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Biomedical subjects

S Khan

Publications and source records attributed to S Khan.

At least 343 records · Page 19Linked to original sources
PubMed1992

Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation.

The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.

Alkylating Agents↗
PubMed1992

Contribution of in vivo proliferation/differentiation studies toward the development of a combined functional and morphologic system of classification of neoplastic diseases.

Proliferation kinetics of both leukemia and a variety of solid tumors have been assessed after in vivo infusions of the thymidine analogues, iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). In acute myeloid leukemia (AML), these data indicate that the pretherapy cell cycle time (Tc) of myeloblasts is a prognostic indicator for remission duration since patients with slowly cycling myeloblasts had more durable remissions. The presence of in vivo differentiation detected from the day 7 biopsy after chemotherapy was also of favorable prognosis as these individuals had statistically significant improvement in their remission duration. The data in solid tumors are not mature enough for determining their clinical significance. Since cell kinetic information is readily available in a prompt fashion using these novel techniques, data can be used to plan therapeutic strategies for patients. This review discusses the state-of-the-art techniques available for cell cycle kinetic studies and the clinical and prognostic utility of data that have been generated thus far.

Acute Disease↗
PubMed1992

Binding of glycoprotein IIIa-derived peptide 217-231 to fibrinogen and von Willebrand factors and its inhibition by platelet glycoprotein IIb/IIIa complex.

Based on previous reports in the literature and the high homology between platelet glycoprotein (GP) IIIa 217-231 and similar portions of other beta subunits of integrin receptors, we hypothesized that this region may participate in ligand binding. Using a polyclonal antibody against GPIIIa 217-231(YC), we tested the interaction of a synthetic peptide representing this region with fibrinogen (Fg), in the enzyme-linked immunosorbent assay (ELISA) system. Results show a calcium-independent, dose-related, direct interaction between GPIIIa 217-231(Y) and immobilized Fg. This peptide also bound to von Willebrand Factor (vWF) and fibronectin (Fn), but did not attach to a 50 kDa Fn fragment which is deficient in the cell attachment site. In addition, purified GPIIb/IIIa displaced GPIIIa 217-231(Y) from Fg and vWF. Binding of 125I-GPIIIa 217-231(Y) to Fg coated tubes was inhibited by soluble Fg and by the GPIIb/IIIa complex. We synthesized this peptide with several alterations; similar peptides with Pro-219 replaced with an Ala showed significantly reduced binding to Fg and vWF. The decreased binding of the peptides with Pro-219 substitutes suggests that the confirmation of GPIIIa 217-230 is important for its ability to bind to adhesive ligands. In conclusion, the amino acid residues between 217 and 231 of GPIIIa appear to be involved in ligand binding and Pro-219 probably plays a significant role in this interaction.

Amino Acid Sequence↗
PubMed1992

Adjunctive therapy with low molecular weight heparin with recombinant tissue-type plasminogen activator causes sustained reflow in canine coronary thrombosis.

Rethrombosis of the infarct-related artery after pharmacologic thrombolysis is a major limitation of the thrombolytic therapy. Platelet and fibrin deposition in the coronary artery after recombinant tissue-type plasminogen activator (rTPA) may play a leading role in reformation of thrombus. Therefore we examined the effect of low molecular weight heparin (LMWH) as adjunctive treatment with rTPA in a dog model of electrically induced intracoronary thrombus. Fourteen dogs, in which a stable coronary thrombus was induced with delivery of 100 microA of anodal direct current, were randomly given an intravenous bolus of LMWH, 75 IU/kg (n = 6), or saline (n = 8), followed by intravenous rTPA, 1 mg/kg over 20 minutes. LMWH (75 IU/kg) or saline was continuously infused over 90 minutes after rTPA-induced thrombolysis. Reperfusion occurred at 29 +/- 7 minutes in six of eight dogs receiving rTPA plus saline (reperfusion rate 75%), while reperfusion occurred at 18 +/- 3 minutes in all six dogs receiving rTPA plus LMWH (both p = NS versus rTPA plus saline group). Coronary reocclusion occurred in 83% of dogs given rTPA plus saline, but only in one dog (17%) given rTPA plus LMWH (p less than 0.05). Magnitude of reflow at 60 minutes of reperfusion was higher in the rTPA plus LMWH group than in the rTPA plus saline group (51 +/- 14 ml/min versus 10 +/- 9 ml/min; p less than 0.05). As expected, partial thromboplastin time was greater in rTPA plus LMWH than in rTPA plus saline-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Hepatocyte cytotoxicity induced by various hepatotoxins mediated by cytochrome P-450IIE1: protection with diethyldithiocarbamate administration.

