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Biomedical subjects

M Khan

Publications and source records attributed to M Khan.

At least 181 records · Page 10Linked to original sources
PubMed1996

Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis.

MS is presumed to be a T-cell-mediated chronic inflammatory disease of the CNS. We examined proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 [anti-CD3] monoclonal antibody (MAb) or concanavalin A (Con A) in subjects with stable relapsing-remitting MS (RR MS) before and after initiating interferon (IFN)-beta 1b treatment. There was no significant difference in pretreatment to on-treatment anti-CD3 mAb or Con A-induced proliferation in RR MS patients. There was significantly increased Con A-induced secretion of tumor necrosis factor (TNF)-alpha, IFN-gamma, interleukin (IL)-2, IL-6, and IL-10 and decreased IL-4 secretion in on-treatment compared with pretreatment peripheral blood mononuclear cell samples. However, on-treatment CD3-mediated secretion of TNF-alpha was significantly decreased, and IL-6 secretion was significantly increased compared with pretreatment values. IFN-gamma was also decreased in on-treatment cultures stimulated with anti-CD3 MAb, but these values did not reach statistical significance. Systemic side effects from IFN-beta 1b were associated with increased IL-6 secretion. There were no significant changes in CD3-mediated IL-4, IL-10, transforming growth factor (TGF)-beta, or IL-2 secretion or Con A-induced TGF-beta secretion. IFN-beta 1b (Betaseron) decreases CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL-6, that could potentially counteract its beneficial immunomodulatory effects.

Autoimmune Diseases↗
PubMed1996

Oral administration of type I interferon modulates the course of experimental allergic neuritis.

We investigated the effect of oral administration of type I interferon (IFN) in experimental allergic neuritis (EAN) in Lewis rats immunized with bovine peripheral nerve myelin. Starting at 7 days preceding immunization, rats were fed daily until sacrifice either with 5000 U rat IFN-alpha/beta or mock-IFN. The clinical severity of EAN was significantly reduced in IFN-alpha/beta fed animals compared to mock-IFN fed controls. Demyelination, but not inflammation, was decreased in IFN-alpha/beta fed compared to mock-IFN fed rats at day 20 after immunization. In situ IFN-gamma production and inflammation were reduced when evaluated by immunocytochemistry at day 13 after immunization. Spleen cells from IFN-alpha/beta fed compared to mock-IFN fed EAN rats showed significantly reduced proliferation to stimulation with Con A or peripheral nerve myelin. IFN-gamma production in draining lymph node cells was significantly reduced after stimulation with bovine peripheral nerve myelin. Our data suggest that oral administration of IFN-alpha/beta reduces the severity of EAN, possibly by a reduction in IFN-gamma production.

Administration, Oral↗
PubMed1996

Phytanic acid oxidation: normal activation and transport yet defective alpha-hydroxylation of phytanic acid in peroxisomes from Refsum disease and rhizomelic chondrodysplasia punctata.

In humans the oxidation of phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum disease (RD) and rhizomelic chondrodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP subjects. Activation of phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of phytanic acid or phytanoyl-CoA in the absence or presence of fatty acid activating cofactors (ATP, MgCl2, and CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of [(2,3)-3H]- or [1-14C]phytanic acid, or [1-14C]phytanoyl-CoA (substrate for the first step of alpha-oxidation) but normal oxidation of [1-14C] alpha-hydroxyphytanic acid (substrate for the second step of the alpha-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of phytanic acid in plasma and body fluids of RD is due to the deficiency of phytanic acid alpha-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of [1-14C]phytanic acid or phytanoyl-CoA or [(2,3)-3H]phytanic acid, the oxidation of [1-14C] alpha-hydroxyphytanic acid was also deficient, indicating that in RCDP the activities both of alpha-hydroxylation of phytanic acid and decarboxylation of alpha-hydroxyphytanic acid are deficient. These observations indicate that peroxisomal membrane functions (phytanic acid activation and transport) in phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the alpha-hydroxylation of phytanic acid; whereas in RCDP both alpha-hydroxylation of phytanic acid as well as decarboxylation of alpha-hydroxyphytanic acid are deficient.

