Biomedical subjects

M M Khan

Publications and source records attributed to M M Khan.

At least 55 records · Page 3Linked to original sources

PubMed1999

Viral ski inhibits retinoblastoma protein (Rb)-mediated transcriptional repression in a dominant negative fashion.

The mechanism by which the viral oncogene ski (v-ski) transforms chicken embryo fibroblasts is currently unknown. Recently, the c-ski gene product (c-Ski) was found to bind to N-CoR (nuclear hormone receptor co-repressor), an element implicated in transcriptional repression mediated by multiple transcriptional repressors including the nuclear hormone receptors and Mad. c-Ski is required for transcriptional repression mediated by Mad involved in negative regulation of cellular proliferation. v-Ski abrogates Mad-induced transcriptional repression in a dominant negative fashion. Here we report that v-Ski also inhibits transcriptional repression mediated by Rb, another tumor suppressor gene product. Rb forms a complex with c-Ski, Sin3A, and histone deacetylase (HDAC) via direct binding to c-Ski and HDAC. c-Ski is required for the transcriptional repression mediated by Rb. These results suggest that inhibition of Rb activity contributes, at least partly, to transformation by v-Ski.

Animals↗

PubMed1999

Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor.

The N-CoR/SMRT complex containing mSin3 and histone deacetylase (HDAC) mediates transcriptional repression by nuclear hormone receptors and Mad. The proteins encoded by the ski proto-oncogene family directly bind to N-CoR/SMRT and mSin3A, and forms a complex with HDAC. c-Ski and its related gene product Sno are required for transcriptional repression by Mad and thyroid hormone receptor (TRbeta). The oncogenic form, v-Ski, which lacks the mSin3A-binding domain, acts in a dominant-negative fashion, and abrogates transcriptional repression by Mad and TRbeta. In ski-deficient mouse embryos, the ornithine decarboxylase gene, whose expression is normally repressed by Mad-Max, is expressed ectopically. These results show that Ski is a component of the HDAC complex and that Ski is required for the transcriptional repression mediated by this complex. The involvement of c-Ski in the HDAC complex indicates that the function of the HDAC complex is important for oncogenesis.

Animals↗

PubMed1999

Long-term survival of a patient with left ventricular free wall rupture without surgical repair.

This report describes the case of a patient who developed postinfarction left ventricular free wall rupture and cardiac tamponade. He was managed conservatively, made a successful recovery, and is alive and asymptomatic 10 months after the index episode. Only 17 cases in which the patients survived subacute rupture of the ventricular free wall over the long term without surgical repair have been reported in the literature.

Aged↗

PubMed1999

Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass.

BACKGROUND: Aprotinin reduces perioperative bleeding after open heart surgery, primarily by inhibiting fibrinolysis. In addition, the drug has both procoagulant and anticoagulant effects that involve complex reactions of coagulation proteins and cells that are incompletely understood. This study tests the hypothesis that aprotinin has an anticoagulant effect on the extrinsic coagulation pathway. METHODS: Human heparinized blood was recirculated through a membrane oxygenator with and without high concentrations of aprotinin (18.4 microM). Serial plasma samples were obtained at intervals up to 240 minutes. RESULTS: Aprotinin significantly reduced the progressive increase in prothrombin fragments (F1.2) and thrombin-antithrombin complex beginning immediately. Aprotinin also significantly reduced monocyte expression of tissue factor and Mac-1. Aprotinin did not significantly reduce factor VII or factor VIIa. CONCLUSIONS: During simulated cardiopulmonary bypass, aprotinin immediately inhibits kallikrein and thrombin formation via the intrinsic coagulation pathway. Later, aprotinin inhibits monocyte expression of tissue factor and the extrinsic coagulation pathway. The ability of aprotinin to inhibit monocyte tissue factor provides a means to reduce thrombin formation in blood aspirated from the wound during open heart surgery.