The objective of this study was to determine whether the thiol drug, diethyldithiocarbamate (DEDC) and its two metabolites, disulfiram (DS) and carbon disulfide (CS2) could be used as inhibitors of cytochrome P-450IIE1 to protect hepatocytes from cytotoxic xenobiotics. (1) Hepatocytes isolated from rats following pyrazole administration to induce cytochrome P-450IIE1 were much more susceptible to carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN) than hepatocytes from untreated rats. Microsomes isolated from P-450IIE1-induced liver were also much more effective at catalysing a NADPH-dependent metabolism of CCl4 and DMN. The activities of aniline hydroxylase and p-nitroanisole-O-demethylase increased whereas ethoxyresorufin-O-dealkylase activity was much less induced and pentoxyresorufin-O-dealkylase activity was decreased. The P-450IIE1 antibody markedly inhibited the NADPH-dependent metabolism of these compounds indicating that IIE1 is a major catalyst of the microsomal metabolism of CCl4 and DMN. (2) Hepatocytes isolated from rats treated with DEDC or its metabolites, DS and CS2, on the other hand, were resistant to CCl4 and DMN. Microsomes isolated from the liver of animals treated with DEDC or DS or CS2 were also much less effective at catalysing the NADPH-dependent metabolism of the above compounds. DEDC markedly decreased the activities of aniline hydroxylase, p-nitroanisole-O-demethylase and pentoxyresorufin-O-dealkylase but had no effect on ethoxyresorufin-O-dealkylase activity. (3) Hepatocytes isolated from pyrazole-treated rats were also more susceptible to bromobenzene (BB) and naphthalene-induced cytotoxicity than hepatocytes from untreated rats. Furthermore, DEDC or CS2 administration beforehand significantly protected hepatocytes against both xenobiotics. (4) By contrast, hepatocytes isolated from P-450IIE1 induced rats were not more susceptible to lactonitrile or cyclophosphamide. Instead, cyclophosphamide was activated by phenobarbital-induced P-450 isozymes whereas lactonitrile was activated by alcohol dehydrogenase. Hepatocytes isolated from DEDC-treated rats were also resistant to cyclophosphamide but not lactonitrile. (5) The above results suggest that P-450IIE1 catalyses the cytotoxic activation of CCl4, DMN, BB and naphthalene but not of lactonitrile or cyclophosphamide. Furthermore, the administration of DEDC and its metabolites, disulfiram or CS2, inactivates P-450IIE1 so that the hepatocytes become resistant to these hepatotoxins.

Animals↗
PubMed1992

Effect of prosthetic aortic valve design on the Doppler-catheter gradient correlation: an in vitro study of normal St. Jude, Medtronic-Hall, Starr-Edwards and Hancock valves.

To evaluate the normal range of Doppler-derived velocities and gradients, their relation to direct flow measurements and the importance of prosthetic valve design on the relation between Doppler and catheter-derived gradients, five sizes of normal St. Jude bileaflet, Medtronic-Hall tilting disc, Starr-Edwards caged ball and Hancock bioprosthetic aortic valves were studied with use of a pulsatile flow model. A strong linear correlation between peak velocity and peak flow, and mean velocity and mean flow, was found in all four valve types (r = 0.96 to 0.99). In small St. Jude and Hancock valves, Doppler velocities and corresponding gradients increased dramatically with increasing flow, resulting in velocities and gradients as high as 4.7 m/s and 89 mm Hg, respectively. The ratio of velocity across the valve to velocity in front of the valve (velocity ratio) was independent of flow in all St. Jude, Medtronic-Hall, Starr-Edwards and Hancock valves when the two lowest flow rates were excluded for Hancock valves. Although Doppler peak and mean gradients correlated well with catheter peak and mean gradients in all four valve types, the actual agreement between the two techniques was acceptable only in Hancock and Medtronic-Hall valves. For St. Jude and Starr-Edwards valves, Doppler gradients significantly and consistently exceeded catheter gradients with differences as great as 44 mm Hg. Thus, Doppler velocities and gradients across normal prosthetic heart valves are highly flow dependent. However, the velocity ratio is independent of flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic Valve↗
PubMed1992

Bacterial chemoreceptor signaling probed by flash photorelease of a caged serine.