Biological Transport↗
PubMed1995

Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid alpha-oxidation.

The imidazole antimycotics like ketoconazole, clotrimazole, bifonazole, miconazole and CO, known as powerful inhibitors of cytochrome P-450, are potent inhibitors of peroxisomal phytanic acid alpha-oxidation to pristanic acid suggesting the possible involvement of the cytochrome P-450 mono-oxygenase system in this oxidation. In contrast to the inhibition of the oxidation of [1-14C]phytanic acid, [1-14C]phytanoyl-CoA and [(2,3)-3H]phytanic acid, these drugs and CO have no effect on the oxidation of [1-14C]alpha-hydroxy phytanic acid indicating that these drugs and CO inhibit only the alpha-hydroxylation of phytanic acid. These studies using purified peroxisomes from liver and cultured human skin fibroblasts and Hep G2 cells clearly demonstrate that alpha-hydroxylation, an intermediate step in the alpha-oxidation of phytanic acid found to be impaired in Refsum Disease, is mediated by cytochrome P-450 containing enzyme.

Carbon Monoxide↗
PubMed1995

A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex.

Signaling through surface CD40 is essential for selecting B cells that have mutated their immunoglobulin variable region genes in germinal centers and is an important signal in the early stages of antibody responses to T cell-dependent antigens. It is shown that a subset of CD45RO+, CD4+ T cells isolated from human tonsil contains preformed 30-35-kD ligand for CD40. This is expressed on their surfaces within 5 min of their antigen-receptor complexes interacting with CD3 epsilon antibodies bound to ox erythrocytes. This surface expression does not require de novo protein synthesis and lasts for only 1-2 h. Preformed CD40 ligand (CD40L) was not detected in any CD4+ CD45RA+ T cells, but > 90% of all CD4+ T cells from the tonsil can be induced to express large amounts of CD40L on culture with phorbol myristate acetate and the calcium ionophore ionomycin. This expression of CD40L starts between 1 and 2 h, peaks at 6 h, and remains at a high level for > 20 h. It is totally prevented by adding a concentration of cycloheximide that inhibits CD25 synthesis by these activated cells. While CD3 epsilon antibody bound to ox red cells is a good inducer of surface expression of CD40L, it is a much less potent inducer of CD40L synthesis than phorbol myristate acetate with ionomycin. Immunohistological analysis of tonsil sections shows that cells containing CD40L are located mainly in the outer zone of germinal centers and the margins of the T zones that are rich in dendritic cells (interdigitating cells). The distribution of these cells is consistent with: (a) their interaction in T zones with B cells that have taken up and processed antigen and (b) their involvement in B cell selection in germinal centers.

Adolescent↗
PubMed1995

Decreased CD3-mediated interferon-gamma production in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that has been postulated to be T-cell mediated. We examined the proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 (anti-CD3) monoclonal antibody concanavalin A, or ionomycin plus myristic acid palmityl ester in subjects with stable relapsing-remitting MS. Control subjects demonstrated good proliferation to anti-CD3 monoclonal antibody whereas subjects with relapsing-remitting MS showed a significantly decreased anti-CD3 monoclonal antibody-mediated response. There was no difference in concanavalin or ionomycin plus myristic acid palmityl ester stimulation between control subjects and MS subjects. Secretion of interferon-gamma was significantly decreased and transforming growth factor-beta was significantly increased from cultures stimulated with anti-CD3 monoclonal antibody, but not ionomycin plus myristic acid palmityl ester or concanavalin A, in MS patients compared to control subjects. Secretion of interleukin-10 and tumor necrosis factor-alpha was not different between control subjects and MS patients following stimulation with anti-CD3 monoclonal antibody, concanavalin A, or ionomycin plus myristic acid palmityl ester, or of interleukin-2 and interleukin-4 following stimulation with anti-CD3 monoclonal antibody or concanavalin A. An abnormality of signal transduction and secretion of the immunomodulatory molecule interferon-gamma may exist in MS via the CD3 T-cell receptor complex.