Antithrombin III↗

PubMed1999

Effect of lysine modification on the conformation and indomethacin binding properties of human serum albumin.

In order to study the involvement of lysine residues of human serum albumin (HSA) in the binding of indomethacin, HSA was treated with different molar excess of acetic anhydride, succinic anhydride and O-methylisourea which resulted in differently modified preparations: 30%, 62% and 87% acetylated, 20%, 34%, 64% and 78% succinylated and 21%, 43% and 86% guanidinated HSAs. All the preparations were found to be homogeneous with respect to charge as well as size as judged by polyacrylamide gel electrophoresis and gel filtration on a Seralose-6B column. Hydrodynamic and circular dichroic results showed that pronounced conformational changes (both tertiary and secondary structures) were induced in the maximally acetylated (87%) and succinylated (78%) preparations. On the other hand, guanidinated preparations showed no expansion in the hydrodynamic volume. The percent decrease in alpha-helical content was 34% for 87% acetylated, 31% for 78% succinylated and 10% for 86% guanidinated HSAs. A significant increase in the values of Stokes radii and frictional ratios (from 3.43 nm and 1.29 for native HSA to 4.07 nm and 1.52 for 87% acetylated and 4.35 nm and 1.60 for 78% succinylated HSAs, respectively) was also noticed in these highly modified preparations. Fluorescence quench titration results obtained at pH 7.4 and ionic strength 0.15 showed that only 54.1% and 64.7% binding of indomethacin at 4:1 drug/protein molar ratio was retained by 87% acetylated and 78% succinylated HSAs, respectively, as compared to 91% retention in binding in 86% guanidinated preparation. No reversal in the binding of drug to 87% acetylated and 78% succinylated HSA preparations was observed on increasing the ionic strength to 1.0. Therefore, it seems that one or two critical lysine residue(s) that can form salt linkage with the carboxyl group of indomethacin, was (were) probably modified in these preparations. A small decrease in the binding of drug to the guanidinated preparation also confirms the involvement of positive charge, probably contributed by lysine residue(s), in the binding of indomethacin to HSA.

Acetic Anhydrides↗

PubMed1999

Surgical removal of subfoveal choroidal neovascularization in age-related macular degeneration.

OBJECTIVE: To assess the results of surgical excision of subfoveal choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, noncomparative case series. PARTICIPANTS AND INTERVENTION: Sixty-four consecutive patients undergoing surgical removal of AMD-related subfoveal CNV were studied. The surgical method included a small retinotomy, subretinal tissue plasminogen activator (t-PA), perfluoro-n-octane, and air-fluid exchange. MAIN OUTCOME MEASURES: Final visual acuity was the main outcome measure; surgical complications and recurrence rates were also assessed. RESULTS: Preoperative visual acuity ranged from 20/100 to 1/200, with a mean of 20/400. Average follow-up was 19 months. The best acuity achieved after surgery ranged from 20/20 to hand motions, with a mean of 20/200. Final visual acuity ranged from 20/50 to light perception, with a mean of 20/400. Final acuity was improved 3 or more lines in 19 eyes (30%) (median, 5 lines), stable in 27 eyes (42%), and 3 or more lines worse in 18 eyes (28%) (median, 4 lines). Factors associated with greater visual improvement included poorer initial acuity, larger CNV size, and smaller subretinal hemorrhage. Analysis of groups similar to Macular Photocoagulation Study subgroups A through D showed an average improvement of 1 line for group C (visual acuity, 20/200 or worse; CNV larger than 2 disc areas). Other preoperative, intraoperative, and postoperative factors, including recurrence and retinal detachment, did not have a significant effect on final visual outcome. CONCLUSIONS: After surgical excision of AMD-related subfoveal CNV, vision improved or stabilized in the majority of patients. Surgery may be of greatest value for patients with poorer vision, larger subfoveal CNV, and minimal hemorrhage. Further evaluation of this technique should be accomplished via completion of a controlled, randomized multicenter study.