A caged serine, a photolabile compound that liberates serine upon photolysis, has been synthesized. Smooth-swimming responses of the bacterium Escherichia coli to caged serine photorelease were videotaped. The mean latency was measured from the videorecords using computerized motion analysis. This time was approximately 0.2 s. Caged photorelease of a photolabile but nonchemotactic serine analogue had no effect on the swimming behavior of the bacteria. A tumbly mutant strain lacking tsr, the serine chemoreceptor, did not respond to caged serine photorelease.

Bacterial Proteins↗
PubMed1992

Growth factor requirements for DNA synthesis by Leydig cells from the immature rat.

Puberty in the male is dependent upon the elevated production of testosterone by the Leydig cells. LH affects this increase in testosterone output by increasing the total number of Leydig cells in the testis and by stimulating the steroidogenic pathway in these cells. Since Leydig cell proliferation is a prerequisite for the onset of puberty, we have examined the ability of LH and growth factors known to be present in the testis to promote DNA synthesis. Leydig cells were isolated from 21-day-old rats, cultured in serum-free medium for 48 h to become quiescent, and then treated with LH and growth factors for 18 h. [3H]Thymidine incorporation into DNA was assessed over the subsequent 4-h incubation period. Cells in control cultures incorporated low levels of [3H]thymidine into DNA and were stimulated after treatment with LH (100 ng/ml). Insulin/insulin-like growth factor-1 (IGF-1) and transforming growth factor-alpha (TGF-alpha), previously localized in Leydig cells by immunohistochemistry, also stimulated [2H]thymidine incorporation into DNA. The responses of the Leydig cells to maximum levels of insulin and TGF-alpha were dependent on the cell density. Insulin and TGF-alpha alone and in combination increased the number of cells labeled with [3H]thymidine, as assessed by autoradiography. TGF-beta, known to be secreted by Sertoli cells, also stimulated DNA synthesis under basal conditions, but the maximum response was significantly lower than that achieved in the presence of TGF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Harlequin fetus with abnormal lamellar granules and giant mitochondria.

A case of harlequin ichthyosis was studied with electron microscopy. From the basal cell to granular cell layers, keratinocytes contained giant mitochondria (860 nm) which exhibited vesicular cristae. Typical lamellar granules were absent; instead, numerous dense cored granules (DCG) and particles containing cored granules (PCG) were produced. Some of these were discharged into the intercellular spaces of granular cells, but the majority failed to be released from the cytoplasm. These retained DCG and PCG coalesced to form large vacuoles and cavities in the stratum corneum. In the hair follicle, keratinized cells failed to loosen and desquamate into the hair canal; instead, they formed concentric keratin rings surrounding hair, a diagnostic feature of this disease. It is suggested that the abnormal lamellar granule underlies the pathogenesis of this disease and that giant mitochondria may be related to an abnormal lipid metabolism of keratinocytes which may affect lipid composition of lamellar granules.

Adult↗
PubMed1992

Membrane ultrastructure of alkaliphilic Bacillus species studied by rapid-freeze electron microscopy.

Cells of Bacillus firmus OF4 and Bacillus alcalophilus were examined by rapid-freeze freeze-fracture and freeze-substitution electron microscopy. No special vesicular structures linked to growth at alkaline pH were found, either within or associated with the cytoplasmic membrane. The cytoplasmic membranes of the alkaliphilic bacilli and the neutrophilic Bacillus subtilis BD99 were indistinguishable. Distinctive intramembrane particle rings, presumed to be flagellar structures on the basis of distribution and morphological characteristics, were found in all of these species. These observations indicate that the adaptations required to effect oxidative phosphorylation and flagellar rotation at extreme alkaline pH occur without gross morphological rearrangement.

Bacillus↗
PubMed1992

Color Doppler regurgitant characteristics of normal mechanical mitral valve prostheses in vitro.