CD3 Complex↗
PubMed1995

Coronary air embolism: incidence, severity, and suggested approaches to treatment.

Because no well-controlled study of inadvertent coronary air embolism has been done to truly quantify the incidence of this cardiac catheterization complication, we wanted to determine its incidence and severity in an active teaching medical center and assess approaches to treatment. We retrospectively reviewed 3,715 coronary angiogram and PTCA reports performed over 32 months. Further, we classified severity based on angiographic findings and symptoms as minimal, mild, moderate, and massive. Two independent angiographers reviewed 764 consecutive cines performed in the first 2 months of training of each new fellow and 740 cines performed in the last 2 months of training. We found that during the first 2 months of training the overall incidence for significant intracoronary air embolism was 0.19% (7 documented cases) compared with 0.2% (3 cases) for non-reported, minimal asymptomatic air embolism. The estimated incidence for total air emboli events was 0.27% (10/3,715). We did not find coronary air emboli in the 740 cines performed at the end of fellowship training. Additionally, the incidence of coronary air emboli during PTCA training was much higher compared with coronary angiography training (0.84 vs. 0.24%). Although there is no best technique to restore blood flow after blockage by air emboli, we suggest as options aspirating the air or forcefully injecting saline, with auxiliary supportive measures like 100% oxygen, IABP, CPR, and DC cardioversion.

Aged↗
PubMed1995

High-frequency ultrasound: determination of the lowest frequency required for cellular imaging and detection of myocardial disease.

We have previously demonstrated that a 600 MHz transducer enables the visualization of cellular detail in specimens of myocardium. However, lower-frequency transducers are more practical and provide better tissue penetration for possible in vivo application of this technique. This study was designed to ascertain the lowest frequency at which cellular detail can be imaged. We performed ultrasound imaging of 5 microns sections of 14 samples of myocardium. Each specimen was examined serially with 600 MHz, 400 MHz, 200 MHz, and 100 MHz transducers. Normal cardiac myocytes and pathologic phenomena such as fibrosis, cell fallout, and round cell infiltration were clearly identified with a 600 MHz transducer. Although there was a slight decrease in resolution, normal and pathologic phenomena were also identified with 400 and 200 MHz transducers. However, cellular detail could not be adequately identified with a 100 MHz transducer. In conclusion, transducer frequencies of 600 to 200 MHz enable visualization of cell detail and detection of pathologic changes in the myocardium. A transducer frequency of at least 200 MHz is probably required for possible in vivo application of this technique.

Cardiomyopathies↗
PubMed1995

Oral administration of human or murine interferon alpha suppresses relapses and modifies adoptive transfer in experimental autoimmune encephalomyelitis.

Chronic relapsing experimental autoimmune encephalitis (CR-EAE) is an inflammatory process of the central nervous system (CNS) that closely resembles the human disease multiple sclerosis (MS). EAE was induced in SJL/J mice and following recovery from the initial attack, animals were fed varying doses of human or murine interferon alpha (IFN-alpha), or mock IFN three times per week. After relapse, concanavalin A-activated spleen cells were transferred adoptively from orally fed animals into recipient animals. Oral administration of human or murine IFN-alpha suppressed relapse in actively immunized animals, modified adoptive transfer of EAE, and decreased mitogen/antigen proliferation and IFN-gamma secretion in both donors and recipients. IFN-alpha acts orally by modifying the encephalitogenicity of donor spleen T cells.

Administration, Oral↗
PubMed1995

Delivery of class I and class II MHC-restricted T-cell epitopes of listeriolysin of Listeria monocytogenes by attenuated Salmonella.