Aged↗

PubMed1999

Involvement of protein kinase A in histamine-mediated inhibition of IL-2 mRNA expression in mouse splenocytes.

The release of histamine from mast cells and basophils during allergic reactions can regulate functions of T cells and may influence the nature of the immune response to a given antigen. The effects of histamine on T lymphocytes are associated with its binding to H2-receptors linked with adenylate cyclase, elevation of cAMP levels and activation of cAMP-dependent protein kinase (PKA). In this report we explore the role of PKA in histamine-mediated effects on IL-2 mRNA expression and IL-2 protein secretion. Fresh isolated mouse splenocytes (C57Bl/6) were pretreated with histamine (10(-4) M) for 1 h in the presence or absence of Rp-cAMPS (50 microM), an inhibitor of PKA regulatory subunit. The cells were then washed thoroughly and activated with plate-bound anti-CD3 (5 microg/ml), or PHA (1:100) or PMA + ionomycin (10 ng/ml, 1 microg/ml) for 6 h. Pretreatment with histamine inhibited IL-2 mRNA expression and secretion in cells activated with anti-CD3 or PMA, but not in cells activated with PMA + ionomycin. Rp-cAMPS prevented histamine-mediated suppression and did not itself affect IL-2 production. These results provide evidence that histamine affected IL-2 production when the cells were activated via the T cell receptor (TCR)/CD3 complex, but did not interfere with signal transduction pathways downstream of PKC leading to production of IL-2. These effects of histamine on IL-2 secretion and mRNA expression were mediated via PKA.

Animals↗

PubMed1999

Primary structure of guinea pig plasma prekallikrein.

A full length guinea pig plasma prekallikrein (PK) cDNA was cloned from a liver cDNA library. The nucleotide sequence with 2242 bp was analyzed and the amino acid sequence with 618 residues was deduced. Kallikrein was purified from guinea pig plasma and cleavage site in the activation was determined. The amino acid sequence around the cleavage site -368Ile-Asp-Ala-Arg-Ile-Val-Gly-375Gly- differed from that of the human PK -368Thr-Ser-Thr-Arg-Ile-Val-Gly-375Gly-. Protease substrates containing penta-peptides which mimicked the sequence of the cleavage sites from P3 to P2' of guinea pig Hageman factor (HF) and PK were synthesized, and kinetic analyses of the hydrolysis by guinea pig activated HF (HFa) and kallikrein were carried out. The combination between HFa and the PK mimicking peptide provided the best kinetics. These results in part explain why the cascade activation of PK by HFa is predominant in the guinea pig system.

Amino Acid Sequence↗

PubMed1999

Immunoregulatory effects of N9-benzyl- and N7-benzyl-8-bromoguanines.

In this study we investigated the effects of two guanine derivatives, 9-benzyl- (I) and 7-benzyl-8-bromoguanines (II) on the proliferation of human T-cell leukemia and T-cell lymphoma, normal human peripheral blood mononuclear cells (PBMC), and mouse Th1 (pGL10) and Th2 (D10.G4.1) clones. We also assessed their effects on cytokine production (IL-3, IL-10 and IFN-gamma) in PBMC, T-cell lymphoma, HUT78 (IL-2), and murine Th1 (IL-2) and Th2 (IL-4 and IL-5) clones. These compounds were synthesize as analog of known inhibitors of purine nucleoside phosphorylase (PNP) 8-amino-9-benzylguanine. These compounds suppressed proliferation of human leukemia MOLT-4 cells, human cutaneous lymphoma HUT78 cells and normal PMBC. Compound II was a significantly more potent inhibitor than compound I. Exogenous recombinant human IL-2 reversed the anti-proliferative effects of both compounds on HUT78 cells. These compounds had low toxicity to human EBV-transformed B-lymphocytes. Both compounds suppressed the production of IL-2 by activated human HUT78 cells, IFN-gamma by PBMC and did not affect IL-3 and IL-10 production in PBMC. Compound I inhibited anti-CD3-activated IL-2 secretion from the murine Th1 clone. The murine Th2 clone was less sensitive to both compounds as compared with Thl. The production of IL-4 and IL-5 by this clone was not suppressed. Thus, it has been shown that not only 9-substituted guanines but also their 7-isomers selectively inhibit T-cell functions and both selectively inhibit Th1-related cytokines secretion.