BACKGROUND: To evaluate normal regurgitant characteristics of St. Jude (SJ) and Medtronic-Hall (MH) mitral valves, four sizes (25-31 mm) of each were studied in a pulsatile flow model. METHODS AND RESULTS: Regurgitant flow was measured by flowmeter at left ventricular pressures of 80, 130, and 180 mm Hg. Peak regurgitant flow rates ranged from 6.2 to 12.7 cm3/sec in SJ valves and from 7.9 to 17.5 cm3/sec in MH valves. Regurgitant orifice areas calculated from the Doppler continuity equation ranged from 1.6 to 2.0 mm2 in SJ valves and from 2.2 to 2.9 mm2 in MH valves. Regurgitant volumes across the closed valve at a left ventricular pressure of 130 mm Hg were normalized to an ejection time of 280 msec and ranged from 1.5 to 1.9 cm3 in SJ valves and from 2.1 to 2.8 cm3 in MH valves. Jets were imaged by color Doppler in six rotational planes, and jet size and morphology were compared with those of regurgitant jets from circular orifices with sizes comparable to the calculated prosthetic valve regurgitant orifices (1.1-3.1 mm2). SJ valves showed two converging jets from the pivot points, one central jet, and a variable number of peripheral jets. The mean color jet area derived from the six image planes ranged from 1.6 to 5.3 cm2. Aliasing occurred only close to the valve (maximal distance 0.5-2.0 cm). MH valves showed a large central jet with a maximal length of aliased flow between 2.0 and 5.5 cm. Depending on valve size, driving pressure, and image plane, one or two small peripheral jets were found. These jets did not show aliasing in any case. The mean color jet area ranged from 5.1 to 11.0 cm2. Jets originating from circular orifices of comparable size showed jet areas from 5.5 to 13.9 cm2 and aliasing distances from 3.3 to 7.3 cm. At similar regurgitant orifice areas, driving pressures, and regurgitant flows, the measured color areas and aliasing distances were smallest in SJ valves, larger in MH valves, and largest in simple circular orifices. CONCLUSIONS: Large, complex regurgitant jets can be found in normal closed SJ and MH valves by color Doppler, although regurgitant flow volume is minimal. Jet size and velocity distribution differs markedly between SJ valves, MH valves, and circular orifices, even with comparable driving pressure, regurgitant orifice area, and regurgitant volume. The characteristic patterns of normal regurgitation must be recognized to avoid incorrect diagnoses of pathological regurgitation in SJ and MH prosthetic valves. MH valves should not be removed solely on the basis of a central regurgitant jet with a long aliasing distance. Peripheral jets in MH valves and all jets in SJ valves should be considered normal as long as no or only minimal aliasing is present. In contrast, peripheral jets with significant aliasing may represent strong evidence of pathological regurgitation.

Blood Flow Velocity↗
PubMed1992

Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection.

2',3'-Dideoxyuridine (ddU) is ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T cells, because it is not biotransformed to the active 5'-triphosphate. The metabolic block resides in the poor substrate affinity of ddU for cellular nucleoside kinases. This problem cannot be overcome by supplying the preformed nucleotides, because such compounds are unable to penetrate cells. To circumvent the requirement of ddU for enzymic phosphorylation, we have prepared bis(pivaloyloxymethyl) 2',3'-dideoxyuridine 5'-monophosphate (piv2 ddUMP), as a potential membrane-permeable prodrug of ddUMP, and investigated its metabolism and anti-HIV activity in two human T cell lines, one with wild-type thymidine kinase activity (MT-4) and the other deficient in thymidine kinase activity (CEM-tk-). The 5'-mono-, di-, and triphosphates of ddU were formed in both cell lines after exposure to piv2-ddUMP. In contrast, phosphorylated metabolites were not observed in cells treated with ddU or ddUMP alone. piv2-ddUMP also reduced the cytopathic effects of HIV-1 in MT-4 cells (ED50, 4.75 microM) and inhibited virus production in culture fluid (ED50, 20 microM). In addition, piv2-ddUMP protected CEM-tk- cells from HIV-1 infection, as demonstrated by inhibition of intracellular p24 antigen levels (ED50, 3 microM) and reverse transcriptase activity in culture medium (Ed50, 2.5 microM). Based on these findings, we propose that the "masked nucleotide" strategy may make available for development nucleoside analogues hitherto considered inactive because of failure to undergo biotransformation to the corresponding 5'-monophosphates. Moreover, by circumventing metabolic dependency on nucleoside kinases, the strategy may overcome acquired resistance to nucleoside analogues caused by the loss or depletion of nucleoside kinases.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Determination of ampicillin in human plasma by high performance liquid chromatography using ultraviolet detection.

A high performance liquid chromatographic method for isocratic mode of elution has been developed for the determination of ampicillin in human plasma. The method comprises injection of the plasma after protein precipitation, separation by reversed-phase C18 column, using heptane sulphonic acid, sodium salt monohydrate as an ion-pairing agent in the mobile phase which consists of pH 3.5 phosphate buffer-methanol. The method involves UV-detection at 225 nm. This method provides a simple tool for the rapid analysis of ampicillin with high degree of accuracy and precision, where the drug level is in microgram range.

