of measuring cotinine levels to identify smokers in clinical trials.

First-time-in-humans studies of drugs (phase I) typically exclude unsuitable volunteers by testing for recreational drugs. However, volunteers are usually not screened for cotinine, a metabolite of nicotine, even though tobacco products may alter pharmacokinetic and pharmacodynamic parameters and withdrawal from tobacco may cause additional adverse events. The accuracy of personal histories as a means of excluding smokers was examined prospectively in three phase I units in the northeastern, midwestern, and southwestern United States. In studies intended for nonsmokers, 45 of 282 purported nonsmokers screened before enrollment tested positive for cotinine. This suggests that personal histories are unreliable in determining tobacco use in clinical trials designated for nonsmokers.

Clinical Trials, Phase I as Topic↗
PubMed1994

Assessment of the intestinal retention of beta-carotene in humans.

OBJECTIVE: Assessment of the intestinal absorption of beta-carotene (BC) in humans as well as plasma clearance of BC has been difficult. We have used the total gut washout method (TGWM) to assess BC retention during transit through the intestine, as well as the effect that different diets and age have on BC retention. METHODS: HPLC was used to quantitate fecal and serum BC concentrations from young and elderly subjects who had undergone the TGWM to remove all intestinal contents prior to ingesting BC or placebo with or without a meal. Meals contained different combinations of calories and fat. RESULTS: In subjects receiving no meal, 83% of ingested BC was recovered in rectal effluent collected within 24 hours post-BC administration. The quantity of BC in feces of individuals receiving meals was 49-71%. There was no significant change in serum concentrations of other carotenoids or retinoids following consumption of BC with any of the different meals. Interestingly, both diet and age influenced the efficiency of BC absorption. An increase in dietary fat content resulted in an higher serum BC concentration in young subjects within 8 and at 24 hours post BC administration, whereas a higher caloric content resulted in a decrease in serum BC concentration in older subjects within 8 hours of BC administration. CONCLUSION: Results indicate that the TGWM provides an accurate means for assessing the intestinal retention of BC in humans.

Adolescent↗
PubMed1994

Differences and similarities in permissive A/J versus non-permissive BALB/c murine macrophages infected with Legionella pneumophila: the role of iron.

Legionella pneumophila, a facultative intracellular pathogen, replicates within and kills thioglycolate-elicited (TG) macrophages from A/J mice, while growth is inhibited in TG macrophages from BALB/c mice which show no impaired viability. The role of iron in BALB/c and A/J macrophages regarding their permissiveness to L. pneumophila intracellular growth was investigated. We previously reported that TG macrophages from the A/J mouse strain readily supported the intracellular growth of L. pneumophila, while resident macrophages from the same strain of mice were not permissive. Recently we also found that such a difference in permissiveness between both A/J macrophage populations may be explained, at least in part, to intracellular availability of iron. In this report, differences in permissiveness to L. pneumophila growth between A/J TG macrophages and BALB/c TG macrophages was not due to intracellular iron availability. BALB/c and A/J TG macrophages exhibited similar expression of transferrin receptor and cellular iron content. The treatment of BALB/c TG macrophages with different iron compounds, namely ferric nitrilotriacetate (12.5-100 microM), ferric citrate (12.5-100 microM) and transferrin (0.5-5 mg ml-1), did not stimulate the intracellular proliferation of L. pneumophila. The reduction of intracellular iron availability by treatment with antibodies against transferrin receptor or with desferrioxamine suppressed the growth of L. pneumophila within BALB/c TG macrophages, suggesting that these cells do not restrict L. pneumophila growth because of iron. The production of nitric oxide was also similar in both macrophage populations, as measured by the Griess reaction. However, the synthesis of oxygen reactive species was three times higher in non-permissive BALB/c macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Bacterial heat shock proteins directly induce cytokine mRNA and interleukin-1 secretion in macrophage cultures.

Bacterial heat shock proteins (hsp) have been shown to be important immunogens stimulating both T cells and B cells. However, little is known concerning the direct interactions between hsp and macrophages. In this study, we demonstrated that treatment of macrophage cultures with purified bacterial hsp, including Legionella pneumophila hsp60, Escherichia coli GroEL, Mycobacterium tuberculosis hsp70, Mycobacterium leprae hsp65, and Mycobacterium bovis BCG hsp65, increased the steady-state levels of cytokine mRNA for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor as well as supernatant IL-1 secretion. This effect was shown not to be due to contamination of the hsp preparations with bacterial lipopolysaccharide. However, not all hsp induced cytokines; M. tuberculosis hsp10 showed minimal activity in our study. These results suggest that bacterial hsp might modulate immunity by rapidly and directly increasing cytokine production in macrophages.

Animals↗
PubMed1994

Macrophage permissiveness for Legionella pneumophila growth modulated by iron.

We have investigated the modulation of iron in two populations of macrophages which differ in susceptibility to Legionella pneumophila intracellular proliferation. Previously, we reported that thioglycolate-elicited peritoneal macrophages obtained from the inbred A/J mouse strain readily support the intracellular growth of L. pneumophila, while resident macrophages from the same strain do not. In this study, we show that A/J elicited macrophages exhibit markedly higher expression of transferrin receptor and intracellular iron content than A/J resident macrophages. Furthermore, apotransferrin and desferrioxamine inhibited the intracellular proliferation of L. pneumophila in elicited macrophages, and this suppression was reversed by the additions of Fe-transferrin or ferric nitrilotriacetate. Fe-transferrin and ferric nitrilotriacetate did not further increase the intracellular proliferation of L. pneumophila in thioglycolate-elicited macrophages. However, ferric citrate and ferric nitrilotriacetate stimulated in a dose-dependent manner the growth of L. pneumophila in resident macrophages. Furthermore, equimolar concentrations of desferrioxamine reversed the stimulatory effect of iron in these resident cells. These data provide evidence supporting the hypothesis that differences in susceptibility to L. pneumophila growth between permissive elicited macrophages and nonpermissive resident macrophages from the A/J mouse strain are due to intracellular availability of iron.

Animals↗
PubMed1994

Legionella pneumophila growth restriction and cytokine production by murine macrophages activated by a novel Pseudomonas lipid A.

Peritoneal exudate macrophages from A/J mice activated by purified lipid A preparations from Pseudomonas vesicularis, which contain 2,3-diamino-2,3-dideoxy-D-glucose disaccharide phosphomonoester as the lipid A backbone, restricted the growth of Legionella pneumophila, an intracellular opportunistic bacteria which readily grows in otherwise permissive macrophages from susceptible A/J mice and induced production of the proinflammatory cytokines interleukin 1 and tumor necrosis factor alpha. Activation of the macrophages was similar to that which occurred after stimulation with more conventional lipid A from other bacteria such as salmonellae. A purified fraction A3 preparation from the Pseudomonas lipid A, which lacked only 1 mol of amide-linked fatty acid, in comparison with another fraction (A2), which contained the fatty acid, also markedly activated the usually permissive macrophages from susceptible A/J mice to resist growth of the legionellae. The fraction A3 also induced both interleukin and tumor necrosis factor alpha. These results show that this novel lipid A from P. vesicularis can activate macrophages to resist infection with an opportunistic bacterium in a manner similar to that induced by conventional enterobacterial lipid A and that the hydrophobic portion of this Pseudomonas molecule may have an important role in activation of macrophages.

Animals↗