Animals↗

PubMed1998

Visualization of serum albumin on electrophoretic gels using the specific ligand bilirubin.

Serum albumin, when incubated with bilirubin prior to electrophoresis, was visualized as a yellow-colored band during the electrophoretic run and did not require any staining. Furthermore, free bilirubin served as a tracking dye. A minimum of 20 micrograms of protein was detected very well by this method. The formation of a bilirubin-albumin complex did not affect the electrophoretic mobility as the protein complexed with bilirubin as well as free albumin moved with the same mobility. Only a single protein band was visualized by this method after electrophoresis of human plasma. The method is simple, less time-consuming and may be used in identifying bilirubin-binding proteins in various biological samples.

Animals↗

PubMed1998

Enoxaparin suppresses thrombin formation and activity during cardiopulmonary bypass in baboons.

OBJECTIVE: This study tests the hypotheses that enoxaparin, a low molecular weight heparin and potent inhibitor of factor Xa, alone or in combination with standard heparin, inhibits thrombin formation and activity and modulates complement activation and neutrophil elastase release during cardiopulmonary bypass in baboons. METHODS: After preliminary studies to determine doses and possible species differences to anticoagulants and protamine, 27 anesthesized baboons had normothermic cardiopulmonary bypass with standard, unfractionated, porcine intestinal heparin, enoxaparin, or a combination of heparin and enoxaparin. Protamine in appropriate doses was used to reverse anticoagulation. Blood samples were obtained at 6 time points. Activated clotting times were monitored; template bleeding times were measured before and up to 24 hours after cardiopulmonary bypass. RESULTS: Hemodynamic measurements were not affected by the anticoagulant. Activated clotting times remained above 400 seconds throughout bypass, and no clots were observed. The anticoagulant did not alter platelet count, aggregation to adenosine diphosphate, release of beta-thromboglobulin, release of neutrophil elastase, or complement C3b/c and C4b/c. Enoxaparin alone, but not in combination, significantly reduced plasma levels of prothrombin fragment F1.2, fibrinopeptide A, and thrombin-antithrombin complexes but prolonged template bleeding times for more than 24 hours. CONCLUSION: Enoxaparin significantly reduces thrombin formation and activity during cardiopulmonary bypass but does not suppress complement activation and neutrophil elastase release and is not adequately reversed by protamine after bypass.

Animals↗

PubMed1998

In vitro effects of smokeless tobacco extract on tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production, and on lymphocyte proliferation.

The use of smokeless tobacco (moist snuff) products is associated with mucosal lesions, gingival recession, attachment loss, and oral cancer. Despite numerous reports on the general toxic effects of smokeless tobacco extract, little information is available regarding the specific effects of smokeless tobacco on immune response. Inflammatory cytokines released as a result of smokeless tobacco-induced irritation may play a role in the development of oral mucosal lesions at habitual tobacco placement sites in smokeless tobacco users. Consequently, the purpose of this study was to determine whether an aqueous extract of smokeless tobacco (STE) affects the secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and the proliferation of lymphocytes. A macrophage cell line (J774-A1) was used to measure the effects of STE on tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) secretion. Mouse splenocytes were used to assess the effects of STE on lymphocyte proliferation. We found that STE at low concentrations enhanced the production of both TNF-alpha and IL-1beta. Furthermore, STE at similar concentrations enhanced mitogen-induced murine splenocyte proliferation. Overall, these data suggest that smokeless tobacco upregulated two key proinflammatory cytokines and also induces lymphocyte proliferation.