Journal Article↗
PubMed1991

1-bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes.

The effect of 1-bromlalkanes on intracellular glutathione (GSH) was studied in freshly isolated rat hepatocytes. Treatment of cells with bromoalkanes depleted cellular GSH levels without causing cytotoxicity. The extent of GSH depletion was directly proportional to the concentration and increasing chain length of 1-bromoalkanes (C2-C7). Bromoheptane (100 microM) depleted GSH by 87% in 30 mins which remained depleted for the 4 hr study period without causing cytotoxicity. A 30 fold higher concentration of bromoheptane was required before cytotoxicity ensued. Bromoheptane would therefore be particularly useful for studying the role of GSH in modulating xenobiotic cytotoxicity.

Alkanes↗
PubMed1991

C-jun and jun-B oncogene expression during placental development.

During embryogenesis, growth and differentiation occur in a sequential, predetermined order suggesting that specific genes are turned on and off in a precise and well-regulated manner. Placental development, which is characterized by massive proliferation and differentiation of multiple cell types, must be similarly regulated. Early response protooncogenes, such as c-jun and jun-B, have been associated with both proliferation and differentiation of different cell types. In this study, using Northern blot analysis, we found that c-jun and jun-B expression occurred in human placentas throughout gestation. Maximal expression of c-jun occurred in early gestation, and maximal expression of jun-B occurred in late gestation. We speculate that peak expression of c-jun in human placenta at early gestation may be related to cytotrophoblastic proliferation and that peak expression of jun-B in late gestation may be related to further terminal differentiation of trophoblastic cells.

Blotting, Northern↗
PubMed1991

Transforming growth factor-beta 1 expression during placental development.

Placental growth has several malignant characteristics, including properties of invasiveness, rapid cell proliferation, and a lack of cell contact inhibition. These malignant characteristics of placental development are strictly regulated throughout normal gestation, because placental growth is limited in both extent and duration. Transforming growth factor-beta 1 inhibits growth of many normal and malignant cell lines. In this study, using Northern blot analysis, we found transforming growth factor-beta 1 expression to occur in human placenta throughout gestation. Peak expression was noted at midgestation (near 17 weeks) and again in late gestation (near 34 weeks). Immunohistochemical analysis localized transforming growth factor-beta 1 protein expression to the syncytiotrophoblastic layer. The process of trophoblastic invasion of the decidua and myometrium is usually complete by 18 weeks of gestation, and absolute growth of the placenta ceases in late gestation (near 35 weeks). The time frames of maximal transforming growth factor-beta 1 expression noted in our studies correlate with these events. We speculate that peak transforming growth factor-beta 1 expression at these stages of placental development is suggestive of its regulation of both trophoblastic invasion and proliferation.

Blotting, Northern↗
PubMed1991

Cell cycle parameters and DNA ploidy in colorectal carcinomas.

Seven patients with colorectal adenocarcinoma and one with squamous cell carcinoma of anorectal region were infused preoperatively with iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU) in sequence (100 mg/m2 x 1 hr each with 1-hr interval in between) to label S-phase cells. The tumor biopsy specimens were embedded in glycol-methacrylate and 2-microns thick sections were treated with two monoclonal antibodies which permitted the identification of cells which incorporated IUdR only, BrdU only, both IUdR and BrdU, or neither IUdR or BrdU. The labeling index of tumors varied from 17.3 to 35.6% (mean = 25.78 +/- 6.162), duration of S-phase ranged from 14.0 to 23.9 hr (mean = 18.73 +/- 3.712), and total cell cycle time ranged from 39.4 to 123.4 hr (mean = 76.78 +/- 24.165). The architecture of the tumor was well preserved and a variable number of DNA synthesizing mononuclear cells were identified within and around the tumor. Image analysis of Feulgen-stained smears of the tumors was done to measure the DNA content of seven tumor samples. Each tumor was found to be hyperdiploid with multiple modal values. The studies described here demonstrate the feasibility of performing cell cycle kinetic measurements on gastrointestinal tumors which have been labeled in vivo. The ability to perform these measurements on tumor biopsies allows the avoidance of artifacts introduced when solid tumors are disaggregated in vitro for study.

Adenocarcinoma↗