Using a Salmonella vaccine-Listeria infection model of intracellular infection, we studied the capacity of an attenuated strain of Salmonella carrying T-cell epitopes of listeriolysin (LLO) of L. monocytogenes to elicit epitope-specific T-cell responses. Class II (LLO 215-226) or class I (LLO 91-99) MHC-restricted T-cell epitopes of LLO were inserted within a central, hypervariable domain of the flagellin protein of an attenuated delta aroA Salmonella dublin strain. T cells from Listeria-immunized mice were activated by lysates or heat-killed preparations of Salmonella construct expressing the LLO 215-226 epitope, indicating that LLO 215-226 is processed and presented to T cells when offered to antigen-presenting cells as part of a flagellin-epitope fusion protein. The chimeric flagellin genes were integrated into the chromosome of the flagellin-negative S. dublin strain to obtain stable expression of the epitopes. Immunization with the living, chromosomally integrated Salmonella construct carrying LLO 215-226 epitope as part of the flagellin protein generated T cells reactive with the corresponding LLO peptide, indicating that this chimera can stimulate a class-specific immune response in vitro. The effect of flanking residues on the processing and presentation of MHC class I LLO 91-99 epitope was studied using Salmonella vaccine strains that express chimeric flagellins containing one of three LLO 91-99 inserts: 91-99 (normal flagellin amino acids as flanking residues); KK91-99KK (Lys-Lys flanking residues); and AAA91-99AAA (Ala-Ala-Ala flanking residues).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Calcitonin gene-related peptide promotes Schwann cell proliferation.

Schwann cells in culture divide in response to defined mitogens such as PDGF and glial growth factor (GGF), but proliferation is greatly enhanced if agents such as forskolin, which increases Schwann cell intracellular cAMP, are added at the same time as PDGF or GGF (Davis, J. B., and P. Stroobant. 1990. J. Cell Biol. 110:1353-1360). The effect of forskolin is probably due to an increase in numbers of PDGF receptors (Weinmaster, G., and G. Lemke. 1990. EMBO (Eur. Mol. Biol. Organ.) J. 9:915-920. Neuropeptides and beta-adrenergic agonists have been reported to have no effect on potentiating the mitogenic response of either PDGF or GGF. We show that the neuropeptide calcitonin gene-related peptide (CGRP) increases Schwann cell cAMP levels, but the cells rapidly desensitize. We therefore stimulated the cells in pulsatile fashion to partly overcome the effects of desensitization and show that CGRP can synergize with PDGF to stimulate Schwann cell proliferation, and that CGRP is as effective as forskolin in the pulsatile regime. CGRP is a good substrate for the neutral endopeptidase 24.11. Schwann cells in vivo have this protease on their surface, so the action of CGRP could be terminated by this enzyme and desensitization prevented. We therefore suggest that CGRP may play an important role in stimulating Schwann cell proliferation by regulating the response of mitogenic factors such as PDGF.

Animals↗
PubMed1995

Primary hepatocellular carcinoma and viral hepatitis B and C infection in Bangladeshi subjects.

Potential risk factors for the development of primary hepatocellular carcinoma and the prevalence and role of infection with viral hepatitis B and hepatitis C were investigated in 54 adult patients of Bangladeshi origin (45 male, age range 20-75 years), comprising 46 patients resident in Bangladesh (Group 1) and 8 patients who had emigrated to the UK 10-20 years previously (Group 2). Of the 46 patients in Group 1 (37 male), 16 had hepatocellular carcinoma, 10 had uncomplicated cirrhosis, and 20 had a clinical history of chronic viral hepatitis of more than 6 months' duration. Total hepatitis B virus marker positivity was 82.6%, significantly higher than in Group 2 patients (P < 0.001). Thirty-six per cent were hepatitis B surface antigen positive, 66% were hepatitis Be antigen positive and 45.3% were positive for hepatitis C virus antibody. Taking only the 16 patients with hepatocellular carcinoma, hepatitis B surface antigen positivity was 38%, hepatitis Be antigen 66% and positivity to hepatitis C virus antibody was 56%. The 8 patients with hepatocellular carcinoma in Group 2 were all male and aged between 45 and 56 years. Of these, 3 (38%) cases were positive for hepatitis B surface antibody and none was positive for hepatitis B surface antigen or antibody to hepatitis C virus (3 cases tested). Presenting features of HCC in the two groups differed with a short clinical history of tender abdominal mass in Group 1 and a gradual onset of jaundice in Group 2 UK-resident Bangladeshi subjects.

Adult↗