Animals↗

PubMed1998

Protein kinase A inhibitors reverse histamine-mediated regulation of IL-5 secretion.

Histamine and IL-5 are important autacoid mediators involved in the etiology of allergic diseases. IL-5 is the main factor of eosinophilic reactions in allergy. It has been suggested that the protein kinase A-dependent (PKA) pathway of signal transduction may play the main role in histamine-induced elevation of interleukin-5 production. This study was designed to investigate the effects of the inhibitors of regulatory and catalytic subunits of PKA on histamine-mediated elevation of IL-5 production. In our study, histamine at a concentration range of 10(-4)-10(-6) M enhanced IL-5 production in D10.G4.1 cells, a mouse Th2 helper cell line. Pretreatment of this cell line with histamine at a concentration of 10(-4) M for 6-9 h had the maximum stimulatory effects (226-420%) on IL-5 production. Other cAMP-elevating agents including forskolin and Bt2-cAMP produced similar effects. The PKA inhibitors N-[2-(methylaminoethyl]-5-isoquinoline-sulfonamide (H-8) and Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS) were used for the inhibition of catalytic and regulatory subunits of PKA, respectively. Pretreatment of D10.G4.1 cells with H-8 at a concentration of 10(-5) M completely prevented the effects of histamine at a concentration range of 10(-6)-10(-4) M. Rp-cAMPS at 10(-5) M also prevented histamine-induced stimulation. Neither inhibitor affected IL-5 production when tested alone. These observations suggest a role for PKA in histamine-mediated increase in IL-5 production.

Animals↗

PubMed1998

Does intracoronary thrombus influence the outcome of high risk percutaneous transluminal coronary angioplasty? Clinical and angiographic outcomes in a large multicenter trial. EPIC Investigators. Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications.

OBJECTIVES: We sought to evaluate the impact of angiographically visible thrombus on short- and long-term clinical outcomes after percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Intracoronary thrombus is frequently seen on angiography in patients with acute ischemic coronary syndromes or complex lesion morphology, or both, and is often considered to predict a higher rate of complications in patients undergoing PTCA. METHODS: Prospectively collected data from 2,099 patients undergoing high risk PTCA in the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial were analyzed. In addition to aspirin and heparin, patients were randomized to receive either abciximab bolus and infusion, abciximab bolus alone or placebo. Based on an angiographic core laboratory interpretation, patients were classified into three groups: thrombus absent, thrombus possible or thrombus present. The primary end point at 30 days was the composite of death, myocardial infarction or urgent revascularization. The 6-month end point was the composite of death, myocardial infarction or any revascularization. RESULTS: Although abrupt closure was most common in patients with thrombus present compared with thrombus absent or possible (13%, 10.0% and 7.4%, respectively), neither the 30-day nor the 6-month clinical end points were different among the three groups (9%, 11% and 11.7%, respectively, and 30%, 34% and 31%, respectively). Most notably, the benefit of treatment with abciximab was present in all three thrombus groups, and the magnitude of benefit was not different among the thrombus groups. CONCLUSIONS: In high risk patients undergoing percutaneous coronary revascularization, features of thrombus on the preprocedure angiogram do not indicate an augmented risk of adverse clinical outcomes. Abciximab therapy reduces the rate of adverse outcomes regardless of the presence of thrombus and should therefore not necessarily be reserved for patients whose angiograms have features of intraluminal thrombus.

Abciximab↗

PubMed1998

Suicide and attempted suicide in Pakistan.

Suicide and attempted suicide are understudied subjects in Pakistan, an Islamic country where they are considered criminal offenses. National suicide statistics are not compiled nor are suicide mortality statistics reported to the World Health Organization (WHO). Although there are strong religious sanctions against suicide, there are no clear principles against attempted suicide in Islam. Despite this, Pakistan, like many other Islamic countries, has punitive laws against attempted suicide. This has led to both suicide and attempted suicide being underdiagnosed and underreported. Data on suicide and attempted suicide are also difficult to obtain. This article gives an overview of the current state of suicide and attempted suicide in Pakistan, in the context of existing religious and legal factors, high-lighting the main findings of the few studies carried out over the last 50 years. It is important that researchers in Islamic countries like Pakistan not be deterred by the apparent low rates of suicide in these countries, but conduct further research in this important yet neglected public-health problem.

Humans↗

PubMed1998

Coronary flow reserve may predict myocardial recovery after myocardial infarction in patients with TIMI grade 3 flow.

BACKGROUND: The aim of the study was to determine whether the recovery of global and regional left ventricular function after successful percutaneous transluminal angioplasty (PTCA) could be predicted by measuring coronary flow reserve before performing the intervention. METHODS AND RESULTS: Thirty-two patients underwent PTCA 6.9 +/- 3.4 days after a recent myocardial infarction. Coronary flow reserve was determined in the infarct-related artery before PTCA by using an intracoronary Doppler tipped wire. Global and regional wall motion were determined by 2-dimensional echocardiography before the Flowire study and again 7 weeks after the angioplasty. Whereas the global and regional wall motion score indices improved in 20 patients (recovery group), they deteriorated or did not change in 9 patients (nonrecovery group). Coronary flow reserve distal to the lesion in the infarct-related artery was significantly higher in the recovery group (1.43 +/- 0.57 vs 0.98 +/- 0.70, P = .0001). Coronary flow reserve distal to the lesion in the infarct-related artery was < 1.1 in patients whose global or regional left ventricular function did not improve at follow-up, whereas flow reserve ranged between 1.1. and 1.8 while patients in whom left ventricular function improved. CONCLUSIONS: These results suggest that the absence of inducible coronary flow reserve may predict failure of left ventricular systolic function to improve between the first and sixth week after infarction. Measurement of flow reserve with a Flowire at the time of diagnostic angiography after recent myocardial infarction may ultimately prove helpful in deciding whether to proceed with revascularization.

Adult↗

PubMed1998

Three noncontiguous peptides comprise binding sites on high-molecular-weight kininogen to neutrophils.

The binding of high-molecular-weight kininogen (HK) to neutrophils (polymorphonuclear leukocytes, PMN) is required for the stimulation of aggregation and degranulation by human plasma kallikrein as well as the displacement of fibrinogen from this cell surface. The putative receptor for HK is the leukocyte integrin alphaMbeta2, and domains 3 (D3) and 5 (D5) of HK form its binding site. To further map the binding sites on HK for PMN, we used D3 recombinant exon products and designed peptides from D3 and D5. In D3, a heptapeptide, Leu271-Ala277, from exon 7 product, and a peptide, Cys333-Cys352, from exon 9 product can inhibit binding of kininogen to PMN. Two contiguous peptides from D5 in the histidine-glycine-rich region, Gly442-Lys458 and Phe459-Lys478, each inhibit the binding of HK to PMN. This study has thus delineated three noncontiguous surface-oriented sequences on HK, which together comprise all or most of the binding site for human PMN.

Amino Acid Sequence↗

PubMed1998

The profile of the cytokines secreted during the generation of T-helper cells from atopic asthmatic subjects.

This study investigated cytokine release by T-cell lines from atopic and nonatopic individuals in the presence of specific aeroallergen. Cell lines from atopic and nonatopic individuals secreted IL-2 for less than 14 and more than 21 days, respectively. All of the atopic, but not the nonatopic, cell lines exhibited a biphasic peak in IL-4 and IL-5 secretion. Flow cytometry revealed that, after 35 days, 89.3% of the atopic cells were T helpers and 73.2% were activated. Only 7.4% of the nonatopic cells displayed activation markers. In conclusion, T-cell differentiation may be controlled by other factors in addition to stimulation by aeroallergens.

Adult↗